Talk:Renal System Development

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Cite this page: Hill, M.A. (2021, October 22) Embryology Renal System Development. Retrieved from


Gredler ML, Patterson SE, Seifert AW & Cohn MJ. (2020). Foxa1 and Foxa2 orchestrate development of the urethral tube and division of the embryonic cloaca through an autoregulatory loop with Shh. Dev. Biol. , 465, 23-30. PMID: 32645357 DOI.

Foxa1 and Foxa2 orchestrate development of the urethral tube and division of the embryonic cloaca through an autoregulatory loop with Shh

Congenital anomalies of external genitalia affect approximately 1 in 125 live male births. Development of the genital tubercle, the precursor of the penis and clitoris, is regulated by the urethral plate epithelium, an endodermal signaling center. Signaling activity of the urethral plate is mediated by Sonic hedgehog (SHH), which coordinates outgrowth and patterning of the genital tubercle by controlling cell cycle kinetics and expression of downstream genes. The mechanisms that govern Shh transcription in urethral plate cells are largely unknown. Here we show that deletion of Foxa1 and Foxa2 results in persistent cloaca, an incomplete separation of urinary, genital, and anorectal tracts, and severe hypospadias, a failure of urethral tubulogenesis. Loss of Foxa2 and only one copy of Foxa1 results in urethral fistula, an additional opening of the penile urethra. Foxa1/a2 participate in an autoregulatory feedback loop with Shh, in which FOXA1 and FOXA2 positively regulate transcription of Shh in the urethra, and SHH feeds back to negatively regulate Foxa1 and Foxa2 expression. These findings reveal novel roles for Foxa genes in development of the urethral tube and in division of the embryonic cloaca.

Sutherland MR, Vojisavljevic D & Black MJ. (2020). A practical guide to the stereological assessment of glomerular number, size, and cellular composition. Anat Rec (Hoboken) , , . PMID: 31960613 DOI.

A practical guide to the stereological assessment of glomerular number, size, and cellular composition.

Abstract The evaluation of a range of measures in the kidneys, such as developmental stage, rate and success, injury, and disease processes, relies on obtaining information on the three-dimensional structure of the renal corpuscles, and in particular the glomerular capillary tufts. To do this in the most accurate, comprehensive, and unbiased manner depends on a knowledge of stereological methods. In this article, we provide a practical guide for researchers on how to quantitate a number of structures in the kidneys, including the estimation of total glomerular number, glomerular capillary length and filtration surface area, and the cellular composition of individual glomeruli. Guidance is also provided on how to apply these methods to kidneys at different sizes and levels of maturity. © 2020 American Association for Anatomy. KEYWORDS: glomerulus; kidney development; nephron number; podocyte; stereology PMID: 31960613 DOI: 10.1002/ar.24361


Human Nephron Number

Bueters RR, van de Kar NC & Schreuder MF. (2013). Adult renal size is not a suitable marker for nephron numbers: an individual patient data meta-analysis. Kidney Blood Press. Res. , 37, 540-6. PMID: 24356546 DOI.

Paper Nyengaard 1992 Bendtsen 1992 Keller
McNamara 2008 McNamara 2009 Zimanyi 2009 Cumulative Cumulative
638.6 612.5 1,074.4 925.5 1,053.4 895.3 803.7 921.5

(standard deviation - (202.3) (190.4) (422.4) (225.4) (306.9) (454.7) —_ (340.1) — (851.2)

This is an Open Access article licensed under the terms of the Creative Commons Attribution- NonCommercial 3.0 Unported license (CC BY-NC) (, applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.

Kanzaki G, Tsuboi N, Utsunomiya Y, Ikegami M, Shimizu A & Hosoya T. (2013). Distribution of glomerular density in different cortical zones of the human kidney. Pathol. Int. , 63, 169-75. PMID: 23530561 DOI.

As a whole, compared to the glomerular density in the superficial cortex (3.0 ± 0.7/mm(2)), the average glomerular density in the juxtamedullary cortex (2.2 ± 0.6/mm(2)) was approximately two-thirds. The glomerular density showed maximal 3.5-fold variations between individuals and was inversely correlated with the mean glomerular volume in both cortical areas.

Hughson MD, Douglas-Denton R, Bertram JF & Hoy WE. (2006). Hypertension, glomerular number, and birth weight in African Americans and white subjects in the southeastern United States. Kidney Int. , 69, 671-8. PMID: 16395270 DOI.

Hughson M, Farris AB, Douglas-Denton R, Hoy WE & Bertram JF. (2003). Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int. , 63, 2113-22. PMID: 12753298 DOI.

Keller G, Zimmer G, Mall G, Ritz E & Amann K. (2003). Nephron number in patients with primary hypertension. N. Engl. J. Med. , 348, 101-8. PMID: 12519920 DOI.

Nyengaard JR & Bendtsen TF. (1992). Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat. Rec. , 232, 194-201. PMID: 1546799 DOI.

