2017 Group Project 2
|2017 Student Projects|
- 1 Kidney
- 2 Kidney development
- 3 Developmental abnormalities
- 4 Animal Models
- 5 Current Research
- 6 General info on the renal system
- 7 Glossary of terms
- 8 References
The kidneys are two bean-shaped organs located in the abdomen that play an important role in the renal system (also known as the urinary system). They arise from the intermediate mesoderm and begin their development (nephrogenesis) in week 4 of gestation which is usually completed in week 36.
Postnatally, the kidneys will continue to mature and are responsible for the filtration of blood and subsequent reabsorption of water and other nutrients according to what the body needs. Filtration is carried out in a special compartment called the nephron and in humans, the number of nephrons in each kidney ranges from 200,000 to 2.5 million.
It is quite common to experience developmental abnormalities relating to the kidneys, with about 1 in 500 babies being born with kidney defects.  The reason as to why this occurs is not known. However, research is currently being conducted to see whether nephron number has an impact. Also, there is ongoing research being conducted into possible stem cell therapies.
Unlike other abdominal organs, kidneys lie retroperitoneally in the abdomen, on either side of the vertebral column. They are typical located between the transverse processes from T12 to L3 of the vertebrae, however the right kidney sits slightly more superior due to the large size of the liver.
The kidneys have external coverings which involves complex layers of fascia and fat. From deep to superficial, the layers are as follows:
Renal capsule – Tough fibrous capsule
Perirenal fat – Collection of extra peritoneal fat
Renal fascia – Encloses the kidneys and the suprarenal glands
Pararenal fat – Mainly located on the posterolateral aspect of the kidney.
Their inner structure can be divided into 2 main areas: the outer cortex, and the inner medulla. The extension of the cortex into the medulla gives rise to renal pyramids, with the apex known as renal papilla. Each renal papilla is associated with structures known as minor calyx, which collects urine from the pyramids. Several minor calyces join to form a major calyx, where urine passes before it reaches the renal pelvis and into the ureter.
Kidney development (nephrogenesis) in humans begins in week 4 and commonly ends in week 36 of gestation. This is a brief timeline of the developmental processes.
|4 (early)||Pronephros begins (first stage of nephrogenesis)|
|4 (late)||Mesonephros begins (second stage of nephrogenesis)|
|5||Metanephros begins (third last stage of nephrogenesis)
Development of renal vasculature begins
|6||Ascension of kidneys from pelvis area begins|
|8||Functional kidney is formed. First nephrons are formed, a process that continues until week 36|
|9||Kidneys complete their ascension and now sit just below the adrenal glands|
|10||Kidneys now ready to perform filtration|
|15||Renal vasculature development is completed|
|36||Nephrogenesis completed. No more nephrons formed from this point on.|
|Postnatal||Kidney and its structures continue to mature.|
Development of the kidney is called nephrogenesis and it arises from the intermediate mesoderm in the metanephric blastema. Here are the three main stages of nephrogenesis which begins in week 4 of gestation and ends in week 36. It must be noted that whilst nephrogenesis does not continue beyond week 36, maturation of the kidney and its functional units does continue.
Nephrogenesis involves two transitory stages, pronephros and mesonephros, which end in a final stage (metanephros) giving us the final product of a functional kidney. It is not to say that kidney is ready and functional once metanephros is reached, but rather, it has reached the stage where its structures are set and can continue to mature into a proper functional kidney that can sustain life.
The earliest nephric stage in humans (week 4), arising from the intermediate mesoderm near the pharyngeal arches and extend from the 4th to the 14th somites and consists of 6-10 pairs of tubules. These spill into a pair (a 'pair' because there are two kidneys) of primary ducts (nephric or mesonephric duct) that are formed at the same level and go on to extend caudally. The pronephros is a transient structure that disappears completely by the 4th week of human embryonic life, its degradation can be seen in the diagram.
