Embryology - User contributions [en-gb]

User:Z3465141

2014-10-29T01:19:55Z

Z3465141:

==Attendance==
Lab 1 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 12:45, 6 August 2014 (EST)

Lab 2 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:56, 13 August 2014 (EST)

Lab 3 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:59, 20 August 2014 (EST)

Lab 4 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:19, 27 August 2014 (EST)

Lab 5 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:41, 3 September 2014 (EST)

Lab 6 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:46, 10 September 2014 (EST)

Lab 7 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:21, 17 September 2014 (EST)

Lab 8 ----[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 13:05, 8 October 2014 (EST)

Lab 9 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:18, 15 October 2014 (EST)

Lab 10 [[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:12, 22 October 2014 (EST)

Lab 11 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 12:19, 29 October 2014 (EST)

[http://www.ncbi.nlm.nih.gov/pubmed PubMed]

[[http://www.ncbi.nlm.nih.gov/pubmed]]

==Assessment 1==
<pubmed>25077107</pubmed>
The article above aim was to determine whether vitamin D levels effects women’s clinical pregnancy rates following in vitro fertilization (IVF) treatment. A total of 173 infertile women participated in the study that met the following criteria: being in the age category of 18-41 years, follicle-stimulating hormone level 12 IU/L or lower, as well as consent.

Participants of this study were divided into two categories based on their Vitamin D via the serum 25-hydroxy-vitamin D (25[OH]D) levels. Sufficient levels were classified for women to have ≥ 75 nmol/L of vitamin D whereas insufficient levels were classed as being < 75 nmol/L vitamin D levels. Successful patients IVF cycles resulted in a clinical pregnancy, which is defined as a visible intrauterine sac upon ultrasound.

The study concluded that the womens clinical pregnancy rates were subsequently higher per IVF cycle if the patient had a sufficient level of Vitamin D. Thus forming a relationship between serum 25-hydroxy-vitamin D (25[OH]D) levels and clinical pregnancy rates.

--[[User:Z8600021|Mark Hill]] These should have been 2 references for this assessment item (3/5)
==Assessment 2==
[[File:MRI_confirming_renal_agenesis.jpg]]

<pubmed>24618008</pubmed>

--[[User:Z8600021|Mark Hill]] All information and file naming correct. Next time scale the image to fit the page better and also include a figure legend as well. (5/5)

==Assessment 3==

<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>21079243</pubmed>

--[[User:Z8600021|Mark Hill]] These reference are relevant. You could have also included a single sentence on why/how you selected these references. (4/5)

==Assessment 4==

<pubmed>23998127</pubmed>

Pre-mature ovarian failure (POF) is currently classified into two categories, these include: there are little to no remaining follicles or there is a copious quantity of follicles present in the ovaries. POF in women has been commonly treated by hormone replacement therapy, even though the treatment increases the risks of other complications including the formation of blood clots such as DVT’s and cancers such as ovarian and breast cancer. The study undertaken by Wang et. al. attempted to investigate whether Mesenchymal stem cells utilized from the human umbilical cord “umbilical cord matrix stem cells” or (UCMSCs) originating in Wharton’s Jelly has any therapeutic use for the treatment of premature ovarian failure in mice.

Wang et al. collected and isolated UCMSCs from full term umbilical cords following the drainage of the cord blood. The umbilical cords were then dissected into sections of 5-6 grams of tissue manually and treated chemically in preparation to be cultured and then harvested after 10 days. The mice were then divided into 3 categories, each consisting of 15 mice each, which included the POF and UCMSC groups. Mice in the UCMSC were intravenously injected with 1 x 10^6 hUCMSCs in 100 𝜇L PBS, whereas the mice in the POF group were exclusively injected with 100𝜇L PBS. These groups then received daily injections of intraperitoneal CTX (50mg/kg) for a total of 15 days, instigating the development of POF models of chemotherapy-induced ovarian damage.

The study concluded that following the transplantation of UCMSCs in mice in the chemotherapy treated group, the mice had a decrease in apoptosis of cumulus cells as well as restoring the normal function of the ovary. Mice treated with UCMSCs also reportedly had a significant increase in their sex hormone levels, leading to an increase in follicles present in the treated mice in comparison to the control group. In essence, the study conveyed UCMSCs could successfully restore the function of damaged ovaries as well as significantly decreasing apoptosis of granulosa cells in the developing follicles.

===Vascular shunts===

• '''Ductus venosus''' - connects the pulmonary artery to the proximal segment of the arotic arch allowing oxygenated blood to travel from the left umbilical vein to the inferior vena cava, thus allowing bypass of the liver. This shunt is then closed postnatally and becomes ligamentum venous.

• '''Foramen ovale''' - an opening located between the right and left atrium that directs highly oxygenated blood flow entering from the right atrium to the left atrium. This is then closed at birth and become the fossa ovalis. The remnant of a foramen ovale that had not closed after birth is known as a patent foramen ovale.

• '''Ductus arteriosus''' - connects the pulmonary artery to the proximal descending aorta. This blood vessel prevents the output of the right ventricle from entering the non-functioning and fluid filled lungs of the fetus. Ductus arteriosus then becomes the ligamentum arteriosum postnatally.

==Assessment 5==

===Gastrochisis===

Gastrochisis is a development abnormality of the anterior abdominal wall, where the bowel protrudes without a covering sac between the developing rectus muscles, occurring slightly lateral and towards the right of the fetal umbilicus. Gastrochisis commonly occurs as an isolated malformation, occurring in approximately 2.5 in 10’000 births.

During the fourth week of normal fetal development, the lateral body of the fetus folds, moving ventrally and fusing in the midline to form the anterior body wall. In Gastrochisis it has been theorized that the incomplete fusion of the midline results in this abnormality, resulting in the abdominal viscera to protrude through the abdominal wall, herniating through the rectus muscle. This is one of many theories linked to Gastrochisis as the cause is still unclear. Other theories include, the failure of mesoderm to form in the body wall, rupture of the amnion around the umbilical ring with subsequent herniation of the bowel, abnormal involution of the right umbilical vein resulting in a weakening of the body wall and thus resulting in herniation of the bowel, and disruption of the right vitelline (yolk sac) artery with consequent body wall damage and gut herniation.

<pubmed>25059025</pubmed>
<pubmed>17230493</pubmed>
<pubmed>19419415</pubmed>

==Assessment 6==
===Thyroid Development===

<pubmed>19389367</pubmed>
The current study by Lania et. al. demonstrates that the developmental mechanisms of the endocrine gland, the thyroid, is regulated by genetic networks. Tbx1 is a prominent gene involved in the embryonic development of the thyroid gland, as well as many of the pharyngeal apparatus derivatives. In this study, the role of Tbx1 is emphasized as a key factor for regulating the size of the thyroid in early development of mice. Knockout mechanisms were preformed in mice embryos to remove the expression of Fgf8, in the mesoderm, which is regulated by Tbx1. The lack of Fgf8 thus subsequently leads to cause thyroid hypoplasia in the subjects. Thyroid sizes of the mouse embryos were measured following the removal of Fgf8, in 2 different stages of embryonic stages of development, with both stages showing a significant decrease in thyroid size. These results suggest that a Tbx1-NFgf8 pathway is a key factor in determining the size of he thyroid glands in mammalians.

In addition, mutant phenotypes were observed due to the lack of function of Tbx1. The mutant embryos presented with a hypoplastic thyroid, though the positioning of the organ was predominantly normal. Lania et. al. went on to observe a slightly larger than normal lumen present in the thyroid follicles of the mutants. These results were then supported further by Immunohistochemistry analysis of these embryos, which demonstrated that Nkx2-1 is typically expressed and that thyroglobulin is typically produced by mutant follicles.

===Tooth Development===

• '''Odontoblasts''' - derived from neural crest mesenchymal cells, and are differentiated under the influence of the enamel epithelium. Odontoblasts secrete predentin throughout life, which calcifies to form dentin, located under enamel.

• '''Ameloblasts''' - derived from oral epithelium of ectodermal origin. They produce enamel after the first production of dentin layer by odontoblasts and form the outermost layer of the tooth.

• '''Periodontal ligament''' - a specialised connective tissue layer that acts as an anchor for tooth in its bony socket and surrounds the tooth root coating of cementum.

==Assessment 7==
===Ovary Development===

Initially, the origins of gonadal development are morphologically similar for both the testes and ovaries. It is only when the indifferent stage of sexual development occurs when the differential stages of ovary development begins. Both gonads have derivatives from the structures; Mesothelium, which lines the posterior abdominal wall, as well as underlying mesenchyme and primordial germ cells that form the earliest, undifferentiated sex cells.

During week 5 the development of ovaries begins, when a thickened area of mesothelium develops on the medial side of the mesonephros, a primitive kidney. This is then continued by the development of gonadal ridges, which results from proliferation of the mesothelium and the underlying mesenchymal tissue, as it produces a bulge on the medial mesonephros. Finger like epithelial cords then grow into the underlying mesenchyme forming the gonadal cords. In females (XX), the cortex of the indifferent gonad differentiates into an ovary, and the medulla regresses.

Primordial germ cells dwell amongst dorsal endodermal cells of the umbilical vesicle, where they first populate. They then begin to migrate to the gonadal ridge along the hindgut’s dorsal mesentery where they then migrate to the gonadal ridges during the folding process of the embryo. In week 6, the primordial germ cells enter the underlying mesenchyme and are incorporated in the gonadal cords.

Ovary development is a slow process in female embryos, and It is not until week 10, when the ovaries become histologically recognizable.

====References====
<pubmed>15664455</pubmed>
[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466393265-4#4-u1.0-B978-1-4377-2002-0..00012-6--f0150 Moore: The Developing Human Chapter 12]

[[File:Bailey329.jpg|500px]]

==Assessment 9==

'''Group 1:'''

Firstly, great job on the layout and formatting of the project, everything is easy to find and overall, it reads well. The introduction provides great insight of what to expect on the page. However, it lacks in-text citations for the first three subheadings of the page, as well as the table of lung developmental stages. The first two images also don’t have a description when I click on it, I don’t know what I’m looking at. The “student template” is also missing for the images. I would suggest you look up the tutorial for uploading images on the pages as Mark has extensive information for the proper steps required for uploading images. Otherwise, the lung developmental stages table is informative and easy to read. I would also recommend adding an image for better visualization of the developmental process.

The historical findings and current research models have very detailed content, and look as though they have been referenced correctly using in-text citations, I’m impressed. Although, I would suggest you leave all the references to the end by simply putting </references> at the bottom of the page, as it looks neater to have them all in one place, rather than at the bottom of each sub-heading. The abnormalities section is done well and there are a wide number of abnormalities covered. The detail of the first two is more in depth than the rest, I’m unsure whether they was more information on those particular abnormalities or their still needs to be information added, but I suggest to have the same amount of information on each disease, if possible.
Overall, the project is very informative and presented well. It just need a few minor edits.

'''Group 3:'''

The introduction provides a good basic outline of the overview of the GIT. Although, there are no in-text citations in the introduction and all sub-headings are not included into the overview. Be wary of spelling errors such as “GIT (Gastrointestinal Track) consist of the Fore-gut, Mid-gut and Hind-gut” that should read Gastrointestinal Tract consists of the foregut, midgut and hindgut. This section would be better it was expanded upon and images were added. The timeline provides good detail, though would benefit by better formatting and organisation of the information, maybe putting it all into a table, by week will tidy it up.

Adding images for the sections will definitely be beneficial. The images hand-drawn are great, although the colours used make it hard to read. If you plan to add anymore drawings, try and use dark colours that allow for easy readability. The images already uploaded are missing copyright, referencing and “student template” information for images such as “fetal week 10 sagittal plane”. I would suggest you look up the tutorial for uploading images on the pages as Mark has extensive information for the proper steps required for uploading images.

The deformities section should be re-titled abnormalities as per the assessment criteria and would ensure the group is following similar structure from the other projects. Again, adding an image per disease would be great. Try and do about 1-2 more abnormalities. Great job on putting all the references at the bottom of the page, it makes it very neat and accessible. Overall, a good project just needs a few edits.

'''Group 4:'''

Firstly, great job on all the contents you guys managed to present, it’s quite detailed. There seems to be no introduction though, and the page jumps straight into explaining genital development. I think if an introduction were added, it would give the whole page better structure and formatting so the reader knows what to expect when they decide if they want to read on. The dot points used for the developmental section allows for easy readability of the contents, however, the use of caps lock and arrows takes away from the overall presentation of the page. I would suggest any text you want to emphasize to make bold or underline the word. I also noticed that there was a note stating the attempt to put all the developmental information into a table, but had issues. I suggest you look at the editing basic page you can search for in the top right hand corner as it outlines a step-by-step guide into making tables etc.

In regards to referencing, there are no in-text citations for the first two subheadings. The sections were they do have citations also have a list of references at the bottom of each section. I would recommend just adding a final list of references at the bottom of the page, as it looks much neater.

I’m impressed with the level of hand-drawn diagrams uploaded. I would also recommend adding captions to the image. For example:
[File: Flow Diagram of Fetal Development of External Genitalia.pptx|1000px|thumb|right|alt text]. The “alt text” should be edited to describe the caption of the drawing. This particular image seems to have a broken link though; the “alt text” also appeared in the labeled diagram of the testes. Otherwise, good job on the other images.

The current findings section seems to be untouched, with the exception of some pubmed journal article links, I’m assuming you are still in the process of adding content. The historic findings, however, is extensive and well researched. Good job.

The abnormalities section is done well. There is more than enough abnormalities listed, and they are researched well, I would just suggest adding a few more images for better visualization. Overall, great page, just needs better formatting for the mentioned sections.

'''Group 5:'''

This page has great overall structure and presentation. The introduction gives good insight of the overall contents of the page, however it is very brief and should be expanded upon.

The table included in the developmental overview serving, as a timeline is excellent, really well done. It’s easy to follow and looks very neat. I like how there is an image for each of the weeks mentioned, just don’t forget to add in-text citations for its contents. The glands sub-section is very brief and would benefit if there were more contents added. Great job on the images though. The nail section is the same, more contents needs to be added and image would look really good.

The developmental overview and historic findings sections also seems to lack in-text citations. There is also has an image with a broken link. The subsection hair seems to be well researched, however I would also suggest either bolding or underlining the words you want to emphasize such as “structure” for a neater look.

The recent findings section looks superb I love the purple background colour. Its very well researched and the link to more research papers are very helpful for readers. I would suggest you put the image at the bottom of the mentioned content though, just to avoid the big gap on the page, or even if you can manage to wrap the text around the image, it would look much better in terms of presentation.

Although disturbing, the abnormalities section I could not fault. Very well done. It is evident that it has been research well and the images allow for great visualization of the diseases mentioned.

Overall, excellent page just needs a very formatting edits and some expanded contents mentioned above. Good luck!

'''Group 6:'''

There seems to be no introduction on the page, don’t forget to add content to this section before the final submission. The overall page looks disjointed by the choice of sub-headings. I think an overall timeline is needed to know which glands/organs develop when and originate from where. It would look much neater and would be easier to follow.

The parathyroid gland and pancreas seems to be the only sections that are properly completed. Both sections have good use of images and the tables provide easy readability. The images are all properly cited, good job.

The overall referencing of the page is all over the place and lacks in-text citations. I suggest you go through the contents and add these where necessary. If you are unsure how to do this, just look at the handout Mark gave out in week 2 for further reference. Or, alternatively you could look at some of the other project pages in edit mode. I would also suggest you leave all the references to the end of the page by simply putting </references> at the bottom of the page, as it looks neater to have them all in one place, rather than at the bottom of each sub-heading.

The abnormalities section is lacking content and there is only 2 diseases listed, with no description.

Overall, the page has good content, just needs to be edited to put in-text referencing. Some sections need contents such as the placenta and adding images to the page will also improve its presentation.

'''Group 7:'''

This page is organized well, all the headings and subheadings are thought through. Although, I’m unsure while the sections brain and spinal cord are in bold? The development during fetal period image lacks the necessary “student template” at the bottom of the description summary and I was unable to open the link http://www.nichd.nih.gov/publications/pubs/acute/images/p44.gif.
Otherwise, all the other images uploaded on the page look really good and are referenced correctly.