Kidney Int. 2006 Jul;70(1):104-10. Epub 2006 May 24.

Reduced nephron number and glomerulomegaly in Australian Aborigines: a group at high risk for renal disease and hypertension

Australian study

Hoy WE1, Hughson MD, Singh GR, Douglas-Denton R, Bertram JF. Author information Abstract Aborigines in remote areas of Australia have much higher rates of renal disease, as well as hypertension and cardiovascular disease, than non-Aboriginal Australians. We compared kidney findings in Aboriginal and non-Aboriginal people in one remote region. Glomerular number and mean glomerular volume were estimated with the disector/fractionator combination in the right kidney of 19 Aborigines and 24 non-Aboriginal people undergoing forensic autopsy for sudden or unexpected death in the Top End of the Northern Territory. Aborigines had 30% fewer glomeruli than non-Aborigines--202,000 fewer glomeruli per kidney, or an estimated 404,000 fewer per person (P=0.036). Their mean glomerular volume was 27% larger (P=0.016). Glomerular number was significantly correlated with adult height, inferring a relationship with birthweight, which, on average, is much lower in Aboriginal than non-Aboriginal people. Aboriginal people with a history of hypertension had 30% fewer glomeruli than those without--250,000 fewer per kidney (P=0.03), or 500,000 fewer per person, and their mean glomerular volume was about 25% larger. The lower nephron number in Aboriginal people is compatible with their susceptibility to renal failure. The additional nephron deficit associated with hypertension is compatible with other reports. Lower nephron numbers are probably due in part to reduced nephron endowment, which is related to a suboptimal intrauterine environment. Compensatory glomerular hypertrophy in people with fewer nephrons, while minimizing loss of total filtering surface area, might be exacerbating nephron loss. Optimization of fetal growth should ultimately reduce the florid epidemic of renal disease, hypertension, and cardiovascular disease. PMID: 16723986 DOI: 10.1038/

Nephron number, hypertension, renal disease, and renal failure

J Am Soc Nephrol. 2005 Sep;16(9):2557-64. Epub 2005 Jul 27.

Australian study

Hoy WE1, Hughson MD, Bertram JF, Douglas-Denton R, Amann K. Author information

Congenital oligomeganephronia, in which glomeruli are few, very large, and prone to sclerosis (38,39), is one blatant model of nephron underendowment. Although most cases are sporadic, it sometimes occurs in family clusters, suggesting a genetic background (40), and an association with PAX2 gene mutations has been described (41).

Mice that are heterozygous for glial-derived neurotrophic factor (GDNF), a critical factor for renal development, are born with approximately 30% fewer nephrons and develop hypertension in adulthood in the absence of renal disease (42).


In one remote Australian Aboriginal community with generally low birth weights, birth weight in young adults was strongly and inversely correlated with the level of albuminuria and with the presence of overt nephropathy (84,85). Low birth weight children in this same population had lower kidney volumes than those of higher birth weights (22). Furthermore, adults with the lowest kidney volumes, examined in the context of current weight, had the highest rates of albuminuria and highest BP (23), tending to support a role of nephron underdosing in these pathologies.

PMID: 16049069 DOI: 10.1681/ASN.2005020172

Lancet. 1998 Dec 5;352(9143):1826-7. Low birthweight and renal disease in Australian aborigines. Hoy WE, Rees M, Kile E, Mathews JD, McCredie DA, Pugsley DJ, Wang Z. PMID: 9851387

Hypertension, glomerular number, and birth weight in African Americans and white subjects in the southeastern United States

Kidney Int. 2006 Feb;69(4):671-8.

Hughson MD, Douglas-Denton R, Bertram JF, Hoy WE. Source Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, USA. Abstract Low nephron number has been related to low birth weight and hypertension. In the southeastern United States, the estimated prevalence of chronic kidney disease due to hypertension is five times greater for African Americans than white subjects. This study investigates the relationships between total glomerular number (Nglom), blood pressure, and birth weight in southeastern African Americans and white subjects. Stereological estimates of Nglom were obtained using the physical disector/fractionator technique on autopsy kidneys from 62 African American and 60 white subjects 30-65 years of age. By medical history and recorded blood pressures, 41 African Americans, and 24 white subjects were identified as hypertensive and 21 African Americans and 36 white subjects as normotensive. Mean arterial blood pressure (MAP) was obtained on 81 and birth weights on 63 subjects. For African Americans, relationships between MAP, Nglom, and birth weight were not significant. For white subjects, they were as follows: MAP and Nglom (r=-0.4551, P=0.0047); Nglom and birth weight (r=0.5730, P=0.0022); MAP and birth weight (r=-0.4228, P=0.0377). For African Americans, average Nglom of 961 840+/-292 750 for normotensive and 867 358+/-341 958 for hypertensive patients were not significantly different (P=0.285). For white subjects, average Nglom of 923 377+/-256 391 for normotensive and 754 319+/-329 506 for hypertensive patients were significantly different (P=0.03). The data indicate that low nephron number and possibly low birth weight may play a role in the development of hypertension in white subjects but not African Americans. Comment in Hypertension, race, and glomeruli: more than simply a numbers game. [Kidney Int. 2006]

PMID 16395270

Glomerular number and size in autopsy kidneys: the relationship to birth weight

Kidney Int. 2003 Jun;63(6):2113-22.