This stage sees the continuation of the nephric duct caudally, with mesonephric tubules arising laterally from it. Together, these structures are known as the mesonephros and whilst still a transient structure, it has important excretory functions during early embryonic life (4—8 weeks). Gradually the top two thirds of the mesonephros go onto form the genitals, however the last third continues to form the functional kidney. This part of the mesonephros that goes on to form the kidney is known as the nephrogenic chord which is essentially mesenchymal tissue.
Towards the end of week 4 of development, the nephrogenic chord starts to move away from the nephric duct as seen in the diagram, whilst the nephric duct continues to grow caudally. NOTE: It is important to understand that the nephrogenic chord and nephrogenic duct are two different things. See Figure 3.
At the fifth week of development, a lateral projection called the ureteric bud develops from the nephric duct whilst the nephrogenic chord has now detached itself from the nephric duct to form the metanephric blastema, which has been described as a cloud of mesenchymal cells . After receiving relevant signalling, the metanephric blastema and ureteric bud interact by way of the blastema 'clouding around' the bud. This cloud takes the traditional kidney-bean shape and just gets bigger as time goes on.
Inside the metanephric blastema, the ureteric bud bifurcates to form the calyces, pelvis, ureter and collecting tubules of the kidney, where as blastema's mesenchymal cells go on to form numerous vesicles which develop into glomeruli and Bowman's capsules. Their interaction allows for the formation of the nephron. However, as general overview, the ureteric bud differentiates to create the renal tubule section of the kidney (reabsorption compartment of kidney), while the metanephric blastema's mesenchymal cells differentiate to create the renal corpuscle section (filtration compartment).
The permanent and functional kidney is now ready at week 8. Nephrons are still being made until approximately week 36 as they are incredibly important for life and therefore, there needs to be a lot of them.
In a mature kidney, nephrons function as a complex epithelial network of blood filtration units which work to remove nitrogenous waste metabolites and regulate homeostasis of water and electrolytes in the body. Mammalian nephrons are generated exclusively during late embryonic and early postnatal development, with very limited cell turnover as opposed to intestine, stomach and skin epithelia which constantly renew throughout and individual's lifetime.  Although damaged nephrons are capable of regeneration, extremely damaged nephrons are lost and can not be replaced.
In the kidney, epithelial tubules develop from cell types of distinct embryonic origins using different cellular mechanisms (Little et al., 2010). Both the mesonephric blastema and ureteric bud contribute to the formation of the nephron and its two main units, the glomerulus and Bowman's capsule. The ureteric bud forms as an outgrowth of a pre-existing tubule and undergoes many rounds of branching to form the renal collecting system 
Stages in nephron formation:
1) Metanephric mesenchyme cells condense into a tight pre tubular aggregate near the ureteric bud.
2) The compacted cells then undergo a mesenchymal-to-epithelial transition, forming a sphere of polarised epithelia
3) The sphere of epithelial cells called the renal vesicle, elongates to form comma shaped bodies and primordial tubule called the 'S' shaped body
4) The proximal slit of the 'S' shaped tubules forms the glomerulus, and the distal pole connects to the tip of an adjacent bud tubule.
The ureteric bud is plays a main role in producing factors that promote mesenchymal survival, as well as secreting proteins that induce condensation of mesenchymal cells and differentiation into nephrons. One of the proteins that are produced by the ureteric bud is FGF-2, which was shown to prevent apoptosis in isolated rat mesenchyme and induce up regulation of the important transcription factor WT-1. Leukaemia inhibitory factor (LIF) combines with FGF-2 to form nephrons within 7 days in culture, and addition of TGFβ made by stromal cells speeds up the process to just 2-3 days. 
WT-1 is a zinc finger protein, which is essential at various stages of renal development. It is also implicated to regulate genes such as Pax-2, syndecan, and E-cadherin, which are significant during the later stages on renal development. Absence of WT-1 prevents the metanephrogenic mesenchyme from differentiating into nephrons, leading to apoptosis .