The table under the section brain development is very brief, and expansions on the content will allow for a better understanding of the content. Adding images to appear after the table will also add to the appearance of the page and give it a cleaner look.

The spinal cord and menegies development have been left untouched and the current research models have no content, just pubmed references. I understand the current research models are probably the hardest part of the assignment, but the content appears to be quite good, the formatting of the section could be improved by following the structure Mark uses. You could look at the other group projects as examples.

In regards to referencing, there are no in-text citations for the first two subheadings. I would also like to recommend just adding a final list of references at the bottom of the page, as it looks much neater.

The abnormalities section is done well. But try to minimise the use of dot points as this section lacks any structured paragraphs. It use of images are great, although there is an image that appear to have been removed and as a result, there is a broken link.

Overall, great job so far!

'''Group 8:'''

Let me start by saying, for only having two people in the group, well done. The page should have an introduction though, and this is missing. Just by simply summarizing all the information that will be covered in the page and adding it to the introduction, will improve the overall presentation significantly, you may wish to leave this to last, or edit as you go along.

The section “Making gains” is amusing, but inappropriate and should be omitted from the final submission. The timeline for the page I believe should be put into a table to save time and add to the presentation of the page, it can be easily done if you follow the steps outlined in the ‘editing basics’ page

The background information is comprehensive, however, the page is in desperate need of some images as there are just slabs of text. Images will really help break up the contents of the page and make it visually appealing.

The abnormalities section also seems to be coming along quite well. Keep up the good work.

==Assessment 10==
<pubmed>8955790</pubmed>
The outer oral environment receives chemical stimuli from slender epithelial cells, which are responsible for the assembly of taste buds. To date, there have been few studies documented on the formation and morphology of prenatal human taste buds. Therefore, in this study, taste bud primordium is investigated, including its morphological changes, synaptogenesis, cell differentiation, and taste pore formation from the time of the onset of taste bud formation from approximately the 8th week until the 15th week of gestation.

Forty-two human embryonic and fetal tongues from the 6th week to the 15th week of gestation were used in the study. The tongues were then fixed in 0.1 M cacodylate buffer containing 2.5% glutaraldehyde, or 0.1 M phosphate buffer containing 2% paraformaldehyde and 1% glutaraldehyde. The samples were then contrasted overnight and prepared with uranyl acetate dissolved in 70% ethanol, which were then, washed, dehydrated and embedded in Epon. The sections of tissues were then prepared consisting of three specimens of each tongue and screened for taste bud primordial. The sections were then placed on slot grids and examined by means of transmission election microscopy.

From the results, it can be seen that the sixth to seventh postovulatory week have shown no signs of cell specialization and indicate taste bud formation, although at this stage the epithelial is 2-3 layers thick and nerves fibres begin to approach the lingual epithelium. During the 8th week of gestation, the first signs of cell differ enation responsible for the formation of taste buds were seen at the base of the taste bud primordium and the nerve fibres are able to penetrate the basal lamina. By the 9th – 11th week the lingual epithelium has thicken to compose of approximately 3-4 layers and taste bud primordial were present and resemble those that were found in earlier stages. During week 12, further differentiation of the cells can be seen, as the cells that are electron dense begin to resemble type III cells seen in human adult taste buds, as well as long, slender cells with electron-dense nuclei and electron-dense cytoplasm containing abundant mitochondria and bundles of intermediate filaments. However, the majority of taste pores do not begin to develop up until week 14-15 of gestation.

[https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Taste_Development Taste Development]

User:Z3465141

2014-10-24T04:04:07Z

Z3465141:

==Attendance==
Lab 1 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 12:45, 6 August 2014 (EST)

Lab 2 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:56, 13 August 2014 (EST)

Lab 3 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:59, 20 August 2014 (EST)

Lab 4 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:19, 27 August 2014 (EST)

Lab 5 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:41, 3 September 2014 (EST)

Lab 6 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:46, 10 September 2014 (EST)

Lab 7 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:21, 17 September 2014 (EST)

Lab 8 ----[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 13:05, 8 October 2014 (EST)

Lab 9 --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 11:18, 15 October 2014 (EST)

[http://www.ncbi.nlm.nih.gov/pubmed PubMed]

[[http://www.ncbi.nlm.nih.gov/pubmed]]

==Assessment 1==
<pubmed>25077107</pubmed>
The article above aim was to determine whether vitamin D levels effects women’s clinical pregnancy rates following in vitro fertilization (IVF) treatment. A total of 173 infertile women participated in the study that met the following criteria: being in the age category of 18-41 years, follicle-stimulating hormone level 12 IU/L or lower, as well as consent.

Participants of this study were divided into two categories based on their Vitamin D via the serum 25-hydroxy-vitamin D (25[OH]D) levels. Sufficient levels were classified for women to have ≥ 75 nmol/L of vitamin D whereas insufficient levels were classed as being < 75 nmol/L vitamin D levels. Successful patients IVF cycles resulted in a clinical pregnancy, which is defined as a visible intrauterine sac upon ultrasound.

The study concluded that the womens clinical pregnancy rates were subsequently higher per IVF cycle if the patient had a sufficient level of Vitamin D. Thus forming a relationship between serum 25-hydroxy-vitamin D (25[OH]D) levels and clinical pregnancy rates.

--[[User:Z8600021|Mark Hill]] These should have been 2 references for this assessment item (3/5)
==Assessment 2==
[[File:MRI_confirming_renal_agenesis.jpg]]

<pubmed>24618008</pubmed>

--[[User:Z8600021|Mark Hill]] All information and file naming correct. Next time scale the image to fit the page better and also include a figure legend as well. (5/5)

==Assessment 3==

<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>21079243</pubmed>

--[[User:Z8600021|Mark Hill]] These reference are relevant. You could have also included a single sentence on why/how you selected these references. (4/5)

==Assessment 4==

<pubmed>23998127</pubmed>

Pre-mature ovarian failure (POF) is currently classified into two categories, these include: there are little to no remaining follicles or there is a copious quantity of follicles present in the ovaries. POF in women has been commonly treated by hormone replacement therapy, even though the treatment increases the risks of other complications including the formation of blood clots such as DVT’s and cancers such as ovarian and breast cancer. The study undertaken by Wang et. al. attempted to investigate whether Mesenchymal stem cells utilized from the human umbilical cord “umbilical cord matrix stem cells” or (UCMSCs) originating in Wharton’s Jelly has any therapeutic use for the treatment of premature ovarian failure in mice.

Wang et al. collected and isolated UCMSCs from full term umbilical cords following the drainage of the cord blood. The umbilical cords were then dissected into sections of 5-6 grams of tissue manually and treated chemically in preparation to be cultured and then harvested after 10 days. The mice were then divided into 3 categories, each consisting of 15 mice each, which included the POF and UCMSC groups. Mice in the UCMSC were intravenously injected with 1 x 10^6 hUCMSCs in 100 𝜇L PBS, whereas the mice in the POF group were exclusively injected with 100𝜇L PBS. These groups then received daily injections of intraperitoneal CTX (50mg/kg) for a total of 15 days, instigating the development of POF models of chemotherapy-induced ovarian damage.

The study concluded that following the transplantation of UCMSCs in mice in the chemotherapy treated group, the mice had a decrease in apoptosis of cumulus cells as well as restoring the normal function of the ovary. Mice treated with UCMSCs also reportedly had a significant increase in their sex hormone levels, leading to an increase in follicles present in the treated mice in comparison to the control group. In essence, the study conveyed UCMSCs could successfully restore the function of damaged ovaries as well as significantly decreasing apoptosis of granulosa cells in the developing follicles.

===Vascular shunts===

• '''Ductus venosus''' - connects the pulmonary artery to the proximal segment of the arotic arch allowing oxygenated blood to travel from the left umbilical vein to the inferior vena cava, thus allowing bypass of the liver. This shunt is then closed postnatally and becomes ligamentum venous.

• '''Foramen ovale''' - an opening located between the right and left atrium that directs highly oxygenated blood flow entering from the right atrium to the left atrium. This is then closed at birth and become the fossa ovalis. The remnant of a foramen ovale that had not closed after birth is known as a patent foramen ovale.

• '''Ductus arteriosus''' - connects the pulmonary artery to the proximal descending aorta. This blood vessel prevents the output of the right ventricle from entering the non-functioning and fluid filled lungs of the fetus. Ductus arteriosus then becomes the ligamentum arteriosum postnatally.

==Assessment 5==

===Gastrochisis===

Gastrochisis is a development abnormality of the anterior abdominal wall, where the bowel protrudes without a covering sac between the developing rectus muscles, occurring slightly lateral and towards the right of the fetal umbilicus. Gastrochisis commonly occurs as an isolated malformation, occurring in approximately 2.5 in 10’000 births.

During the fourth week of normal fetal development, the lateral body of the fetus folds, moving ventrally and fusing in the midline to form the anterior body wall. In Gastrochisis it has been theorized that the incomplete fusion of the midline results in this abnormality, resulting in the abdominal viscera to protrude through the abdominal wall, herniating through the rectus muscle. This is one of many theories linked to Gastrochisis as the cause is still unclear. Other theories include, the failure of mesoderm to form in the body wall, rupture of the amnion around the umbilical ring with subsequent herniation of the bowel, abnormal involution of the right umbilical vein resulting in a weakening of the body wall and thus resulting in herniation of the bowel, and disruption of the right vitelline (yolk sac) artery with consequent body wall damage and gut herniation.

<pubmed>25059025</pubmed>
<pubmed>17230493</pubmed>
<pubmed>19419415</pubmed>

==Assessment 6==
===Thyroid Development===

<pubmed>19389367</pubmed>
The current study by Lania et. al. demonstrates that the developmental mechanisms of the endocrine gland, the thyroid, is regulated by genetic networks. Tbx1 is a prominent gene involved in the embryonic development of the thyroid gland, as well as many of the pharyngeal apparatus derivatives. In this study, the role of Tbx1 is emphasized as a key factor for regulating the size of the thyroid in early development of mice. Knockout mechanisms were preformed in mice embryos to remove the expression of Fgf8, in the mesoderm, which is regulated by Tbx1. The lack of Fgf8 thus subsequently leads to cause thyroid hypoplasia in the subjects. Thyroid sizes of the mouse embryos were measured following the removal of Fgf8, in 2 different stages of embryonic stages of development, with both stages showing a significant decrease in thyroid size. These results suggest that a Tbx1-NFgf8 pathway is a key factor in determining the size of he thyroid glands in mammalians.

In addition, mutant phenotypes were observed due to the lack of function of Tbx1. The mutant embryos presented with a hypoplastic thyroid, though the positioning of the organ was predominantly normal. Lania et. al. went on to observe a slightly larger than normal lumen present in the thyroid follicles of the mutants. These results were then supported further by Immunohistochemistry analysis of these embryos, which demonstrated that Nkx2-1 is typically expressed and that thyroglobulin is typically produced by mutant follicles.

===Tooth Development===

• '''Odontoblasts''' - derived from neural crest mesenchymal cells, and are differentiated under the influence of the enamel epithelium. Odontoblasts secrete predentin throughout life, which calcifies to form dentin, located under enamel.

• '''Ameloblasts''' - derived from oral epithelium of ectodermal origin. They produce enamel after the first production of dentin layer by odontoblasts and form the outermost layer of the tooth.

• '''Periodontal ligament''' - a specialised connective tissue layer that acts as an anchor for tooth in its bony socket and surrounds the tooth root coating of cementum.

==Assessment 7==
===Ovary Development===

Initially, the origins of gonadal development are morphologically similar for both the testes and ovaries. It is only when the indifferent stage of sexual development occurs when the differential stages of ovary development begins. Both gonads have derivatives from the structures; Mesothelium, which lines the posterior abdominal wall, as well as underlying mesenchyme and primordial germ cells that form the earliest, undifferentiated sex cells.

During week 5 the development of ovaries begins, when a thickened area of mesothelium develops on the medial side of the mesonephros, a primitive kidney. This is then continued by the development of gonadal ridges, which results from proliferation of the mesothelium and the underlying mesenchymal tissue, as it produces a bulge on the medial mesonephros. Finger like epithelial cords then grow into the underlying mesenchyme forming the gonadal cords. In females (XX), the cortex of the indifferent gonad differentiates into an ovary, and the medulla regresses.

Primordial germ cells dwell amongst dorsal endodermal cells of the umbilical vesicle, where they first populate. They then begin to migrate to the gonadal ridge along the hindgut’s dorsal mesentery where they then migrate to the gonadal ridges during the folding process of the embryo. In week 6, the primordial germ cells enter the underlying mesenchyme and are incorporated in the gonadal cords.

Ovary development is a slow process in female embryos, and It is not until week 10, when the ovaries become histologically recognizable.

====References====
<pubmed>15664455</pubmed>
[http://www.mdconsult.com.wwwproxy0.library.unsw.edu.au/books/page.do?eid=4-u1.0-B978-1-4377-2002-0..00012-6--s0095&isbn=978-1-4377-2002-0&uniqId=466393265-4#4-u1.0-B978-1-4377-2002-0..00012-6--f0150 Moore: The Developing Human Chapter 12]

[[File:Bailey329.jpg|500px]]

==Assessment 9==

'''Group 1:'''

Firstly, great job on the layout and formatting of the project, everything is easy to find and overall, it reads well. The introduction provides great insight of what to expect on the page. However, it lacks in-text citations for the first three subheadings of the page, as well as the table of lung developmental stages. The first two images also don’t have a description when I click on it, I don’t know what I’m looking at. The “student template” is also missing for the images. I would suggest you look up the tutorial for uploading images on the pages as Mark has extensive information for the proper steps required for uploading images. Otherwise, the lung developmental stages table is informative and easy to read. I would also recommend adding an image for better visualization of the developmental process.

The historical findings and current research models have very detailed content, and look as though they have been referenced correctly using in-text citations, I’m impressed. Although, I would suggest you leave all the references to the end by simply putting </references> at the bottom of the page, as it looks neater to have them all in one place, rather than at the bottom of each sub-heading. The abnormalities section is done well and there are a wide number of abnormalities covered. The detail of the first two is more in depth than the rest, I’m unsure whether they was more information on those particular abnormalities or their still needs to be information added, but I suggest to have the same amount of information on each disease, if possible.
Overall, the project is very informative and presented well. It just need a few minor edits.

'''Group 3:'''

The introduction provides a good basic outline of the overview of the GIT. Although, there are no in-text citations in the introduction and all sub-headings are not included into the overview. Be wary of spelling errors such as “GIT (Gastrointestinal Track) consist of the Fore-gut, Mid-gut and Hind-gut” that should read Gastrointestinal Tract consists of the foregut, midgut and hindgut. This section would be better it was expanded upon and images were added. The timeline provides good detail, though would benefit by better formatting and organisation of the information, maybe putting it all into a table, by week will tidy it up.

Adding images for the sections will definitely be beneficial. The images hand-drawn are great, although the colours used make it hard to read. If you plan to add anymore drawings, try and use dark colours that allow for easy readability. The images already uploaded are missing copyright, referencing and “student template” information for images such as “fetal week 10 sagittal plane”. I would suggest you look up the tutorial for uploading images on the pages as Mark has extensive information for the proper steps required for uploading images.

The deformities section should be re-titled abnormalities as per the assessment criteria and would ensure the group is following similar structure from the other projects. Again, adding an image per disease would be great. Try and do about 1-2 more abnormalities. Great job on putting all the references at the bottom of the page, it makes it very neat and accessible. Overall, a good project just needs a few edits.

'''Group 4:'''

Firstly, great job on all the contents you guys managed to present, it’s quite detailed. There seems to be no introduction though, and the page jumps straight into explaining genital development. I think if an introduction were added, it would give the whole page better structure and formatting so the reader knows what to expect when they decide if they want to read on. The dot points used for the developmental section allows for easy readability of the contents, however, the use of caps lock and arrows takes away from the overall presentation of the page. I would suggest any text you want to emphasize to make bold or underline the word. I also noticed that there was a note stating the attempt to put all the developmental information into a table, but had issues. I suggest you look at the editing basic page you can search for in the top right hand corner as it outlines a step-by-step guide into making tables etc.

In regards to referencing, there are no in-text citations for the first two subheadings. The sections were they do have citations also have a list of references at the bottom of each section. I would recommend just adding a final list of references at the bottom of the page, as it looks much neater.

I’m impressed with the level of hand-drawn diagrams uploaded. I would also recommend adding captions to the image. For example:
[File: Flow Diagram of Fetal Development of External Genitalia.pptx|1000px|thumb|right|alt text]. The “alt text” should be edited to describe the caption of the drawing. This particular image seems to have a broken link though; the “alt text” also appeared in the labeled diagram of the testes. Otherwise, good job on the other images.

The current findings section seems to be untouched, with the exception of some pubmed journal article links, I’m assuming you are still in the process of adding content. The historic findings, however, is extensive and well researched. Good job.

The abnormalities section is done well. There is more than enough abnormalities listed, and they are researched well, I would just suggest adding a few more images for better visualization. Overall, great page, just needs better formatting for the mentioned sections.

'''Group 5:'''

This page has great overall structure and presentation. The introduction gives good insight of the overall contents of the page, however it is very brief and should be expanded upon.

The table included in the developmental overview serving, as a timeline is excellent, really well done. It’s easy to follow and looks very neat. I like how there is an image for each of the weeks mentioned, just don’t forget to add in-text citations for its contents. The glands sub-section is very brief and would benefit if there were more contents added. Great job on the images though. The nail section is the same, more contents needs to be added and image would look really good.

The developmental overview and historic findings sections also seems to lack in-text citations. There is also has an image with a broken link. The subsection hair seems to be well researched, however I would also suggest either bolding or underlining the words you want to emphasize such as “structure” for a neater look.

The recent findings section looks superb I love the purple background colour. Its very well researched and the link to more research papers are very helpful for readers. I would suggest you put the image at the bottom of the mentioned content though, just to avoid the big gap on the page, or even if you can manage to wrap the text around the image, it would look much better in terms of presentation.

Although disturbing, the abnormalities section I could not fault. Very well done. It is evident that it has been research well and the images allow for great visualization of the diseases mentioned.

Overall, excellent page just needs a very formatting edits and some expanded contents mentioned above. Good luck!

'''Group 6:'''

There seems to be no introduction on the page, don’t forget to add content to this section before the final submission. The overall page looks disjointed by the choice of sub-headings. I think an overall timeline is needed to know which glands/organs develop when and originate from where. It would look much neater and would be easier to follow.

The parathyroid gland and pancreas seems to be the only sections that are properly completed. Both sections have good use of images and the tables provide easy readability. The images are all properly cited, good job.

The overall referencing of the page is all over the place and lacks in-text citations. I suggest you go through the contents and add these where necessary. If you are unsure how to do this, just look at the handout Mark gave out in week 2 for further reference. Or, alternatively you could look at some of the other project pages in edit mode. I would also suggest you leave all the references to the end of the page by simply putting </references> at the bottom of the page, as it looks neater to have them all in one place, rather than at the bottom of each sub-heading.

The abnormalities section is lacking content and there is only 2 diseases listed, with no description.

Overall, the page has good content, just needs to be edited to put in-text referencing. Some sections need contents such as the placenta and adding images to the page will also improve its presentation.

'''Group 7:'''

This page is organized well, all the headings and subheadings are thought through. Although, I’m unsure while the sections brain and spinal cord are in bold? The development during fetal period image lacks the necessary “student template” at the bottom of the description summary and I was unable to open the link http://www.nichd.nih.gov/publications/pubs/acute/images/p44.gif.
Otherwise, all the other images uploaded on the page look really good and are referenced correctly.

The table under the section brain development is very brief, and expansions on the content will allow for a better understanding of the content. Adding images to appear after the table will also add to the appearance of the page and give it a cleaner look.

The spinal cord and menegies development have been left untouched and the current research models have no content, just pubmed references. I understand the current research models are probably the hardest part of the assignment, but the content appears to be quite good, the formatting of the section could be improved by following the structure Mark uses. You could look at the other group projects as examples.

In regards to referencing, there are no in-text citations for the first two subheadings. I would also like to recommend just adding a final list of references at the bottom of the page, as it looks much neater.

The abnormalities section is done well. But try to minimise the use of dot points as this section lacks any structured paragraphs. It use of images are great, although there is an image that appear to have been removed and as a result, there is a broken link.

Overall, great job so far!

'''Group 8:'''

Let me start by saying, for only having two people in the group, well done. The page should have an introduction though, and this is missing. Just by simply summarizing all the information that will be covered in the page and adding it to the introduction, will improve the overall presentation significantly, you may wish to leave this to last, or edit as you go along.

The section “Making gains” is amusing, but inappropriate and should be omitted from the final submission. The timeline for the page I believe should be put into a table to save time and add to the presentation of the page, it can be easily done if you follow the steps outlined in the ‘editing basics’ page

The background information is comprehensive, however, the page is in desperate need of some images as there are just slabs of text. Images will really help break up the contents of the page and make it visually appealing.

The abnormalities section also seems to be coming along quite well. Keep up the good work.

==Assessment 10==
<pubmed>8955790</pubmed>
The outer oral environment receives chemical stimuli from slender epithelial cells, which are responsible for the assembly of taste buds. To date, there have been few studies documented on the formation and morphology of prenatal human taste buds. Therefore, in this study, taste bud primordium is investigated, including its morphological changes, synaptogenesis, cell differentiation, and taste pore formation from the time of the onset of taste bud formation from approximately the 8th week until the 15th week of gestation.

Forty-two human embryonic and fetal tongues from the 6th week to the 15th week of gestation were used in the study. The tongues were then fixed in 0.1 M cacodylate buffer containing 2.5% glutaraldehyde, or 0.1 M phosphate buffer containing 2% paraformaldehyde and 1% glutaraldehyde. The samples were then contrasted overnight and prepared with uranyl acetate dissolved in 70% ethanol, which were then, washed, dehydrated and embedded in Epon. The sections of tissues were then prepared consisting of three specimens of each tongue and screened for taste bud primordial. The sections were then placed on slot grids and examined by means of transmission election microscopy.

From the results, it can be seen that the sixth to seventh postovulatory week have shown no signs of cell specialization and indicate taste bud formation, although at this stage the epithelial is 2-3 layers thick and nerves fibres begin to approach the lingual epithelium. During the 8th week of gestation, the first signs of cell differ enation responsible for the formation of taste buds were seen at the base of the taste bud primordium and the nerve fibres are able to penetrate the basal lamina. By the 9th – 11th week the lingual epithelium has thicken to compose of approximately 3-4 layers and taste bud primordial were present and resemble those that were found in earlier stages. During week 12, further differentiation of the cells can be seen, as the cells that are electron dense begin to resemble type III cells seen in human adult taste buds, as well as long, slender cells with electron-dense nuclei and electron-dense cytoplasm containing abundant mitochondria and bundles of intermediate filaments. However, the majority of taste pores do not begin to develop up until week 14-15 of gestation.

[https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Taste_Development Taste Development]

2014 Group Project 2

2014-10-24T03:40:48Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==

{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
| '''Year''' || '''Discovery'''
|- bgcolor="FFFAFA"
| 1883<ref>Foster, M., Balfour, F. M., Sedgwick, A., & Heape, W. (1883). '''The Elements of Embryology'''. (2nd ed.). Organs from Mesoblast. London: Macmillan and Co.</ref> || The supra-renal bodies and the urinogenital organs are found to originate from the mesoblast
|- bgcolor="FFFAFA"
| 1902<ref>Keith, A. (1902). '''Human Embryology and Morphology'''. Uro-genital System. London: Edward Arnold.</ref> || It has been found that the pronephros exists first, before the mesonephros (Wolffian body).
The Wolffian duct is formed from the mesoblastic cells in the intermediate mass. These cells produce vesicles which form into tubular structures, opening into the duct. This has developed enough by the second month (Week 8) to be fully formed, but is almost completely degenerated by the end of that month. The permanent kidney forms in its place, arising from a stalked bud that extends forward from the Wolffian duct. The stalk portion of the bud becomes the ureter, which extends until it reaches a part of the cloaca that will form into the bladder later on in development.

The common uro-genital mesentery connects the mesentery of the genitals and the mesentery of the Wolffian bodies together around Week 8.

In females, the Müllerian duct forms the Fallopian tube, while the Wolffian body in males forms the epididymis, the seminal vesicles, the vas deferens and the common ejaculatory duct.
|- bgcolor="FFFAFA"
| 1907<ref>Heisler, J.C. (1907). '''A Text-book of Embryology'''. (3rd ed.). Genito-urinary System. Philidelphia and London: W.B. Saunders Company</ref> || The allantois is formed by a pouching-out of the ventral wall of the gut tract, and eventually goes on to form the urinary bladder and part of the urethra. The ureter is formed from the mesonephric ducts and opens into the urogenital sinus, later coming to open into the bladder.
|- bgcolor="FFFAFA"
| 1912<ref>Keibel, F. and Mall, F.P. (1912). '''Manual of Human Embryology II'''. The Development of the Urinogenital Organs. J. B. Lippincott Company, Philadelphia</ref> || Before the pronephros begins to degenerate, both the mesonephros and pronephros function together.
The cloaca divides three times to form the rectum, bladder, urethra and the urogenital sinus.

The bladder separates and becomes distinct from urethra by enlarging in size and by a differentiation in epithelium. This change begins to take play when the embryo is about 13mm in length. The first muscle layer of the bladder forms when the embryo is about 22.5mm in length due to a condensation of loose mesenchyme tissue that surrounds the bladder. This continues until the embryo is 80mm, when all muscle layers are distinct.
|- bgcolor="FFFAFA"
| 1921<ref>Bailey, F.R. and Miller, A.M. (1921). '''Text-Book of Embryology'''. Urogenital. New York: William Wood and Co.</ref> || When the tubules of the mesonephros are formed, a branch of the aorta enters the condensation of mesenchymal cells occurring at these areas, and divides and ramifies into smaller vessels, the entire structure of which forms a glomerulus. The tubule surrounding it flattens and becomes the two layers of epithelium around the glomeruli.
The outgrowth of the mesonephric duct forms the epithelium for the ureter, renal pelvis, and the collecting tubules, while the mesenchyme gives rise to the convoluted tubules and the glomeruli.
|- bgcolor="FFFAFA"
| 1943<ref>Potter, E.L., Thierstein, S.T. (1943). '''Glomerular Development in the Kidney as an Index of Fetal Maturity'''. The Journal of Pediatrics, 22(6), 695-706</ref> || The maturity of the fetus can be determined by the state of glomerular production, which ceases at Week 35 and/or when the fetus is 2.1-2.5kg in weight.
|- bgcolor="FFFAFA"
| 1962<ref>Robert L. Vernier, Aksel Birch-Andersen. (1962). '''Studies of the human fetal kidney: I. Development of the glomerulus'''. The Journal of Pediatrics, 60(5), 754-768</ref> || Glomeruli begin to mature at about Week 6 until roughly about Week 35 of gestation. It is believe that at five months of gestation, the kidney has formed structurally enough to fully function.
|- bgcolor="FFFAFA"
| 1973<ref name="PMID12623969"><pubmed>12623969</pubmed></ref> || Luciano Barajas was able to demonstrate that when renal sympathetic nerve terminals are in contact with the basement cell membrane of the renal tubules, they are able to innervate all segments of this area. It was previously thought these nerves served little function.
|- bgcolor="FFFAFA"
| 1976<ref name="PMID12623969"/> || Sodium reabsorption increased due to renal sympathetic nerve stimulation and occurred in the proximal convoluted tubule, the thick ascending limb of Henle’s loop, the distal convoluted tubule, and the collecting duct.
|}

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins; pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Metanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect <ref>Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623</ref><ref>Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier</ref>.

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys <ref>Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623</ref>.

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. Furthermore, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) are necessary for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID16767405"><pubmed>16767405</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
[[File:Horseshoe_Kidney.jpg|300px|thumb|Horseshoe Kidney]]

Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the mid abdomen <ref name="PMID22970063"><pubmed>22970063</pubmed></ref> <ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

There are typically two main theories outlining the cause of this anomaliy. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s <ref name="PMID16407023"><pubmed>16407023</pubmed></ref>
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

==References==
<references/>

2014 Group Project 2

2014-10-24T03:36:23Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==

{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
| '''Year''' || '''Discovery'''
|- bgcolor="FFFAFA"
| 1883<ref>Foster, M., Balfour, F. M., Sedgwick, A., & Heape, W. (1883). '''The Elements of Embryology'''. (2nd ed.). Organs from Mesoblast. London: Macmillan and Co.</ref> || The supra-renal bodies and the urinogenital organs are found to originate from the mesoblast
|- bgcolor="FFFAFA"
| 1902<ref>Keith, A. (1902). '''Human Embryology and Morphology'''. Uro-genital System. London: Edward Arnold.</ref> || It has been found that the pronephros exists first, before the mesonephros (Wolffian body).
The Wolffian duct is formed from the mesoblastic cells in the intermediate mass. These cells produce vesicles which form into tubular structures, opening into the duct. This has developed enough by the second month (Week 8) to be fully formed, but is almost completely degenerated by the end of that month. The permanent kidney forms in its place, arising from a stalked bud that extends forward from the Wolffian duct. The stalk portion of the bud becomes the ureter, which extends until it reaches a part of the cloaca that will form into the bladder later on in development.

The common uro-genital mesentery connects the mesentery of the genitals and the mesentery of the Wolffian bodies together around Week 8.

In females, the Müllerian duct forms the Fallopian tube, while the Wolffian body in males forms the epididymis, the seminal vesicles, the vas deferens and the common ejaculatory duct.
|- bgcolor="FFFAFA"
| 1907<ref>Heisler, J.C. (1907). '''A Text-book of Embryology'''. (3rd ed.). Genito-urinary System. Philidelphia and London: W.B. Saunders Company</ref> || The allantois is formed by a pouching-out of the ventral wall of the gut tract, and eventually goes on to form the urinary bladder and part of the urethra. The ureter is formed from the mesonephric ducts and opens into the urogenital sinus, later coming to open into the bladder.
|- bgcolor="FFFAFA"
| 1912<ref>Keibel, F. and Mall, F.P. (1912). '''Manual of Human Embryology II'''. The Development of the Urinogenital Organs. J. B. Lippincott Company, Philadelphia</ref> || Before the pronephros begins to degenerate, both the mesonephros and pronephros function together.
The cloaca divides three times to form the rectum, bladder, urethra and the urogenital sinus.

The bladder separates and becomes distinct from urethra by enlarging in size and by a differentiation in epithelium. This change begins to take play when the embryo is about 13mm in length. The first muscle layer of the bladder forms when the embryo is about 22.5mm in length due to a condensation of loose mesenchyme tissue that surrounds the bladder. This continues until the embryo is 80mm, when all muscle layers are distinct.
|- bgcolor="FFFAFA"
| 1921<ref>Bailey, F.R. and Miller, A.M. (1921). '''Text-Book of Embryology'''. Urogenital. New York: William Wood and Co.</ref> || When the tubules of the mesonephros are formed, a branch of the aorta enters the condensation of mesenchymal cells occurring at these areas, and divides and ramifies into smaller vessels, the entire structure of which forms a glomerulus. The tubule surrounding it flattens and becomes the two layers of epithelium around the glomeruli.
The outgrowth of the mesonephric duct forms the epithelium for the ureter, renal pelvis, and the collecting tubules, while the mesenchyme gives rise to the convoluted tubules and the glomeruli.
|- bgcolor="FFFAFA"
| 1943<ref>Potter, E.L., Thierstein, S.T. (1943). '''Glomerular Development in the Kidney as an Index of Fetal Maturity'''. The Journal of Pediatrics, 22(6), 695-706</ref> || The maturity of the fetus can be determined by the state of glomerular production, which ceases at Week 35 and/or when the fetus is 2.1-2.5kg in weight.
|- bgcolor="FFFAFA"
| 1962<ref>Robert L. Vernier, Aksel Birch-Andersen. (1962). '''Studies of the human fetal kidney: I. Development of the glomerulus'''. The Journal of Pediatrics, 60(5), 754-768</ref> || Glomeruli begin to mature at about Week 6 until roughly about Week 35 of gestation. It is believe that at five months of gestation, the kidney has formed structurally enough to fully function.
|- bgcolor="FFFAFA"
| 1973<ref name="PMID12623969"><pubmed>12623969</pubmed></ref> || Luciano Barajas was able to demonstrate that when renal sympathetic nerve terminals are in contact with the basement cell membrane of the renal tubules, they are able to innervate all segments of this area. It was previously thought these nerves served little function.
|- bgcolor="FFFAFA"
| 1976<ref name="PMID12623969"/> || Sodium reabsorption increased due to renal sympathetic nerve stimulation and occurred in the proximal convoluted tubule, the thick ascending limb of Henle’s loop, the distal convoluted tubule, and the collecting duct.
|}

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins; pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Metanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect <ref>Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623</ref><ref>Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier</ref>.