During metanephros, the ureteric bud forms the ureter. The ureter of each kidney descends from the kidney complex and connects to the urinary bladder. At week 6, the ureters ascend upwards as the torso of the foetus continues to extend. At week 9, they assume their permanent and proper anatomical position under the adrenal glands.
Current literature highlights two stages during organogenesis in which signalling molecules play a crucial role in the development of the functional kidney. The first is the outgrowth of the ureteric bud and the second instance being the inductive signal from the ureter that dictates differentiation of the mesenchyme. During these major signalling cascades, there are other more complex mechanisms which serve to ‘fine-tune’ this development through the regulation of cell proliferation, apoptosis, differentiation and motility. Without these growth factors and their respective receptors, outgrowth of the ureteric bud and differentiation of the mesenchyme will become severely affected.
The GDNF (Glial cell derived neurotrophic factor) / RET (REarranged during Transfection) pathway is the primary signalling complex that regulates ureteric bud growth. RET is expressed in the Wolffian duct from E8 to E11.5 and eventually in the ureteric bud as it emerges from the metanephric mesenchyme. During E13.5-17.5 expression of RET is confined to the growing tips of the ureteric bud epithelium. The RET protein acts cell autonomously by receiving a signal from the mesenchyme, that activates the proliferation and branching pathway of the ureteric bud epithelium. Targeted inactivation of RET results in a failure of the ureteric bud to emerge and respond to signals in the metanephric blastema.
Although kidneys are relatively small as compared to other organs, they are responsible for filtering about 20% of the blood output from the heart.  A constant and stable blood flow is important for the tissues to carry out respiration, thus ensuring the normal functioning of the kidneys. Renal infarction , that is, interruptions to the supply of oxygenated blood to the kidneys may result in kidney failure and subsequently the loss of kidney functions. A person with a damaged kidney is able to survive with the other functional kidney. In the case where both kidneys fail, dialysis or kidney transplant is needed to filter metabolic wastes from blood.
Angiogenesis and vasculogenesis
Blood vessels in kidneys are formed via angiogenesis and vasculogenesis. The first endothelial cells in early gestation are formed by vasculogenesis while those in later gestation are formed by both angiogenesis and vasculogenesis. The co-expression of Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGF-R) during kidney organogenesis stimulates the development of renal blood vessels and is important in regulating vascular permeability. High levels of VEGF and VEGF-R are expressed in the kidneys during both embryonic development and adulthood. The high expression of VEGF and VEGF-R by the glomerular endothelium supports the hypothesis that VEGF and VEGF-R play an important role in the regulation of vascular permeability. When VEGF and VEGF-R levels are high, vascular permeability increases. Conversely, when VEGF and VEGF-R levels are low, the blood brain barrier permeability decreases. Hypoxia induces the production of VEGF by glomerular epithelial mass and the expression of VEGF-R by endothelial precursor cells. VEGF and/or anti-VEGF are believed to be therapeutically useful in treating many disorders. 
The glomerulus is a specialised network of blood capillaries that filters metabolic waste products in blood carried via the afferent blood arterioles. Metabolic waste products are filtered through fenestrae, which are small pores with diameter of 50nm to 100nm, on endothelial cells lining the glomerular capillaries. The resultant glomerular filtrate of water and soluble solutes is transported to the Bowman’s capsule and subsequently, to the renal tubule of the nephron to form urine. The glomerular capillaries converge into efferent arterioles in which filtered blood is carried away from the glomerulus. The juxtaglomerular cells lining the walls of the afferent arterioles secrete renin and regulate the volume and pressure of blood flow via the renin-angiotensin system. The efferent arterioles have high resistance that generates hydrostatic pressure that is sufficient for ultrafiltration within the glomerulus. The glomerulus serves as the connection between the vascular system and the nephron. The glomerulus and Bowman’s capsule form the filtration unit of the kidney known as the renal corpuscle. The glomerular filtration rate is the rate at which blood is completely filtered through the glomerulus and is a measure of the renal function. 