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys <ref>Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623</ref>.

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. Furthermore, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) are necessary for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID16767405"><pubmed>16767405</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
[[File:Horseshoe_Kidney.jpg|300px|thumb|Horseshoe Kidney]]

Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the mid abdomen <ref name="PMID22970063"><pubmed>22970063</pubmed></ref> <ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s <ref name="PMID16407023"><pubmed>16407023</pubmed></ref>
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

==References==
<references/>

2014 Group Project 2

2014-10-23T23:51:25Z

Z3465141: /* Renal agenesis */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. Furthermore, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) are necessary for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID16767405"><pubmed>16767405</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
[[File:Horseshoe_Kidney.jpg|300px|thumb|Horseshoe Kidney]]

Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the mid abdomen <ref name="PMID22970063"><pubmed>22970063</pubmed></ref> <ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s <ref name="PMID16407023"><pubmed>16407023</pubmed></ref>
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

==References==
<references/>

2014 Group Project 2

2014-10-23T23:29:08Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID16767405"><pubmed>16767405</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
[[File:Horseshoe_Kidney.jpg|300px|thumb|Horseshoe Kidney]]

Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the mid abdomen <ref name="PMID22970063"><pubmed>22970063</pubmed></ref> <ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s <ref name="PMID16407023"><pubmed>16407023</pubmed></ref>
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

==References==
<references/>

2014 Group Project 2

2014-10-23T23:27:07Z

Z3465141:

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID16767405"><pubmed>16767405</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
[[File:Horseshoe_Kidney.jpg|400px|thumb|Horseshoe Kidney]]

Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the mid abdomen <ref name="PMID22970063"><pubmed>22970063</pubmed></ref> <ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s <ref name="PMID16407023"><pubmed>16407023</pubmed></ref>
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

==References==
<references/>

File:Horseshoe Kidney.jpg

2014-10-23T23:24:08Z

Z3465141: ==Horseshoe Kidney diagnosis by intravenous pyelography== Diagnosis of horseshoe kidney was made by intravenous pyelography. Coronal volume rendering multidetector CT image shows various blood supply to the horseshoe kidney. Right and left renal arter...

==Horseshoe Kidney diagnosis by intravenous pyelography==

Diagnosis of horseshoe kidney was made by intravenous pyelography. Coronal volume rendering multidetector CT image shows various blood supply to the horseshoe kidney. Right and left renal arteries (white arrows) supply the upper and middle pole of each kidney, two aortic branches (yellow arrows) supply the lower pole of both kidneys and the isthmus. The isthmus is just below the inferior mesenteric artery (green arrow) origin. Multiple renal stones are also seen in the right kidney.

===Reference===
<pubmed>22970063</pubmed>
Copyright © 2012 Biomedical Imaging and Intervention Journal
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

{{Template:Student Image}}

2014 Group Project 2

2014-10-23T22:56:53Z

Z3465141:

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID16767405"><pubmed>16767405</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the mid abdomen <ref name="PMID22970063"><pubmed>22970063</pubmed></ref> <ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s <ref name="PMID16407023"><pubmed>16407023</pubmed></ref>
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

==References==
<references/>

2014 Group Project 2

2014-10-23T22:51:19Z

Z3465141: /* Polycystic Kidney Disease */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID16767405"><pubmed>16767405</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the mid abdomen <ref name="PMID22970063"><pubmed>22970063</pubmed></ref> <ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s <ref name="PMID16407023"><pubmed>16407023</pubmed></ref>
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

==References==
<references/>

2014 Group Project 2

2014-10-23T22:48:18Z

Z3465141:

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the mid abdomen <ref name="PMID22970063"><pubmed>22970063</pubmed></ref> <ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s <ref name="PMID16407023"><pubmed>16407023</pubmed></ref>
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

==References==
<references/>

2014 Group Project 2

2014-10-23T22:45:02Z

Z3465141:

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the mid abdomen <ref name="PMID22970063"><pubmed>22970063</pubmed></ref> <ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s <ref name="PMID16407023"><pubmed>16407023</pubmed></ref>
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

==References==
<references/>
===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>
The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.
<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T22:42:20Z

Z3465141: /* Duplicated Ureter */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the mid abdomen <ref name="PMID22970063"><pubmed>22970063</pubmed></ref> <ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s <ref name="PMID16407023"><pubmed>16407023</pubmed></ref>
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.
<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T22:39:13Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the mid abdomen <ref name="PMID22970063"><pubmed>22970063</pubmed></ref> <ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s <ref name="PMID16407023"><pubmed>16407023</pubmed></ref>
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T22:33:03Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s <ref name="PMID16407023"><pubmed>16407023</pubmed></ref>
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T20:19:50Z

Z3465141: /* Duplicated Ureter */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the ureteric bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T20:14:32Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

Talk:2014 Group Project 2

2014-10-23T19:57:39Z

Z3465141:

{{Template:ANAT2341Project2014discussionheader}}
==Peer Reviews==

The introduction to this page was will written and the information was clear and to the point. Each component of the renal system was mentioned in your group’s introduction which gave an overall/holistic preview of the information that is evidently discussed underneath. There is a developmental timeline showing the key events of renal development at the embryonic, fetal and post-natal stages. Perhaps consider presenting this information in a table. The historic findings section, however, was lacking information. This section needs to be further researched and added to make this project complete.

Your choice of content, clear structure, headings and images is evident that your group is working well and have a good understanding of this topic area. However, there is no hand drawn image yet. The image chosen form Langman’s Medical Embryology is a great image to show as it demonstrates the progressive stages of kidney ascent, perhaps you could consider re-drawring that image rather than just immediately upload it from the textbook. Your descriptions and information presented can be understood at the peer level. It is both engaging and informative, well done!! There is also a good balance between text and images that are appealing for the reader. The information presented in the first half of your project is ample however this is not coherent with the second half of your project page, where descriptions are not as developed.

There is a great selection of images that are used in your group project. Most of these images are correctly cited and have been uploaded in the correct manner. Some images are just missing the student template image:

Note - This image was originally uploaded as part of an undergraduate science student project and may contain inaccuracies in either description or acknowledgements. Students have been advised in writing concerning the reuse of content and may accidentally have misunderstood the original terms of use. If image reuse on this non-commercial educational site infringes your existing copyright, please contact the site editor for immediate removal.

You can just copy (edit mode) this into your image summaries and it will appear: {{Template:Student Image}}

There are a great number of resources that are used in this project, and all your references are correctly cited. As your project is still underway, I am sure that you will add additional references and also make it one complete this at the end of your project.

Overall, I enjoyed reading about the renal system on presented by your group and I am confident you will earn high marks for your project. Best of wishes group 2!

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The introduction successfully touches on the project as a whole, including describing the system and its development, and the abnormalities that may arise. However it has failed to mention the importance of historical and current research. Also adding an image of the renal system or the renal units in particular will heighten the readers interest in this project.

There seems to be no information under the historical findings subheading, it might be hard to find research papers on this system, however a good start would be reading Mark Hill’s page on the renal development.

A very brief developmental timeline, however it does simply provide the information required to understanding the timeframe of renal development. More information about the structures mentioned in this timeline is required, this can be added within the timeline or following it.

The current research model section needs more information, if you are unable to find enough to make a substantial section then a possibility to work around that is to integrate the various research models with the organ sections. However, if more information can be obtained then this section should be left and continued as the image is correctly included and the information is written at a high standard.

The division of this page into the various organs in the renal system, the kidney, urethra, and ureter is clever as providing information on all in one section may be overwhelming. Each of these organs are well researched and written about. The layout looks fine with the paragraphs placed under subheadings and an abundant amount of images are located next to their corresponding information. Some images do not have a description, it is best to add a description, even a short one, to guide the reader and pinpoint the reason for uploading. An error has occurred for the first image under the Kidney section which has been removed by the administrator. Please take care with copyright.

I really like the abnormality section and the information added thus far. It is evident that you plan to continue as this section is not finished, however with what is there, great work. Both images used contain captions and clearly understood descriptions. One fault is the presence of references in this section. The group has one reference heading at the end of the project, however some of the references doubled up within the abnormalities section. One that note, please look carefully through the referencing list as you have the same articles more than once in the list, for example 23 and 24. There is a way of merging them together and having superscripts indicate that this article has been cited more than once, use article 28 and 30 as examples.

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Overall the group has done a good job at referencing and has derived information from a variety of mediums including video clips and animations. What I would suggest however is to keep all the references at the end of the page under an exclusive references heading. I think this would make the project appear much more organized and easier to read. I think the use of quotation marks should be avoided in the introduction. It would be a better idea to summarise the sentence in your own words and reference it.

Though the introduction is informative, I think it could be structured better so as to flow on from each paragraph, particularly with the last two paragraphs. With the developmental timeline, it would be a great idea to put that into a table and expand a little more on each stage you have listed to make it easier to understand the process.

Current research models mentioned were explained well and provided context to the information given however I’d suggest to use two subheadings for each of the different research models used (mice and lambs) so that the text isn’t so chunky. I think the kidney development, urethra, bladder and abnormality section were written exceptionally well and the text was supported with relevant images. The referencing here however was a little inconsistent with the rest of the format but that can easily be fixed during the editing process.

Overall however, the information was presented well in an interesting and meaningful way, perfectly suited as an educational resource for university students. Great job!

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Very nice introduction. Keeps the reader engaged and outlines what the page is about specifically.
Historic findings have been untouched but do not worry I think you still have 1-2 weeks to complete this project. Try using pubmed and also it will be helpful to looks at Mark’s (course coordinator/convenor) historical textbooks/journal articles on his page.
Try having in text citations for the timeline. Also try making a table instead of dot points as well as use images if possible. Also try including a little more information in the timeline as this can give the reader a greater idea of what to expect.
Try including the years of when the current findings were discovered. Also try to have some information on the molecular signals which drive the development of renal in fetus.
The abnormalities section is well researched and well organised though I suggest putting the references in the end of the page as a bulk.
Well use of images throughout the page. All the images were related to the topic and were very well put together in the text.
I insist for you to put all the references in one place.
Finally just fix few minor things and add information to the historic section then you will be done. Overall well done as the page is well organised and is not missing much in terms of contents.

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The introduction section of the page is well written and provides a nice overview to the whole project that unifies each subheading of the project as a whole. Some potential ideas for historic findings section may be to use some sort of timeline or table with some visual effects through historical images/ drawings. Developmental timeline is clear and concise however this section would be more effective with a greater amount of detail and perhaps a panel of images to convey visually each stage of development. The current research models section was very well written with two relevant current papers discussed- perhaps a few additional papers can be cited- even under an expanded box format so that the readers can be linked to other current studies in the area of interest. The explanation of the figure is also really well presented and described. The section with the subheadings of kidney, ureter and bladder is very well researched and presented- well informed, great use of images and also well referenced. One area for improvement could perhaps be presenting the information in a simpler way as at times it seems too bunched up- maybe smaller bullet points. The image within the urethra subheading is missing a figure caption. Abnormalities section was very descriptive and informative- may be a few more abnormalities could be listed. Overall reference section is also done correctly although some sections individual references need to be integrated into this overall section.

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The introduction provides a very informative description of the functions of the kidney and bladder. Perhaps it would be good to give some more details of the embryonic development just to quickly summarise what has been happening with the fetus up until this point. Also, maybe the introduction should introduce what the page’s content is going to cover. The order of historic findings and then developmental timeline is appropriate as historic findings can be used to compile the timeline. It would also be useful to have the timeline in a table format to make the page look neater and more simplified. Also, there is no research done on ‘historic findings’ so need to address that before final submission.

‘Current research models’ section is good but brief and requires more extensive research as only two articles are cited. There should be information on current models used to study renal development as well as current research and findings. The image in this section is well presented, with appropriate titling, referencing, image descriptions and copyright information with the student image template.
Sections 1.5-1.8 should be smaller sub headings under the larger heading ‘System Development’ and perhaps should go at the top of the page, beneath the introduction seeing as in order to understand research and historic findings, it is necessary to understand renal development first.

It is very good that there is a small section on early development, however maybe it would be better to have it more briefly explained, perhaps in the form of a student drawn diagram or presented as a table. There also is a problem with the image uploaded in the early development section, so should fix that before final submission. The ‘abnormalities’ section is also done well however more conditions should be listed and described with pictures for each one. There are also only abnormalities of the kidneys listed, so maybe it would be better to have more of the other components of the renal system as well (bladder, ureter, urethra).

Also, maybe more information regarding the anatomy of the kidneys and renal system should be added, as this is an anatomy course. Some images are also missing the student image template.
Most images are uploaded correctly with the right information, maybe more would make the page look more aesthetically pleasing as well as assist learning.

Referencing is done correctly with a numbering system and in-text citations are also correct. The in-text referencing in the ‘anatomical position’ sub section of ‘fetal development’ of the ‘Kidney’ section is not referenced appropriately so just fix that minor problem.

Overall, this is great work and should just include more information in certain sections and upload more images, preferably some student drawn images as well. Well done!

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The introduction is well addressed as it sufficiently describes what the renal system is about and its function. Not to mention its anatomical structure as well as the difference between the embryonic and fetal stages of development. This differentiation enables viewers to understand what the content will be focused on, which is fetal development. Also, it helps focus the viewer’s attention on how the project will be divided as the group mentions abnormalities in the last paragraph. Overall the introduction has the right amount of information from each subheading and is very easy to comprehend.

There isn’t any information under ‘historic findings’. If there are any difficulties in finding some historic findings, members of the group can go to pubmed and on the side will be dates such as 1920 that could contain key historical events when renal is entered on search. The use of a development timeline was great as they outlined the major events that occur in a concise manner. Although, I believe a glossary is needed for words like ‘metanephros’ since the viewers would not know what that is. The content under current research models is interesting and correctly describes what the studies were about. Overall, the content used in the project was relating to the topic (fetal development of the kidney) and clearly showed extensive research. I really like how the group divided the different parts of the renal system as well as describing their anatomical positions. The abnormalities listed are also interesting and very easy to understand. I’m hoping to see information under the Horseshoe kidney disease.

In terms of images, there should be an image under introduction perhaps having all features of the renal system. Most images are missing the ‘student template’ aspect of the referencing and needs to be added right away. Other aspects such as description, copyright and referencing were correct. I also like the use of footnotes to describe what the images are about, however some are missing on the page such as the one under ‘anatomical position’ and ‘urethra’. The image used for the ‘development of the kidney’ should be removed from the page as it isn’t permissible. It should be replaced with an image relating to the content and have all the correct copyright and referencing information. Overall, I like the number of images used and its significance to the renal system. They accurately relate to the content of the project.

There is use of in-cite referencing which is good, however some references are just listed and should be placed under the proper ‘references’ subheading such as the ones under ‘ureter’ and ‘renal agenesis’. Some references in the ‘references’ list are used over again and can be fixed by combining it under one reference number. To make the project even more appealing, the group could format the information under ‘developmental timeline’ or even ’historic findings’ in a table. Overall, I think this project is great and by making edits based on the peer-reviews received could enhance their project.

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Good introduction with integrated citations. Content is easy to understand and well presented. There needs to be more references in some sections like development to compare with the rest of the work, which is well done.

Obviously historic findings needs to have some content added

Timeline is simple and easily gives information on sections

As a whole, the project feels like a wall of text even with the images included. breaking some sections up to more concise, dot pointed content could do well.

more work needs to be done tidying up referencing. Changing the references so that they link to a list at the end would be a good idea. You can always look at other project pages and just copy the reference style

Images are well used throughout the project. Again, relocating the references for these would be a good idea. A few have no flavour text to identify what the viewer is looking at. Look at adding this to page.

That all being said, well thought out and executed project so far

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I think that this is a great start to the project. Your project appears well researched and informative, yet there are a few areas which need improvement to ensure that your project clearly demonstrates the developmental stages of renal development. I thought that over, the introduction was a good start to the project and clearly identifies the major components of the renal system and its functions. Because this is highly descriptive, I think it would benefit from a diagram or even video which could couple your description. The developmental timeline is a good idea, however I think severely lacks content. It would be a good idea to add a table or some form of diagrammatic representation of the historical findings, and the addition of pictures would greatly benefit the clarity of your work.

The current research is quite well done and seems heavily researched. There are areas which are a little bit too wordy at times, and your paragraphs are quite long- I think it would be of great benefit if you were to reduce your paragraphs into shorter bullet points so as to convey the main ideas that you are speaking about. Also, maybe a table would assist in ensuring the clarity of your work.

Overall, I think this is a great project and is off to a good start! There are a few things that need fixing- such as the developmental timeline, but I’m sure that it will come along nicely by the time submission is due.

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Really good introduction! It clearly outlines what is in the page. Most key points were done really well except for historic findings. There is a section on the Wikipage that has old books on embryology. It’s under the “Explore” tab and you’ll see “Historic embryo”. The developmental timeline would’ve been better if it was in a table, has an image showing the major steps in development, and is within the development section of the page. Regarding the development section, very detailed and informative. It clearly outlines the development of the renal system in the fetal stage. Dividing this section into the different organs is a very smart decision. It makes it a lot less confusing to the reader. Maybe try to breakdown some of the information and use dot points. There are lots of images to give the readers a visual of the developmental process. Also, the images have captions, which is great.

Great job on the current research section. The articles chosen for current research is highly relevant to the topic and to the project. This section is written concisely and very detailed. The image really helps to understand the findings of the research. The same can be said to the abnormalities section. Each disease was written concisely and is very informative. The images really help in terms of understanding the clinical manifestation/s of each disease. Try to find information on current treatments and/or management techniques for each disease.

Looking at the images included, all of them seems to be properly uploaded except for the “Kidney ascent.jpg”. It is missing its copyright information. From what I know, images from textbooks normally can’t be used because of copyright. Other than that, all the images are relevant and function as an aid to understanding what each section is about. In regards of citation and references, everything looks good. Each section was well-researched and properly cited. Great job on organising most of your references at the bottom of the page. The page looks very clean. In summary, focus on getting the historic findings section done and just minor fixes on images. Well done!

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In this review I will attempt to highlight the strengths of your project and identify some areas for improvement, in light of the criteria provided.

I believe the developmental timeline is a great way to summarise the major events at each stage in fetal development and serves as a simple introduction to the project. However I think it would be best if you presented this information in a tabulated format, and perhaps you should include a little more detail for each developmental stage. For instance “Week 8 – Mature kidney is formed” you could also mention some structures features that allow us to recognise that it is a mature kidney (hallmarks of a mature kidney)

I think the current research section delves into a number in interesting areas, mentioning studies investigating treatment options for congenital renal abnormalities. I think another interesting area that you could address is the molecular signalling and gene expression process that drives the underlying differentiation and development of the renal system.

The abnormalities associated with renal development in the feral period have been well researched and the information provided is well structured. However this section seems incomplete. I see a number of additional links to interesting scholarly articles. I think you should discuss some more abnormalities and divide them up into abnormalities arising in the early and late stages of fetal development. I also suggest including images or diagrams to break up the text and make the descriptive text easy to visualise.

There is has been little information added on the historic findings. This is an essential component of the project. I suggest looking at text books in the library or searching the UNSW database to find information for this section.

I really like how you have selected labeled diagrams to compliment and break up the text. Each image is relevant to the topic being discussed and the small description attached really help the reader orient them selves. Overall this project is coming along nicely. Just ensure that you are making progress on all the sections. Also only include relevant references. Finally proof read and review your work before the final submission.

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This is an excellent introduction and gives a great expectation for the information to come later in the project. The current research models section needs to be checked for spelling and grammar. The information here is good but is also very dense and hard to follow. It would be great if you could break it up a bit with bullet points or more images or tables. This style of writing is very professional and would be perfect for a report or essay, however as a wiki page it is too hard to follow. Breaking up the information into bullet point and tables would allow you to guide the reader through a journey of renal system development.

There has clearly been a lot of research and work put into this project and that is very commendable. However on a whole, there is too much information. It’s difficult to read and grasp a wholesome understanding of the renal system when it delves too deep too quickly. One suggestion is giving a more brief explanation of the timeline of nephrogenesis, urethra, ureter and bladder development and then go into more detail in a subheading called “current research findings”. The references under the abnormalities heading should be incorporated at the very end.

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The introduction delivers a conventional scope of the renal system, allowing the audience to understand the structure and function to the parts of this system. Maybe consider uploading a picture that would illustrate the overall information in the introduction.

The developmental timeline is a great idea that outlines the significant events and in turn helps put major events into perspective, making it more effective for students to study and understand. However maybe consider presenting this information in the table format or see if you can get a vertical/horizontal line to represent the timeline. I feel that there is not enough information in the 'Historic findings' and perhaps you could do some more research.

The "Current research" section is very detailed and shows a great amount of research of recent articles that are relevant. The images included in the current research and the abnormalities section is great as it makes reference to the topic spoken about, giving the student a further understanding of the topic. The images are referenced properly except for “Kidney ascent.jpg”, it's missing a reference.

Overall this page is coming along nicely however you need to work on your development timeline formatting it in order to present a systematic presentation as a means to make it more friendly.

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This so far is a really good. You have all obviously done your research as well as you have got a lot of references throughout your page which again is great. The introduction is well done, clear and concise which is good. Maybe think about adding an image to make it a bit more appealing. You will obviously need to add some historic findings, but I’m sure your aware of that. The developmental timeline I think could be improved if you were to tabulate it as other projects have done that and it looks really good and more professional. The referencing is well done as it looks good having all the references down the bottom of the page. There are some references over the page which have just been listed so it may be a good idea to change this so that they are all down the bottom.

You have made a good start on the current research models. Note the buy in the line ‘One recent research paper buy Al-Odat et al.’ should be by. I don’t think you should actually reference the paper in your writing either. You should reference it but do so by using a footnote rather than actually saying the names of the people. The development of the kidney image has not worked so look at the formatting of that image.

On the bigger picture of this project something that I have noticed is that the balance of writing to images is heavily towards the information writing side. So I think it would be good if you were able to tip this balance with a few more pictures as it would make the page more appealing. I think in doing so you could add some student images as this will make the page more interesting, Also spacing your information out as at times when you look at a whole chink of writing you don’t feel like reading it, so I think spacing it out more will help.

Overall though it is a well done project. A few things such as the references that have been just listed on the page that need to go down the bottom, inclusion of some more student images, and tipping the balance of your page more in favor of images would go a long way in making your project even better. But you have done a good job so far and best of luck with the rest of it.

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At the first scroll of this page it already seemed completely sufficiently. The structural layout is done really well and it’s good to see that it’s done according to the advised sub headings. The introduction is really well done, provides a great explanation into renal development, an abundant overview of the whole page and topics that will be addressed. The info for ‘historic findings’ seems to be lacking content, might be useful to search under the “Explore” tab on the left had side of the embryo page, clicking on the sub heading ‘historic embryo’. Also a useful source is the unsw library as it spans a longer period of time and following the unsw search then research the article in the pubmed site. Might be nice to format a proper timeline or use a table. The ‘current research models’ section is done really well with an abundant amount of detail in each study presented and good use of images. The use of a descriptive caption under each image is done proficiently, it is nice to see that each section has incorporated some form of visual whether histological or from research studies. The ‘kidney’ section is structured really well, the use of the content under early development is unnecessarily but is useful in introducing the stage prior to fetal development. Under the’ anatomical position’ sub heading the in text citations need to be adjusted. For references that are not pubmed use this format; <ref> insert source </ref>. Also the image provided will most likely need to be deleted and then drawn, as we are not allowed to use images directly from textbooks. Just re draw the image if you can and then upload it as you would with any other image. Another suggestion for each of the corresponding organs in renal development, try to format some of the content into dot points or tables so not all lengthy paragraphs. Also noticed one of the images doesn’t have a caption this being under the urethra section. Very well detailed info on the abnormalities, would suggest to add a few more to be completely sufficient.

Lastly, the page has been completed to a high standard in the completion of all the info provided and subsequent images among each section. A few things have been noted, and there are only a few minor modifications that will need to be made these includes; referencing and some formatting as mentioned previously. The use of in text citations throughout the whole page is done efficiently, try to just try keep your references under one main heading. There is great effort noted in the research accumulated so far through the long list of references used to gather the info. Fantastic work everyone, keep up the great work !

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The introduction provided by this project is very good and includes in-text citations. Not only does it introduce the renal system’s components but also discusses its development briefly into the embryonic and fetal stages, focusing more on fetal. Also, by having the references as one long list at the very end of the page, this gives the project a clean and tidy look, which some of the others lack. I thought this was a great idea and very orderly.

While some sections are full of information, others are scarce or empty, such as the ‘Historical findings’ section. Some information on the development of knowledge on the renal system throughout history should be included here, maybe making use of dot points detailing specific year dates. The ‘Developmental Timeline’ provides a good overview of the system’s development, although weeks 3-5 may not be necessary as these are during the embryonic period and the focus here is on fetal development. However, it does provide an overall context which is good. This information may also be effectively translated into a table format for easier readability.

The section on ‘current research models’ was nicely written, with solid analysis of 2 research articles. Using any more articles to that level of depth may be too much information, so this is a good balance. It was very good to see the text actually explaining the accompanying image, which was labelled with a caption too. The introduction to the use of animal models and why these are important was effective also.

I particularly thought the sub-sectioning of the page into the main organs of the renal system was a smart idea rather than having the entire system as a clump of information as this way, it is easier to navigate through the information. The ‘kidney’ section was of a very high standard as the information was relevant and nicely split into different processes of fetal development such as nephrogenesis and renin production. It is very helpful as a reader to have explanations of the images used, making the page more interactive and useful. However, this is a file with a ‘Permission error’ present which would need removal due to copyright infringement; this should be sorted out before the project is due.

The following three sections on the urethra, ureter and bladder were also well-written, referenced correctly with in-text citations and the images used were relevant to the text. However, captioning the image in the urethra section would be good to give the reader knowledge of exactly what it shows. The ‘abnormalities’ section was again, well -researched and full of information, however it seems a little cluttered as lengthy references are placed under the text. Integrating these into the overall reference list at the end of the page would look clearer.

Overall, this project has been well done and there is evidence of consistency throughout the section formatting, suggesting the group members have been communicating between each other, which is good to see. Some improvements I would suggest are the use of hand-drawn images to make it easier for a student to learn off the project, and using tables to summarise some information e.g. timeline.

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The introduction is good and describes the project well. It is good to mention the function of renal system. It would be better if it states that the website will be focused on fetal development, current research and abnormalities to give a better understanding of the content.

Information under historic findings is missing, it would be a good way to start it by looking at textbooks. Images, bullet points and table can be used for an easy understanding of this section.

Using timeline to summarise the development of kidney is a good idea, however it would be clearer if a table is used, more descriptions under each stages and some images are include. Also, some references should be included in this section.

There are a lot of details under development, current research and abnormalities. It would be easier to read if they are written in point form. It is a good idea to divide renal system into several parts (kidney, urethra…) for the explanation of development. For the abnormalities, it is well-researched but some of the details are missing. It would be better if the each type of abnormalities is discussed equally.

Regarding the images, it is good and clear to explain each of them. The only problem is that there is no copyright information under the file “kidney ascent.jpg”.

The project is informative but lacking some information under historic findings and the developmental timeline.

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The introduction of Group 2 is very succinct and straight to the point. I believe it could be improved with clear subheadings- such as ‘Bladder’ or ‘Nephrons’ (only a suggestion though!). I believe the group could add what they’re page hopes to achieve (outcomes).

The timeline/develop section of this project could be improved with a better. Add the table before or after the findings of the research paper. I believe with the table, that it could be better described and more information added to it. There is a good choice of headings though, as it has been clearly classified into distinct time points. The scientific research that accompanies this section also has a very good choice of headings/sub-headings. I do believe that this section could, however, be summarised and added to the table format above. There is excellent referencing and strong evidence of significant scientific research.
I believe more recent and varying studies in the “recent research and findings’ section could be included. I also believe this section could be improved with a better layout- with clear, concise headings identifying what these studies found and when.
The historic findings section needs to be addressed/included!

The Abnormalities section is excellent. It is informative, with a good choice of abnormalities and appropriate headings/sub-headings. It has a good choice of images and is correctly referenced.

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The introduction to renal development in the embryonic stages has been written well as it clearly summarises this and conveys to the reader what will be covered below. Furthermore, renal development flows well as the information provided is clear and concise further displaying understanding of the topic. An image could be used that can help summarise the renal development stages in the embryonic period.

====Strengths====

• Introduction written well as it summarises the concepts well.

• Some images have a description such as ‘Glomerula number in Smoke Exposed and Control offspring’.

• Headings are short and to the point.

• Abnormalities section written well with in-text citations and the use of footnotes to good effect.

• Overall structure looks good.

====Weaknesses====

• Some images do not have a description of what the image is showing or an image name. For example, the image in the urethra development section.

• Consistency is not followed to great effect such as some images push the writing to the left side and others to the right side.

• Introduction could be updated indicating that these areas in renal development are covered in detail below as well as for more detailed information to be found in articles that have referenced.

• Some references have been placed under headings in the ureter for example. These references should be put in the end so as to maintain structure and consistency.

• Minimal grammatical errors found.

• Ensure that copyright clearance checked on images as one image has been removed and should be taken note of.

• Tabulated form of the timeline could be used or a good summary image.

• Information should be added to the historic findings heading ( 1700’s and on)

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Introduction is very well-written with a precise background on the renal system anatomy and function. There is also a brief introduction on the development of renal system in both embryonic and fetal period as well as the abnormalities that can be associated with the development of this system. Therefore the reader can gain an expectation of what is going to be included in the wiki-page by reading the introduction first. In-cite referencing is also used to support the information provided. I suggest including an image of the anatomy of organs in the renal system to make the introduction even more perfect.

The developmental timeline is a very good way to start the development section; however your timeline is missing some of the important features such as when the ureter and urethra develop. I would also recommend tabulating the data so that it looks neater. I also recommend placing the “current research models” section after the sections describing the development of different organs so that the timeline is located right before the section explaining the development of “kidney”. Dividing the development into different organs and the subheadings used (especially under the heading of “kidney”) are very appropriate and are evidence of significant research that has been done for this project. The information provided is very comprehensive; however it is all formatted in paragraphs. I would suggest using dot points or adding your own diagrams and figures to summarise the text and make it more interesting to the readers. For example the diagram used to illustrate the anatomical position is very helpful and effectively summarises the information to readers. You should also make sure that you remove the image used for the development of kidney since it cannot be used due to copyright. In addition, most images are missing the ‘student template’ so make sure the template is added.
There isn’t any information under the heading ‘historic findings’. I understand that this section is a bit more difficult than the rest. A suggestion I can make is to search for old articles in PubMed (by adjusting the year) which can include key historical events. Review articles that summarise historic findings related to renal development may also be helpful.

The content under “current research” is very interesting and relevant. A minor spelling error exists (“buy” instead of “by”). To further improve this section, I suggest searching for recent models that aid in better understanding of kidney development. The abnormalities section is very informative. Each disease is explained thoroughly and concisely. The images are also very helpful with the understanding of clinical manifestations. To improve this section, I suggest using dot-points and using more images. Make sure you include information for “Horseshoe Kidney” as well.

Overall, the content used in this project was very relevant and showed extensive research and understanding. The use of headings and subheadings was very appropriate which showed that the work has been well-divided among members. The use of in-cite referencing is also very good and references are all listed under one subheading; however, some references are used more than once, this can be fixed and they can be all combined under one number.