The juxtaglomerular apparatus regulates the renal blood flow (volume and pressure) and glomerular filtration rate. It has three different types of cells, namely macula densa, juxtaglomerular cells and extraglomerular mesangial
- Macula densa: The macula densa is a specialized area of the distal convoluted tubule where afferent arterioles enter the glomerulus and the efferent arterioles leave the glomerulus. The macula densa is able to detect changes in the levels of sodium chloride in the distal tubule of the nephron by the tubuloglomerular feedback loop
- Juxtaglomerular cells: Juxtaglomerular cells are responsible for the synthesis, storage and secretion of renin in the kidneys. They line the walls of the afferent arterioles and regulate the volume and pressure of blood flow via the renin-angiotensin system. Juxtaglomerular cells secrete renin in response to (1) stimulation by macula densa cells when the concentration of sodium in tubular fluid decreases, (2) stimulation of β1 adrenergic receptors by epinephrine or norepinephrine and (3) a decrease in renal perfusion pressure. Poorly perfused juxtaglomerular cells activate the renin-angiotensin system.
- Extraglomerular mesangial: The specific function of extraglomerular mesangial is not well understood.
A decrease in plasma sodium level leads to the conversion of prorenin into renin by the juxtaglomerular cells. Renin secreted into the blood cleaves a short peptide of 10 amino acids called angiotensin I from plasma protein angiotensinogen. Angiotensin-converting enzyme converts angiotensin I into angiotensin II. Angiotensin II constricts arterioles, thus increasing renal blood pressure. It also stimulates the release of hormone aldosterone from the adrenal cortex, thus increasing the reabsorption of sodium ions into the blood.
As mentioned in the Introduction, every 1 in 500 newborns suffer from congenital abnormalities of the kidney and urinary tract (CAKUT). Studies have shown that certain CAKUT increases the risks of developing hypertension and cardiovascular diseases at adulthood.
An increase in anti-α smooth muscle actin (α-SMA), vimentin and fibronectin expression in renal tissue   as well as a decrease of the proximal tubule cubulin receptor  have been associated with disruptions in renal development. The proximal tubule receptor is important as it characterises the epithelial-mesenchymal transition (EMT) process, which is a physiological process that occurs during early embryogenesis, tissue repair, and pathology. 
Vimentin and α-SMA are only expressed before the differentiation or transdifferentiation processes in epithelial cells. During this process, cells can proliferate, migrate and produce extracellular matrix. Therefore, these proteins can be utilised as a marker of cell indifferentiation.
Studies have shown that the renin-angiotensis system (RAS) participates in renal development, and that exposure to RAS blockers resulted in the presence of acute kidney injury, chronic kidney disease, and tubular dysfunction in children. These studies demonstrate that inhibition of the RAS causes an increase in the relative interstitial area from the renal cortex, high levels of apoptosis, decreased cell proliferation and impaired expression of growth factors in the kidney. Furthermore, Chen at al.'s treatment of neonatal rats with losartan for 2 days promote down regulation of genes encoding cytoskeletal and extracellular matrix ECM components, which results in ECM malformation and cell-cell and cell-matrix interaction dysfunctions. 
Although calcitriol is widely known for its important role in the homeostasis of calcium homeostasis and bone metabolism , recent studies have shown that it is also involved in the homeostasis of other cellular processes. These processes include the control of of autoimmunity, inflammatory process as well as blood pressure. Furthermore, calcitriol regulates the cell proliferation and differentiation processes as well as the renin gene. 
Kidney developmental abnormalities are diverse and they correspond to defects at different stages of the kidney development. Renal vascular anomalies are defects involving renal arteries and renal veins while fusion anomalies results in conditions such as fused pelvic kidney, crossed fused renal ectopia and horseshoe kidney.