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[[RENAL SYSTEM]]

Introduction
Background
Timeline of development - everyone will research first to get general idea of when,what and how long it will develop. Divide this area up from there.
Development of Actual system - all organs and parts that contribute to it (will be divided up later)
Abnormalities

ACTUAL RESEARCH FIRST, THEN DIVIDE. SEE HOW MUCH INFO AND PARTS THERE IS FIRST

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This page was well done and the introduction gave a clear insight into what the page was going to present. The strong point of this page was the descriptions of the developments the organs of the renal system. There were plenty of images to support the information in this section of your page that complimented the text and made it easier to read. The ‘Current Research’ section was another strong point and made the page really interesting because of the relevance to the rest of the text. I think this section in particular could spark the audience’s interest in this page. There seems to be plenty of references for each section and I think this is another real strong point of your page.

The weak point in terms of information was the ‘Historic Findings’ section. The individual in my group in charge of the ‘Historic Findings’ section found information in ‘Historic Embryo’ tab and if your group is unaware of this resource it may help. The ‘Abnormalities’ section does not yet seem to be completed and I think some of the abnormalities need to text written under their titles and some more images would make this section more interesting.

In terms of the organisation of this page, the strong point is the breaking up of the development into organs. It was a wise mood because it broke the text up into easy to understand segments with a good level of detail. The references still need to be organised particularly in the ‘Abnormalities’ section but I am sure this is something that will be handled during the finishing stages of the project.
Overall, the page has its strong points and there are only some small issues that need to be rectified to make this page perfect.

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They key topics under renal are listed clearly in the contents box. The subsections seem to cover all the relevant topics related to renal. The introduction is useful in that broadly explains what the page is mainly about and gives context. They have also ordered the sections well; introduction, historic findings, developmental timeline… references. Currently there is no information under ‘Historic findings’ and this information will be added I trust. The developmental timeline is good and succinct. However more information could be added to it but it is understood its ok if it doesn’t have much information because the other sections like “Kidney”, “Ureter” and “Urethra” sections cover it in more detail.

The current research model section is good and discusses use of animal models and their use in some current research. The Kidney, Urethra and Ureter development research is extensive with lots of information and some diagrams which is useful in explaining. The diagrams used are useful, in particular the nephrogenesis diagram. It is useful and relevant to what is being discussed. Also the diagram for anatomical position of the Kidney is useful in explaining. It would be hard to clearly convey such a pictorial concept without such a diagram. The MRI diagram of renal agenesis is interesting and useful also in describing renal agenesis abnormality.
One image under the Urethra section doesn’t have a description unlike the other images, it could be added if you think it is necessary.

Throughout the page the content is cited and referenced. There are separate references list for abnormalities which could be added to the main reference list. Multiple reference lists can be collated into one. Also there a number of references under ‘Polycystic Kidney disease’ which if added to main reference list would be good. Also there are some repeats in the main reference list, in particular the paper ‘The number of fetal nephron progenitor cells limits ureteric branching and adult nephron endowment’. This could be fixed by referring to the how to reference page provided; https://embryology.med.unsw.edu.au/embryology/index.php/Help:Reference_Tutorial
Teaching at a peer level was accomplished with the many useful diagrams as mentioned before. More teaching elements could be added to the page, like a video link or tables. These would be helpful in trying to explain development of renal structures.

Your group’s page is really good and if you keep adding more information and fix up the references it would make even better.
Group 2

This group has put appropriate subheadings which follow the learning aim of embryology. Introduction is not to long could cut down on the physiology of the renal system and put more in its anatomical features and its development in fetal stage, also like how they introduced abnormalities in the introduction. There is no historic finding and I would suggest the historic findings being underneath the timeline heading. There is a basic timeline which is good as it helps clearing and understanding the key event occurring at a particular time frame. Good integration of recent finding and model and image was relevant and easy to interpret. Could include a bit more recent research.

The development of each component of the renal system is well structured. Each structure involved in the renal system is clearly shown as a heading. For kidney it is good there is a brief outline of what happens in the embryonic stage as kidney’s and then more detail explanation of development of the different parts of the kidney in the fetal stage. It helps readers to understand the basic start of kidney development to then understand how it grows form there in the fetal stage. Urethra and Bladder is well explained clear and concise, it shows research has been done while Ureter needs more work put into it, it looks incomplete and reader is left unsure of when the event are occurring.

Overall a well orientated project referencing is in correct format there is just some error with the reference under the Ureter heading which needs to be fixed ( have same format as the rest of the group project). Images used were excellent as there was a variety of historic picture, simple drawings and labelled diagrams. They were correctly referenced and labelled helping showing a good understanding of the topic and helping teach readers. For variety could possibly use a table for timeline and maybe video.
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The introduction to this group project is informative and explains the basic components and function of the Renal system. It gives us a nice overview of the whole project .
Historical section needs to have information put it? (maybe tabulated data or a timeline structure?)

Developmental timeline is laid out simply and basic information which is good for the average readers but not so helpful when it comes to someone who has no idea what the words mean (from an outside point of view) maybe even tabulate the data to clean it up a bit and make it look formal as well as putting in diagrams of the different developmental stages of Renal.

The current research model has a interesting article view added however, it just seems like a condensed wall of words, maybe lay out the section in a way to help readers read the text easily? Its really hard to keep track. Interesting diagram used :) Maybe add more current research papers, more citations? (just a suggestion)

The section with the subheadings of kidney, ureter and bladder is extremely well explained with appropriate diagrams included throughout the descriptions! However it would also be better to split up certain parts of the text as, like the current research model section, it is hard to keep up.

Maybe include more Renal abnormalities in your group project, the ones listed are interesting and some have diagrams to follow on with them, but some of them have just the basic information and nothing else. More diagrams and more information on the abnoralities you have put would greatly help in the project structure.

For referencing, the scattered references throughout the project interrupt with the flow of the project, maybe put all the references in a separate subheading at the bottom of the wiki-page to help with looks :)

Overall great work, some touch-ups to structure and visual aesthetics and you should be good :)

==ANNOUNCEMENTS==
http://www.ehd.org/science_main.php?level=a&submit3.x=73&submit3.y=21&s18=on&ops=&re=on&L1=1&L2=0 have a look at this web site, good time line --[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 10:50, 26 August 2014 (EST)

Looks good. There wont be much we can say for all the individual events that occur since all of it is up to the 8th week, but it'll give us a good starting point. We can say 'such and such has been formed during the embryo period' and we can move on from there. I also found the following site which gives a nice intro into the components of the renal system and some general info on each part. Thought we might be able to incorporate a bit of it, talk about what the system/organ does, then follow on how it develops. Use it as a bit of a guide to how we could do our own. http://www.myvmc.com/anatomy/urinary-system-renal-system/ --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 13:48, 24 August 2014 (EST)

https://docs.google.com/viewer?url=http%3A%2F%2Fpediatrics.med.unc.edu%2Feducation%2Fcurrent-residents%2Frotation-information%2Fnephrology%2Ffiles-1%2FNephrogenesis.ppt this web site goes into quite a lot of detail regarding how the renal system develops.

I think in terms of dividing the work:
*1- urine formation (week 11~12) & amniotic sac
*2- kidneys descending from where they developed to adult anatomical positions (week 9)
*3- development of trigone of the bladder and allantois
*4- structures that arise from the Metanephric mesoderm
*5- structures that arise from the Ureteric bud
*6- abnormalities (developmental and genetic)
*7- introduction
*8- timeline of events in development

I've thought of 8 topics we can divide the work into, so lets choose 2 each?
I preferably want to do abnormalities and urine formation (number 1 and 6), is that ok? we need this sorted out for our lab homework thing for this week. please reply asap. --[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 10:50, 26 August 2014 (EST)

On the actual project page when you expand the bit at the top there are 5 bullet point but the first one is just to come up with our title, shall we divide our project into those 4 different headings?:
Review that system development during the fetal period.
Identify current research models and finding.
Identify historic findings.
Identify abnormalities that can occur in this system during the fetal period

Hey guys, i have now gone and updated the page and added sub-headings as suggested by above, please feel free to add or delete anything you seem unfit for the page. As for the online assessment due tomorrow, i agree that 2 each is appropriate although the timeline will be very long and would be unfair if one person to do the whole thing... We should probably divide the timetable based on weeks and then assign who wants to do what. Although i thought we agreed that i would do the abnormalities as discussed in the last lab...? i have already started to do some research on the topic....

Here is a basic summary of some of the development structures in the renal system, as well as their abnormalities
https://web.duke.edu/anatomy/embryology/urogenital/urogenital.html

--[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 16:52, 26 August 2014 (EST)

Ill look at 4 and 5 if that is alright with everyone (structures that arise from the Metanephric mesoderm
and the Ureteric bud), I think we need to also write a bit about Historic findings and current research models
--[[User:Z5030311|Z5030311]] ([[User talk:Z5030311|talk]]) 17:24, 26 August 2014 (EST)

I can do the descending of the kidneys and the development of the bladder (2 and 3) if everyone is fine with that --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 18:39, 26 August 2014 (EST)

Uh I guess that leaves 1 & 8 then, since no one wants to do the timeline xD
It doesnt look too hard so i dont mind doing timeline :)
so whoever only took 1 topic, can you please do the intro as well please?
Also im not 100% on the topics, but it'll have to do for now. add as we go i guess.
--[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 20:26, 26 August 2014 (EST)

yeah no worries, there will most likely be changes to the topics, or at least the headings. It's only set out the way it is now just so we can have a general layout, have some idea what to research. I also dont think we'll end up sticking to the subheading we chose, as there is a lot of stuff that will cross over to other topics.
I think we said that the timeline would be one of the last things we would do yeah? cause after we research all the organs and stuff as it develops, it would be easier to determine when it all develops as well, so we could just stick all that info together at the end. --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 21:04, 26 August 2014 (EST)

--[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 12:53, 27 August 2014 (EST)
*kidney(nephrogenesis0 - Sam
*ureter - Bahar
*urethra & fetal urination - Emily
*bladder - Rachel

*intro - Emily
*historic findings - Emily
*abnormalities - Bahar
*current models - Rachel

*developmental timeline (everyone)

HOW IS EVERYONE GOING WITH THEIR PART????
www.lab.anhb.uwa.edu.au/hsd212/.../KidneyDevelopmentPrint.ppt
--> this powerpoint gives a good general intro to renal development btw if anyone wants to see?

GIRLS
are we going to keep the whole assignment as apa referencing or as harvard? --[[User:Z3463310|Z3463310]] ([[User talk:Z3463310|talk]]) 01:36, 22 September 2014 (EST)

umm i guess APA since thats the actual formal type of referencing. or you can just try and structure it the way its auto generated when you type in pubmed links haha. im gonna try and put some more content up about the kidneys in a couple days and a drawing or two. ill get some historic findings done as well.--[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 21:16, 23 September 2014 (EST)

hey guys, sorry i havent been putting anything up recently. i moved in to my new place over the weekend but the internet isnt up yet so i havent been able to upload anything. i dont know how much longer until its up, so ill be coming to uni just to use the internet (its where i am now lol). so when did the majority of our content have to be up by? was it friday or sunday? i cant remember. --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 12:48, 1 October 2014 (EST)

i found this really good article. it mainly focuses on the kidneys but there are a couple of lines here and there where it mentions some facts about the rest of the renal system. thought u guys might wanna take a look. i dont know whether full access to the article is normal or whether i only managed it because im using the uni library internet, but if u cant access it just let me know and ill send u the article (i downloaded it haha). --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 14:15, 1 October 2014 (EST)
oh i also just found this book, it has A LOT of info about the embryology of the renal system, though half the chapters seem to be focused towards abnormalities and defects of the organs http://books.google.com.au/books?id=IKexq6xCRmIC&pg=PA542&lpg=PA542&dq=rotation+of+fetal+kidney&source=bl&ots=0O-4VfybHS&sig=3VeDlTrB9HnJsdYQLP66IKNGPDU&hl=en&sa=X&ei=1ocrVPuiIoKUoQSyroEQ&ved=0CCoQ6AEwBA#v=onepage&q=rotation%20of%20fetal%20kidney&f=false --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 15:10, 1 October 2014 (EST)

Hey Girls hows the "break" going? :) i was wondering how many abnormalities we should have? 3/4? Also, is it just me or can we not access some of the journals that are free on Pubmed for e.g.
http://www.ncbi.nlm.nih.gov/pubmed/11458035 ?? --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 19:20, 1 October 2014 (EST)

Sorry this is way too late but I think 3/4 abnormalities sound good and for references I have just been doing the automated way of the references --[[User:Z5030311|Z5030311]] ([[User talk:Z5030311|talk]]) 23:07, 7 October 2014 (EST)

Also at the moment I have done 2 research models, do you think that is enough or shall I do another one? --[[User:Z5030311|Z5030311]] ([[User talk:Z5030311|talk]]) 00:01, 8 October 2014 (EST)

----

*Great introduction! Your entire page's contents was introduced well and simple. I'm just wondering if you'd have to include more references to further justify some of the aspects you've mentioned in your explanation of the renal system development
*I noticed the historic findings have been left untouched. This section is in my opinion the trickiest because of the difficulty in finding information out there. My suggestions are to go onto pubmed and use key words like "Renal system development: a historical perspective" and then work from there. You can also adjust years to look at earlier papers from the 1920s and onwards. Also use Mark's historical textbooks on this website as a starting point, it's helpful too to see how ideas in fetal development have changed over the years
*I like how the timeline overview has been simplified. Maybe think of tabulating the findings? You can get the template for doing that off any other group project that has tables by copy and pasting, then just editing in what you need
*I wouldn't add that first like under "Current research models" but if you wanted to do that, maybe think of rewording it. An example could be: "Animal models are ideal to work with when researching renal system development due to their short gestation periods, making the identification of mutations much quicker." Although what you've said about ethics is technically true, the ethics of working with animal models are still lengthy considerations and the fact that our pages are accessed to the public, maybe something like ethics don't need to be mentioned
*Include the years of when the current research findings were discovered. Otherwise, good work on this section. Just proofread over it to fix minor errors
*Great images used throughout
*Maybe think of having some sections more concise rather than wordy by including dot points

----
Ok i found how to reference without repeating the numbered hyperlink!! it'll have subscripts like 12.0, 12.1 ...blah blah instead of repeating them as 12, 13, 14 whatever every time you use the same reference. So the site is: https://embryology.med.unsw.edu.au/embryology/index.php/Help:Reference_Tutorial. You can just write that short command for every other time you use it and itll work, you done need to write that entire command which is awesome --[[User:Z3465654|Z3465654]] ([[User talk:Z3465654|talk]]) 12:34, 15 October 2014 (EST)

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 01:00, 16 October 2014 (EST) OK here is the approval. Please ensure that when you upload images that they have an appropriate descriptive name for the figure.

Your order details and publisher terms and conditions are available by clicking the link below:
http://s100.copyright.com/CustomerAdmin/PLF.jsp?ref=2b4b8918-8fdc-4b91-9826-da8e545e34c8

Order Details
Licensee: Mark A Hill
License Date: Oct 15, 2014
License Number: 3490230833626
Publication: Wiley Interdisciplinary Reviews: Systems Biology and Medicine
Title: Lower urinary tract development and disease
Type Of Use: Website
Total: 0.00 USD

Girls - I've gone ahead and fixed all the references that had double-ups, let me know if there are anymore! :) --[[User:Z3465141|Z3465141]] ([[User talk:Z3465141|talk]]) 06:57, 24 October 2014 (EST)

2014 Group Project 2

2014-10-23T10:52:08Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Trisomy 18 <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T10:33:39Z

Z3465141: /* Ureter */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm
<ref name="PMID17928823"><pubmed>17928823</pubmed></ref>. Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T10:29:58Z

Z3465141: /* Ureter */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T10:27:17Z

Z3465141: /* Ureter */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref> <ref name="PMID17928823"/>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T10:24:27Z

Z3465141: /* Ureter */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T10:21:44Z

Z3465141: /* Ureter */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed> <ref name="PMID17928823"><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T10:14:25Z

Z3465141: /* Renal agenesis */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T10:10:51Z

Z3465141: /* Renal agenesis */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T10:08:40Z

Z3465141: /* Renal agenesis */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation <ref name="PMID17878895"/>.

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T10:03:15Z

Z3465141: /* Polycystic Kidney Disease */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name="PMID11746154"><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T09:59:13Z

Z3465141: /* Polycystic Kidney Disease */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T09:56:04Z

Z3465141: /* Polycystic Kidney Disease */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios
<ref name="PMID11746154"/>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T09:52:10Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID24469670"/>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T09:49:00Z

Z3465141: /* Renal agenesis */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T09:43:29Z

Z3465141: /* Renal agenesis */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth<ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T09:37:38Z

Z3465141: /* Introduction */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules<ref name="PMID21079243"><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T09:13:08Z

Z3465141: /* References */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T09:08:42Z

Z3465141: /* Polycystic Kidney Disease */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T09:05:02Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T09:00:52Z

Z3465141: /* Polycystic Kidney Disease */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"><pubmed>21079243</pubmed></ref><ref name="PMID23169372"><pubmed>23169372</pubmed></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T08:56:23Z

Z3465141: /* Polycystic Kidney Disease */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"/><ref name="PMID23169372"/></ref>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T08:52:00Z

Z3465141: /* Renal agenesis */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"/><ref name="PMID23169372"/>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T04:00:30Z

Z3465141:

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"/><ref name="PMID23169372"/>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>
==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T03:54:36Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"/><ref name="PMID23169372"/>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T03:51:05Z

Z3465141:

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"/><ref name="PMID23169372"/>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

<pubmed>18059107</pubmed>
<pubmed>17593682</pubmed>
<pubmed>10862660</pubmed>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter<ref><pubmed>9017803</pubmed></ref>.

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref>. A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner<ref><pubmed>1013379</pubmed></ref>.

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

==References==
<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

2014 Group Project 2

2014-10-23T03:47:22Z

Z3465141: /* Duplicated Ureter */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"/><ref name="PMID23169372"/>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

<pubmed>18059107</pubmed>
<pubmed>17593682</pubmed>
<pubmed>10862660</pubmed>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney.<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter. <ref><pubmed>9017803</pubmed></ref>

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema. <ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner.<ref><pubmed>1013379</pubmed></ref>

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

==References==
<references/>

2014 Group Project 2

2014-10-23T03:44:13Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"/><ref name="PMID23169372"/>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>
<ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

<pubmed>18059107</pubmed>
<pubmed>17593682</pubmed>
<pubmed>10862660</pubmed>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney.<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter. <ref><pubmed>9017803</pubmed></ref>

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema. <ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner.<ref><pubmed>1013379</pubmed></ref>

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

==References==
<references/>

2014 Group Project 2

2014-10-23T03:40:23Z

Z3465141: /* Duplicated Ureter */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"/><ref name="PMID23169372"/>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

<pubmed>18059107</pubmed>
<pubmed>17593682</pubmed>
<pubmed>10862660</pubmed>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney.<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter. <ref><pubmed>9017803</pubmed></ref>

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema. <ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner.<ref><pubmed>1013379</pubmed></ref>

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

==References==
<references/>

2014 Group Project 2

2014-10-23T03:06:16Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"/><ref name="PMID23169372"/>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis<ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus.

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

<pubmed>18059107</pubmed>
<pubmed>17593682</pubmed>
<pubmed>10862660</pubmed>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney.<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder. <ref> Maria M Rodriguez (2014) Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT): Fetal and Pediatric Pathology, Early Online:1–28, 2014 </ref> Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter. <ref><pubmed>9017803</pubmed></ref>

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema. <ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner.<ref><pubmed>1013379</pubmed></ref>

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

==References==
<references/>

2014 Group Project 2

2014-10-23T03:02:59Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"/><ref name="PMID23169372"/>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis. <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

<pubmed>18059107</pubmed>
<pubmed>17593682</pubmed>
<pubmed>10862660</pubmed>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney.<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder. <ref> Maria M Rodriguez (2014) Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT): Fetal and Pediatric Pathology, Early Online:1–28, 2014 </ref> Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter. <ref><pubmed>9017803</pubmed></ref>

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema. <ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner.<ref><pubmed>1013379</pubmed></ref>

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

==References==
<references/>

2014 Group Project 2

2014-10-23T02:59:04Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"/><ref name="PMID23169372"/>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis. <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus

Horseshoe kidney is typically associated with other congenital defects, including:

- Turners syndrome
- Duplicated ureter
- Wilms tumor
- Increased risk of UTI’s
- Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

<pubmed>18059107</pubmed>
<pubmed>17593682</pubmed>
<pubmed>10862660</pubmed>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney.<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder. <ref> Maria M Rodriguez (2014) Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT): Fetal and Pediatric Pathology, Early Online:1–28, 2014 </ref> Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter. <ref><pubmed>9017803</pubmed></ref>

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema. <ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner.<ref><pubmed>1013379</pubmed></ref>

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

==References==
<references/>

2014 Group Project 2

2014-10-23T02:57:09Z

Z3465141: /* Horseshoe Kidney */

{{ANAT2341Project2014header}}
=Renal=

==Introduction==

The renal system's main function is the production, storage and elimination of urine, and to maintain the balance of chemicals and water of the body. Kidneys are the primary organ of the renal system, and consist of smaller units known as nephrons - which filter the blood to remove urea and other wastes, and reabsorb or excrete excess water according to the needs of the body as directed by hormones released by the pituitary glands. Nephrons are made up of glomeruli to filter the blood, tubules to reabsorb any solutes or fluids, and more tubule networks to carry the urine to the bladder and outside the body. Small amounts of urine is released from the kidneys every 1 ~ 15 seconds into the ureter, which carry the urine to the bladder.<ref>Kim Ann Zimmermann (2013). “Urinary System: Facts, Functions & Diseases” Feb 11 2013 </ref> The bladder is a hollow organ which has the ability to change its epithelium according to how full the bladder is of urine. "The bladder's walls relax and expand to store urine, and contract and flatten to empty urine through the urethra. The typical healthy adult bladder can store up to two cups of urine for two to five hours.”<ref> Stanford (2014). “Anatomy of the urinary system” </ref> Two sphincter muscles are present at the base of the bladder, and two more at the end of the urethra (internal & external) to voluntarily control the excretion of urine.

Development of these components begin during the embryonic phase, and continue to develop and mature throughout the fetal stages. During the fetal stages, some abnormalities may form. During the embryonic period and fetal periods, the mother's placenta work to remove wastes from the fetus.

Abnormalities may arise during the embryonic and fetal stages of development of the renal system, such as Hereditary renal adysplasia, or polycystic kidney disease. Hereditary renal adysplasia is an inherited condition, where there is malformations in organs derived of the embryonic mesoderm <ref name="PMID20388228"><pubmed>20388228</pubmed></ref>. Polycystic kidney disease is a fairly common genetic disorder in which fluid-filled cysts displace normal renal tubules <ref name=”PMID21079243”><pubmed>21079243</pubmed></ref>.

==Historic findings==
{| class="wikitable"
|- align="center" bgcolor="DDCEF2"
|'''Year''' || '''Achievement'''
|}

[http://www.sciencedirect.com/science/article/pii/S0022347643802262 glomerular development in the kidney as an index of fetal maturity 1943]
[http://www.sciencedirect.com/science/article/pii/S0022347662801036 Studies of the human fetal kidney 1: I. Development of the glomerulus 1962]
[http://link.springer.com/article/10.1007/BF00301876 The ultrastructural development of distal nephron segments in the human fetal kidney 1982]

@SAM: we can maybe use these articles? I can't find the full article for the first 2, but the abstract should be able to give us enough info as to what / how much was known about fetal kidney development in 1943, 1962, 1982 respectively.

==Developmental Timeline==

{| class="wikitable"
|-bgcolor="#9ACD32" align="centre"
|'''Week''' || '''Development'''
|-bgcolor="#F0FFF0"
| 3 || Nephrogenesis begins, pronephri formation
|-bgcolor="#F0FFF0"
| 4 || Embryonic development of ureter begins from the ureteric bud
|-bgcolor="#F0FFF0"
| 5 || Examplemetanephros formation
|-bgcolor="#F0FFF0"
| 8 || Mature kidney is formed
|-bgcolor="#F0FFF0"
| 9 || Urethral sphincter complex histologically identifiable within the urogenital sinus
|-bgcolor="#F0FFF0"
| 10 || Kidneys begin to produce urine
|-bgcolor="#F0FFF0"
| 11-12 || Degeneration of the mesonephri
|-bgcolor="#F0FFF0"
| 15 || Allantois regresses and becomes known as the urachus. Vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus.
Inner layer of smooth muscle fibres and outer layer of striated muscle layers of urethral sphincter complex developed
|-bgcolor="#F0FFF0"
| 36 || Nephrogenesis is complete, however can occur as early as week 32
|-bgcolor="#F0FFF0"
| Postnatal || Maturation of neonatal glomerular filtration
|}

==Current research models==

Animals are good models to use when researching the development of the renal system as there are fewer ethical issues surrounding animals compared with humans and their generation time is much shorter so mutations can be identified much faster.

[[File:Glomerular_number_in_Smoke_Exposed_offspring.png|300px|thumb|left|Glomerular number in Smoke Exposed and Control offspring]]
One recent research paper buy Al-Odat et al. used mice in order to determine the impact of maternal cigarette smoke exposure on the development of the renal system, in particular kidneys. It was proposed that smoke exposure would lead to a change in the expression of growth and transcription factors which would lead to kidney disease later on in life. The experiment found that some fibroblast growth factors were up-regulated whilst others were down-regulated and this led to delayed nephron development and fewer nephrons present at birth.
As you can see in the image on the left glomerular numbers in the control offspring are higher compared with smoke exposed offspring at birth, early postnatal period and adulthood; in addition the glomerular in the smoke exposed offspring are not mature and are not fully vascularised. The lack of numbers and vascularisation of the glomerular lead to fewer and less developed nephrons.
By using an animal model the study showed that cigarette smoke exposure during pregnancy and lactation period leads to underdeveloped renal system which can result in chronic kidney disorders in adulthood. <ref name=”PMID25058584”><pubmed>25058584</pubmed></ref>

Pringle et al. carried out a study and used lambs as their model in order to look at the affects and possible cures for Lower Urinary Tract Obstruction. Lower Urinary Tract Obstruction affects many newborns and is one of the most common causes of renal failure in young children; therefore it is important to find a way to prevent the damages to the renal system caused by the obstruction.
A bladder obstruction was created in the lambs; this was done by ligating the urachus, 3 or 4 weeks after the obstruction was created shunts were put into the lambs so that the urine was able to bypass the obstruction; two different shunts were created, one had a valve and the other did not.
The results found that the shunt without a valve resulted in the lamb foetus having a small, shrunken and thick-walled had poor function whereas the lambs with a valve shunt had a much better bladder function which was similar to the bladder without the shunt. This shows that the cycle of filling and emptying the bladder with urine during foetal development is very important for the formation of the bladder.<ref name=”PMID24013366”><pubmed>24013366</pubmed></ref>

==Kidney==
[[File:Mouse Kidney Development Cartoon.jpg|250px|thumb|The development of a mouse kidney from epithelial origin to fully formed. Although the timeframe is much shorter compared to a human, the same process of development applies.|left]]
===Early Development===
The kidneys first develop in the embryo by a process called nephrogenesis, in which self-renewing mesenchymal renal stem cells produce nephrons, the main functional unit, and form a simple embryonic kidney called the pronephros <ref name="PMID24855634"><pubmed>24855634</pubmed></ref>. This process of nephron formation is stimulated by the signaling between the ureteric buds and these stem cells, named progenitor cells and located at the tips of the ureteric buds, causing nephrons to develop and the ureteric buds to branch <ref name="PMID24656820"><pubmed>24656820</pubmed></ref>.

When sufficient development has occurred during week 3 of gestation, two pronephri are produced and nephrotomes, a series of tubules, begin to fuse together with the pronepheric duct. As the pronephri continue to develop, they elongate and induce the nearby mesoderm to form mesonephri, and the pronepheric duct to become the mesonephric (Woffian) duct. Towards the bottom of this duct, close to where it connects to the cloaca, is the ureteric bud connected by the ureter. Surrounding this bud is a mass of metanephric mesoderm (blastema), the two of which react together to form the metanephros which goes on to form the mature kidney. The cells of the ureteric bud differentiate to form the major and minor calyces as well as the collecting tubules, while the cells of the metanephrogenic blastema develop into the renal tubules and glomeruli. This process begins from as early as week 3 and continues until week 8 of gestation. The development of the nephrons however, continue through to week 32-36 of gestation.<ref name="PMID25088264"><pubmed>25088264</pubmed></ref>

===Fetal Development===
There are a number of factors that occur in regards to the kidneys during the fetal period of development, the most important of which is the continued generation of nephrons. There are specific genes expressed for the continued nephrogenesis, with vasculature created to supply the newly formed kidneys. There are certain events that occur for the kidneys to achieve their correct anatomical position before they are fully formed, as well as further maturation of the glomeruli post-natally before the kidneys are fully functional.

'''Nephrogenesis''' [[File:Nephron Maturation.jpg|250px|thumb| (A) The mesenchymal cells interact with the ureteric bud, causing branching of this structure to occur (B). Renal vesicles are also formed at these branch points which then fuse to the ureteric stalk (C), creating S-shaped bodies. (D) Glomerular development occurs as this structure continues to develop, forming a nephron.]]

The formation of nephrons continues well after the embryonic period in concert with the branching of the ureteric bud <ref name="PMID24656820"/>, ending between week 32-36 of gestation <ref name="PMID24488483"><pubmed>24488483</pubmed></ref>. It is during this period that the self-renewing process of the progenitor cells ceases and they differentiate into nephrons for the final time he ureteric bud <ref name="PMID24656820"/>. The process of nephron formation is shown in the first diagram to the right <ref name="PMID24011574"><pubmed>24011574</pubmed></ref>.
Although nephrogenesis is terminated by week 36, the resulting kidney is not yet fully functional. At birth, although the infant’s kidneys are developed enough to maintain homeostasis and are sufficient for growth and development, their functional capabilities are decreased. This is a result of the transition from depending on the placenta to maintain homeostasis of fluid and electrolyte balance while in-utero, to maturation of the neonatal glomeruli once born <ref name="PMID24781774"><pubmed>24781774</pubmed></ref>. This maturation phase due to postnatal adaption to extrauterine life occurs during early infancy <ref name"PMID24623338"><pubmed>24623338</pubmed></ref>.

While it is not well known the mechanisms by which nephron number is determined, the causes of several disorders and diseases, such as renal disease and hypertension, have been attributed to a low nephron count <ref name="PMID24656820"/>. It has been determined that a decrease in the number of progenitor cells, a possible result of genetic abnormalities, toxic insults, and nutritional deficiencies <ref name="PMID24488483"/>, can result in fewer branching of the ureteric buds, leading to impaired kidney growth <ref name="PMID24656820"/>. Therefore, nephron number is important as it can show the success/extent of nephrogenesis, and thus be used to determine if any and what genes and environmental factors may aid this process <ref name="PMID24022365"><pubmed>24022365</pubmed></ref>.

'''Genes'''

While there are many genes and transcription factors that regulate the formation of early kidney development, the main factor that continues to be expressed as the fetal kidney develops is the Gremlin gene. The gene, coded GREM1, has been found to play a key role in the formation of the kidneys and nephrogenesis in general. When the kidney is fully formed, the expression of this gene is relatively low in an adult. However, it is thought that many renal diseases and their progressions are linked to an overexpression of this gremlin gene <ref name="PMID25036148"><pubmed>25036148</pubmed></ref>.
[[Image:The kidney of a FA-injected mouse compared to a wildtype mouse.jpg|250px|thumb| The morphology of the kidney when Gremlin is expressed at normal levels (left), compared to when the gene is over-expressed (right).]]