Common congenital kidney defects include:
- Renal agenesis (absence of one or both kidneys)
- Multiple ureters (more than one ureter draining a kidney)
- Hypoplastic kidneys (underdevelopment of the kidneys)
- Dysplastic kidneys (abnormal development of kidneys which arises from tubules failing to branch out completely)
- Wilms tumours (kidney cancer)
- Patterning defects
- Common congenital abnormality of the kidneys.
- The horseshoe kidney can be T-, horseshoe, or L-shaped, depending on the manner of fusion of the two kidneys. It occurs during development, when the left and right kidneys fuse at their lower poles by a parenchymal isthmus located ventral to the abdominal aorta, forming a "U" shape.
- It is usually located in the lower lumbar position (L3 to L5), in front of the aorta and inferior vena cava, posterior to the inferior mesenteric artery . The inferior mesenteric artery blocks the isthmus, preventing the ascension of the kidneys and causing them to remain at a lower position.
- It shows a wide variation of arterial blood supply. 
- During migration from the sacral region, the two metanephric blastemas can come into contact, mainly at the lower pole.
- The ureters pass in front of the zone of fusion of the kidneys.
- Despite the abnormality, kidneys and ureters are still able to function. However, there is increased chances of developing upper urinary tract obstruction of infection.
- Horseshoe kidney is typically associated with other congenital defects, including Turners Syndrome, Wilms' Tumour, duplicated ureter, and Trisomy 18.
- Most common intraabdominal cancer in children ; 9 out of 10 kidney cancers in children are Wilms' tumours.
- Most Wilms' tumours are unilateral, meaning they occur in one kidney. In some cases, they can occur bilaterally.
- Transcription factor Wilms' Tumour 1 (WT-1) is known as a classic suppressor gene in Wilms' tumour.  Although the exact function of WT-1 is still unclear, research suggests that gemline mutations of WT-1 is the main cause for Wilms' Tumour.
- A classic Wilms' tumour has three main cell types (stromal, epithelia, blastomal), giving it a triphasic appearance.
- Renal agenesis is a congenital abnormality occurring when there is a failure of development of the kidneys and ureter. It is induced by a lack of interaction between the ureteric bud and the metanephric mesenchyme.
- This defect usually occurs around 5 weeks of embryonic life. 
- It can occur in two forms: bilateral or or unilateral renal agenesis.
- Renal agenesis occurs when the ureteric bud fails to become a ureter, the renal pelvis and the collecting ducts and the mesenchyme to form nephrons. 
- Renal agenesis patients frequently have extra-renal anomalies, such as cardiac, genital or gastrointestinal malformations. .
- It is usually associated other congenital defects including oligohydramnios, as well as facial abnormalities including, wide set eyes and low-set ears, and a broad flat nose.
Most of our current understanding of molecular regulation of kidney development has been derived from either using genetically altered (knock-in) or knock out mice. To obtain knock-out mice, homologous recombination of a gene of interest and a reporter gene like green-fluorescence protein (GFP) is used. Using knock-out mice with a reporter gene like GFP makes it possible for the researchers to detect and visualize transcriptional control and gene expression of the gene of interest during development. However, during to many cases of embryonic motility when knocking out a gene, conditional knock-out mice are used instead.
One of the more common methods to create conditional knock-out mice is the use of Cre/loxP recombination. Cre-recombinase is an 38kB enzyme, which is produced by bacteriophage P1. It recognizes a 34-bp sequences called loxP and can mediate DNA recombination between two lox sites. Since Cre recombinase is not found in mammalian cells, this makes this technique very specific. . Using this method it has been possible to identify several kidney-specific promoters.
Hoxb7/GFP transgenic mouse model
The best known reporter mouse model used for studying kidney development is the Hoxb7/GFP transgenic mice. The model was developed in 1999 by Srinivas et al.  In this mouse model, the GFP is under the control of HoxB7 promotor, and this allows visualization of the Wollfian duct, ureteric tree and its derivatives (collecting ducts, calyces, renal pelvis, ureter).