'''Anatomical Position'''

The kidneys initially begin to develop proximally to the pelvis, located at the level of the upper sacral segments. In order to attain the correct anatomical position, as the fetus develops, they continuously become more cranial in position until they reach the dorsal sides of the body at around the T12~L3 levels. This process is usually completed by week 9 of fetal development and occurs as a result of the kidneys coming into contact with the supra-adrenal glands, as well as due to the growth of the embryo’s body and abdominal cavity. These organs are medially rotated by up to ninety degrees during their ‘ascension’, so that the renal pelvis will lie on their medial aspect (Keeling & Khong, 2007; Moore, 2011).

During the entire process of anatomical positioning, the kidneys receive a bloody supply from arteries branching off at various points of the abdominal aorta. While they are initially vascularized by the lateral sacral branches of the aorta, during the ascent, they continue to receive blood at progressively higher levels. When the kidneys have achieved their correct position, they are supplied by the renal artery at the level of the 2nd lumbar vertebrae. The simultaneous rise of the vasculature helps to contribute to the ascending of the fetal kidneys (Keeling & Khong, 2007).

[[Image:Ascension of the Kidneys.jpg|500px|thumb|A hand drawn image of the ascension of the kidney.|left]]

Keeling, J.W. & Khong, T.Y. (2007). The Urinary System, Fetal and Neonatal Pathology. London: Springer. 4th Ed, pp. 623

Moore: the developing human 9th edition. Saunders 2011. An imprint of Elsevier

'''Renin Production'''

While the kidneys develop, particularly the tubules, the production of renin can be found within these areas. As the tubular activity increases and this component proliferates in number and size, it is noted that growth is proportional to the amount of renin produced; as growth and functional state of the tubules increase, so does the concentration of renin created <ref name="PMID19871238"><pubmed>19871238</pubmed></ref>.

==Urethra==

The urethra is a structure that allows for excretion of urine, and presents as a tube from the urinary bladder to the external urethral orifice. The urethra originally develops from the cloaca during fetal development. The cloaca can be divided into the anorectal canal (dorsally) and the urogential sinus (ventrally). The bladder develops from the superior portion of this urogenital sinus (endoderm), and the inferior portion develops into the urethra. The endoderm of the urogenital sinus derives the urethral epithelium, and the splanchnic mesenchyme develop into the connective tissue and smooth muscle components of the urethra.<ref>Schoenwolf: Larsen's human embryology, 4th ed. chapter 15</ref> [[image:Cartoon of female urethra and bladder.jpg|thumb|Diagram of female urethra and bladder anatomy]]

The anterior part of the urogenital sinus (develops into the bladder) has an opening at the apex which is connected to the allantois during fetal development. The function of this opening at the apex of the fetal bladder is to drain the developing bladder to the allantois via the umbilical cord. At around week 15 of fetal life, the allantois regresses and becomes known as the urachus; at which time the vesicourethral canal develops into the pelvic segment of the urethra in the male fetus, and the entire urethra in the female fetus. The remaining parts of the urogenital sinus (posterior portion) "later develops into the phallic urethra in the male and the lower portion of the vagina and vaginal vestibule with perineal urethra orifice in the female." (Hila Milo Rasouly, Weining Lu. 2013)<ref name="PMID23408557"><pubmed>23408557</pubmed></ref>

The urethral sphincter complex is important in controlling urination frequency and timing, and is histologically identifiable within the urogenital sinus from week 9 of development as a mesenchymal condensation after the cloacal division. It develops into an inner layer of smooth muscle fibres and outer layer of striated muscle layers by week 15 of development, which further develop into an omega shaped muscle apparatus surrounding the urethra. The urethral sphincter complex muscles are innervated by autonomic and somatic nervous systems, and correct development of the muscle nerve innervation and the urethral sphincters are essential in the maintenance of normal urinary continence post natally <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.
External urethral sphincters are thought to develop within week 10 of development. <ref>Ludwikowski B, Oesch Hayward I, Brenner E, Fritsch H. The development of the external urethral sphincter in humans. BJU Int. 2001 Apr;87(6):565-8.</ref>

==Ureter==
[[File:Ureter.jpg|600px|thumb|Renal System Development]]
The ureter is a muscular tube structure responsible for the transportation of urine produced in the kidney to the bladder. The development of the ureter typically begins during week 4 of gestation in infants. The process begins from the ureteric bud, which arises from the caudal region of the mesonephric ducts (also known as Wolffian ducts) that run along the edge of the intermediate mesoderm<ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.Following the migration of the ureteric bud into the metanephric mesenchyme the reciprocal interaction that occur between the tip of the ureteric bud and the metanephric mesenchyme results in the ureteric bud branching morphogenesis for the formation of the renal collecting system <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>. This occurs simultaneously with the elongation of the trunk of the ureteric bud, the portion remaining outside of the metanephric mesenchyme, forming the ureter <ref name=”PMID23123402”><pubmed>23123402</pubmed></ref><ref name=”PMID17928823”><pubmed>17928823</pubmed></ref>.

By week 10, the differentiation of the ureter lining occurs in response to the molecular signals from the ureteral epithelial and mesenchymal cells. This then initiates differentiation of the early simple cuboidal ureteral epithelial cells to form the multilayered urothelium. The urothelium is covered by urothelial plaquesm that express uroplakin proteins and is impermeable to urine. Concurrently, the stromal cells, smooth muscle cells and the adventitial fibroblasts (which are later maturated to form the serosa) all give rise from the differentiated mesenchymal cells <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

The smooth muscle cells go on to be futher arranged into layers with inner circular and outer longitudinal orientation and are characterized with strong expression of α-smooth muscle actin. Together, the mechanism involved give rise to the four layers of lining present in the mature ureter; urothelium, stromal cells, smooth muscle cells, and adventitial fibroblasts <ref name="PMID23408557"><pubmed>23408557</pubmed></ref>.

==Bladder==

[[File:Urinary_Bladder_Histology.jpg|400px|thumb|left|The histology of the urinary bladder showing the different cell layers]]

The role of the urinary balder in the renal system is to store urine produced by the kidneys before it is excreted via the urethra <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>. A flexible epithelium is essential for the bladder as it changes volume by contracting and relaxing depending on the volume of urine in the body.
A fusion event occurs between the common urogenital sinus and the mesonephric duct, this divides the rectal components from the urine components and it allows the bladder to develop.

The urinary bladder develops in the first 12 weeks of gestation from the urogenital sinus and the surrounding splanchnic mesenchyme, these development events are controlled by complex epithelial–mesenchymal signals. The vesical part of the urogenital sinus is attached to the allantois and goes on to form the bladder <ref name="PMID23371862"><pubmed>23371862</pubmed></ref>. The lamina propria, the muscle coat and the adventitia all develop from the splanchmic mesoderm whilst the epithelial lining is derived from the endoderm of the urogenital sinus <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

Initially the epithelium lining of the urinary bladder is made from two distinct cell layers, the superficial layer and the basal layer. Up to week 11 the rest of the balder wall consists of mesenchyme that gradually matures into lose connective tissue. At the 13th week collagen begins to appear, by the 14th week it is abundant in the lamina propria and by week 15 it has extended into the superficial muscle bundles. Smooth muscle cells begin to appear in the connective tissue during week 12, they initially appear in the proximal part of the organ but they spread distally over time. At 21 weeks the epithelium is 3-4 layers thick, the superficial layer, the intermediate layer, lamina propria and the basal lamina. This epithelium is specialised and contains features that are characteristic of urothelial differentiation so that urine is unable to pass through the bladder wall <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

The muscular coat of the bladder does not develop until after the kidneys have begun to produce urine this is not a problem for the embryo as urine is released directly into the amniotic cavity <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>. The muscles in the bladder however are very important for normal urine output once the foetus have been delivered; as development continues the walls of the bladder muscle thicken and there is a decrease in collagen content, this increases the compliance of the bladder <ref name="PMID2621133"><pubmed>2621133</pubmed></ref>.

During development the bladder only produces immature reflexes rather than the voluntary bladder control that is only seen once the infant is toilet trained. It is suggested that the switch between involuntary reflexes and voluntary contractions is due to the development of the central and peripheral neural pathways that control the contraction of the bladder <ref name="PMID22535797"><pubmed>22535797</pubmed></ref>.It also could be due to the increasing number of nerves in the detrusor muscle during foetal development, this would lead to an increase control over the bladder wall due to the increase in nerves present <ref name="PMID3627353"><pubmed>3627353</pubmed></ref>.

==Abnormalities==
[[File:MRI_renal_agenesis_.jpg|200px|thumb|MRI showing renal agenesis]]
===Renal agenesis===

Renal agenesis is a congenital abnormality referring to the failure of the development of the kidneys and ureter produced by a lack of interaction between the ureteric bud and the metanephric mesenchyme. Renal agenesis can occur in two forms, infants can be born with either bilateral or unilateral renal agenesis. Infants born with bilateral renal agenesis are incompatible with life and are born usually stillborn, or die within a few days after birth <ref name=”PMID23169372”><pubmed>23169372</pubmed></ref>. Unilateral renal agenesis has a frequency of 1 in 5,000 newborns, in contrast to bilateral renal agenesis the rarer of the two, occurring in 1 in 30,000 infants <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>.

Induction of the ureteric bud from the nephric duct is mediated by glia cell-derived neurotrophic factor (GDNF), which is secreted by the metanephric mesenchyme and interacts with the tyrosine kinase c-Ret receptor expressed in the ureteric bud in order to induce branching of the nephric duct <ref name="PMID23169372"/>. In animal models, renal agenesis is linked to signalling failures failure of the GDNF–RET signalling <ref name=”PMID18252215”><pubmed>18252215</pubmed></ref>. A complex molecular network that includes regulation by EYA1, the sine oculis homeobox homologues SIX1 and SIX4, and PAX2, controls the activation of GDNF in the metanephric mesenchyme. In addition, members of the HOX11 paralogous genes13 and the signalling molecule growth and differentiation factor 11 (GDF11) 14 are required for GDNF signals that are derived from sources other than the metanephric mesenchyme (for example, the developing gut) are not interpreted in more rostral parts of the embryo. Although Mutations in GDNF or RET have yet to be linked with mutations in patients with kidney defects such as renal agenesis. A possible explanation for this could be because human kidney development is not susceptible to the slight reduction in protein level that results from heterozygous inactivation. <ref name=”PMID17878895”><pubmed>17878895</pubmed></ref>

Renal agenesis is typically associated with other congenital defects, including:
* Oligohydraminos
* Facial abnormalities including: wide set eyes, a recessed chin and low-set ears

===Polycystic Kidney Disease===
[[File:PKD.jpg|400px|thumb|Cyst formation at the level of the cell, nephron, and kidney]]

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the formation of fluid filled cysts in the kidneys, which displace normal renal tubules. There are two types of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

PKD affects approximately 1 in 1000 individuals, with ADPKD accounting for the majority of the cases reported <ref name="PMID21079243"/><ref name="PMID23169372"/>. ADPKD, also known as adult-onset polycystic kidney disease is commonly reported to present in adulthood in association with hypertension and renal failure <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>. The disease is linked to the mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis <ref name="PMID21079243"/>. These mutations ultimately affect multiple signaling pathways, which cause aberrant gene transcription, cell proliferation, and ion secretion, which in turn result in the formation of benign fluid-filled cysts. As cysts balloon out from individual nephrons, their collective effect leads to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity <ref name="PMID21079243"/>. In ADPKD, the growth of renal cysts produces a progressive increase in renal volume and destruction of the parenchyma, leading to terminal chronic renal failure in adulthood <ref name="PMID23169372"/>.

ARPKD, however is the rarer form of PKD, affecting approximately 15% of cases or 1 in 20'000-40'000 live births <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. It commonly presents during the second or third trimester of fetal development. Ultrasound images show kidneys that are usually 'bright' or echogenic and are often associated with progressive oligohydramnios <ref name=”PMID11746154”><pubmed>11746154</pubmed></ref>.

===Horseshoe Kidney===
Horseshoe kidney is a common congenital abnormality causing a fusion of the kidneys. The abnormality occurs when the poles of the lower kidney fuse, and the kidneys develop into one structure, forming an L or U shape, instead of the distinct two separate structures <ref name="PMID18059107"><pubmed>18059107</pubmed></ref> <ref name="PMID25313840"><pubmed>25313840</pubmed></ref>. Horseshoe kidney is the most common abnormality associated with fusion, occurring in 1 in 400 infants, with males being twice as likely to develop the disease <ref name="PMID24469670"><pubmed>24469670</pubmed></ref> <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

Horseshoe kidneys are commonly positioned lower than normal kidneys, being located at the lower lumber vertebrae in between L3-L5, in front of the aorta and inferior venae cavae, and posterior to the inferior mesenteric artery, which usually crosses the isthmus. This is caused by the inferior mesenteric artery, as it prevents the ascent of the kidneys to its normal anatomical position, and it thus trapped in the midabdomen.

There are typically two main theories outlining the cause of this disease. The first theory suggests that while the kidneys have not yet begun their decent during week 4 of gestation (the metanephric stage), and are still located in the pelvis, the two inferior poles come into contact and thus fusion occurs in the midline, resulting in the formation of a horseshoe kidney, with a fibrous isthmus. As the kidneys are still yet to form a renal capsule, the fusion of the kidneys is also accompanying with the fusion of the nephrogenic blastemas, which is caused by abnormal growth of the spine and organs in the pelvis. <ref name="PMID 24178305"><pubmed>24178305</pubmed></ref>.

The fusion is also suggested to be associated with the malrotation. Kidney rotation normally occurs during week 7 and 8 of gestation, as the kidneys migrate from the pelvis and rotate medially. However, in horseshoe kidneys, the inferior mesenteric artery blocks the isthmus and the kidneys fail to ascend and remain at a lower positioning <ref name="PMID25313840"><pubmed>25313840</pubmed></ref><ref name="PMID24178305"><pubmed>24178305</pubmed></ref>.

The second theory proposes that the abnormality is caused by a teratogenic event, and that the abnormality is caused by an abnormal migration of posterior nephrogenic cells that later form the parenchymal isthmus

Horseshoe kidney is typically associated with other congenital defects, including:

* Turners syndrome
* Duplicated ureter
* Wilms tumor
* Increased risk of UTI’s
* Narrow pelvis <ref name="PMID 24469670"><pubmed> 24469670</pubmed></ref>

<pubmed>18059107</pubmed>
<pubmed>17593682</pubmed>
<pubmed>10862660</pubmed>

===Duplicated Ureter===
[[File:Duplicated_ureter_.jpg|400px|thumb|Duplicated Ureter]]

Duplicated ureters are the most common renal abnormality, estimated to occur in 1% of the total population, and is found to be more common in females and is a condition in which more than one ureter drains one kidney.<ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> Ureteral duplications can be complete - in which the individual has two ureters from one kidney entering the bladder, or be incomplete, where there are two separate ureters leaving the one kidney that fuse into one tube before entering the bladder. <ref> Maria M Rodriguez (2014) Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT): Fetal and Pediatric Pathology, Early Online:1–28, 2014 </ref> Incomplete duplicated ureters often have no clinical significance other than a higher risk for urinary tract infections (UTI), however, completely duplicated ureters can present with some complications such as one of the ureters joining to the vagina or urethra instead of the bladder or to its complimentary duplicated ureter. <ref><pubmed>9017803</pubmed></ref>

The development of the ureter begins at around 4 weeks into gestation when the uteral bud branches from the Wolffian duct to extend into the nephrogenic blastema. <ref> J. Gatti, J. Murphy, J. Williams, H. Koo (2013) emedicine overview, Ureteral Duplication, Ureteral Ectopia, and Ureterocele </ref> A study carried out on 30 children with duplicated ureters by Atwell et al. (1976) showed that 66% of children with an ureteral duplication had first degree relatives with either a complete or incompletely duplicated ureter, leading to the conclusion the defect is inherited in an autosomal dominant manner.<ref><pubmed>1013379</pubmed></ref>

<pubmed>24469670</pubmed>
<pubmed>25010444</pubmed>
<pubmed>16407023</pubmed>

<references/>

===References===
<pubmed>18631884</pubmed>
<pubmed>20807610</pubmed>
<pubmed>20388228</pubmed>
<pubmed>11746154</pubmed>
<pubmed>25036148</pubmed>

The overexpression of the gremlin gene (GREM1) has been found to be a cause of renal disease.

<pubmed>24500691</pubmed>

==References==
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