Can kidney disease be associated with nephron number?
Nephron development ceases around week 36 of gestation at the end of nephrogenesis. The body is unable to create new nephrons beyond that point. Due to the wide range of possible nephron numbers (250,000 - 2.5 million), many investigations have arisen to determine whether a lower nephron count predisposes a person to kidney disease later on in life.
Kidney stem cells
Adult kidney stem cells that are capable of regenerating a kidney-like structure from a single cell in vitro have been identified in rats. The stem cells are able to differentiate into a kidney-like structure in the absence of embryonic primordial cell types, such as metanephric mesenchyme and ureteric bud cells. This suggests that there may be different kidney organogenesis pathways, and that the organogenesis starting from adult kidney stem cells differs from that during embryonic development. It is also reported that instead of single stem cells, cell aggregates are needed to regenerate the kidney-like structure. It is suggested that stem cells possess intrinsic property that allows them to produce the three-dimensional structure of the organ from which they originate, which in this case, kidneys. Although the kidney-like structures lack vascularization and are unable to make urine, they are still useful for in vitro kidney regeneration research as well as for in vitro studies toward alternatives to animal experiments and tailor-made medicines. While further research is needed to investigate the physiological roles of these cells, it is hypothesized that analogous cells in the adult human kidney would be a valuable and potential resource for the regeneration of kidneys in vitro. 
General info on the renal system
The renal system consists of the kidneys, ureters, bladder and urethra. The four organs function collaboratively in the production, storage and excretion of urine, in which liquid waste products from blood is eliminated from the body. Other purposes of a renal system includes the regulation of blood pH, blood volume, blood pressure and the levels of metabolites and electrolytes in blood, A healthy human produces an estimated volume of 800mℓ to 2000mℓ urine daily. The volume of urine produced varies depending on fluid intake and renal function, which is measured by glomerular filtration rate.
A healthy human has two ureters, with one leading from each kidney to the urinary bladder. In human adults, the ureters are usually 25cm to 30cm in length and 3mm to 4mm in diameter. They are lined by urothelium and are therefore stretchable. The urothelium appears as columnar epithelia when it is relaxed and as squamous epithelia when it is distended. The ureters carry urine from the renal pelvis of the kidneys to the urinary bladder. The back-flow of urine to the kidneys during urination is prevented as the ureters pass beneath the urinary bladder, and are compressed by the urinary bladder. Back-flow of urine results in cystitis, which is the most common type of urinary tract infection characterised by the inflammation of the ureter and/or urinary bladder. Cystitis is usually caused by bacterial infection and often leads to the development of kidney infection. More women are affected by cystitis than men.
The urinary bladder stores urine before it is excreted from the body. In human adults, the bladder has the capacity to hold about 300mℓ to 500mℓ of urine. Urine is expelled into the urethra from the urinary bladder via micturition, which involves both voluntary and involuntary muscles. Incontinence refers to a lack of voluntary control over micturition.
The urethra is a passageway that leads from the urinary bladder to the outside of the body, through which urine is expelled from the body. The length of urethra differs in males and females. Ejaculation of semen in males also passes through the urethra.
Glossary of terms
|Angiogenesis||The formation of new blood vessels from blood vessels that are pre-existing.|
|Fascia||A sheet of connective tissue beneath the skin that is responsible for the attachment, stabilization, enclosure and separation of muscles and other organs. It is primarily collagen.|
|Metanephric blastema||An embryological structure that develops into a kidney.|
|Pharyngeal arch||Forms the structures of the head and neck. Five arches (1, 2, 3, 4 and 6) are formed in humans with four being visible on the embryo.|
|Vasculogenesis||The formation of new blood vessels via de novo endothelial cell production.|
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