Hughson M, Farris AB 3rd, Douglas-Denton R, Hoy WE, Bertram JF. Source University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, USA.


BACKGROUND: In the Southeast United States, African Americans have an estimated incidence of hypertension and end-stage renal disease (ESRD) that is five times greater than Caucasians. Higher rates of low birth weight (LBW) among African Americans is suggested to predispose African Americans to the higher risk, possibly by reducing the number of glomeruli that develop in the kidney. This study investigates the relationships between age, race, gender, total glomerular number (Nglom), mean glomerular volume (Vglom), body surface area (BSA), and birth weight. METHODS: Stereologic estimates of Nglom and Vglom were obtained using the physical disector/fractionator combination for autopsy kidneys from 37 African Americans and 19 Caucasians. RESULTS: Nglom was normally distributed and ranged from 227,327 to 1,825,380, an 8.0-fold difference. A direct linear relationship was observed between Nglom and birth weight (r = 0.423, P = 0.0012) with a regression coefficient that predicted an increase of 257,426 glomeruli per kilogram increase in birth weight (alpha = 0.050:0.908). Among adults there was a 4.9-fold range in Vglom, and in adults, Vglom was strongly and inversely correlated with Nglom (r =-0.640, P = 0.000002). Adult Vglom showed no significant correlation with BSA for males (r = -0.0150, P = 0.936), although it did for females (r = 0.606, P = 0.022). No racial differences in average Nglom or Vglom were observed. CONCLUSION: Birth weight is a strong determinant of Nglom and thereby of glomerular size in the postnatal kidney. The findings support the hypothesis that LBW by impairing nephron development is a risk factor for hypertension and ESRD in adulthood.

PMID 12753298

Nephron number in patients with primary hypertension

N Engl J Med. 2003 Jan 9;348(2):101-8.

Keller G, Zimmer G, Mall G, Ritz E, Amann K. Source Department of Pathology, University of Heidelberg, Heidelberg, Germany.


BACKGROUND: A diminished number of nephrons has been proposed as one of the factors contributing to the development of primary hypertension. METHODS: To test this hypothesis, we used a three-dimensional stereologic method to compare the number and volume of glomeruli in 10 middle-aged white patients (age range, 35 to 59 years) with a history of primary hypertension or left ventricular hypertrophy (or both) and renal arteriolar lesions with the number and volume in 10 normotensive subjects matched for sex, age, height, and weight. All 20 subjects had died in accidents. RESULTS: Patients with hypertension had significantly fewer glomeruli per kidney than matched normotensive controls (median, 702,379 vs. 1,429,200). Patients with hypertension also had a significantly greater glomerular volume than did the controls (median, 6.50x10(-3) mm3 vs. 2.79x10(-3) mm3; P<0.001) but very few obsolescent glomeruli. CONCLUSIONS: The data support the hypothesis that the number of nephrons is reduced in white patients with primary hypertension. Copyright 2003 Massachusetts Medical Society Comment in Is microanatomy destiny? [N Engl J Med. 2003] Nephron number and primary hypertension. [N Engl J Med. 2003] Nephron number and primary hypertension. [N Engl J Med. 2003] Nephron number and primary hypertension. [N Engl J Med. 2003]

PMID 12519920

Glomerular number and size in relation to age, kidney weight, and body surface in normal man

Anat Rec. 1992 Feb;232(2):194-201.

Nyengaard JR, Bendtsen TF. Source Stereological Research Laboratory, Aarhus University, Denmark.


The number and size of glomeruli in normal, mature human kidneys were estimated by a direct and unbiased stereological method, the fractionator. The number was 617,000 on average, and the mean size 6.0 M microns3. Both glomerular number and size showed significant negative correlation to age and significant positive correlation to kidney weight. Apparently, humans loose glomeruli with age. Body surface area correlated positively to kidney weight and total glomerular volume but not to number of glomeruli. Body surface area correlates significantly with metabolic rate (Robertson and Reid, Lancet, 1: 940-943, 1952). Thus, intraspecies adaptation of kidney filtration capacity to the metabolic demand is performed by changing the size of glomeruli, i.e., the number of glomeruli in individuals of a given species is independent of the metabolic rate.

PMID 1546799


Stereological study of developing glomerular forms during human fetal kidney development

Pediatr Nephrol. 2018 May;33(5):817-825. doi: 10.1007/s00467-017-3874-2. Epub 2017 Dec 23.

Dakovic Bjelakovic M1, Vlajkovic S2, Petrovic A3, Bjelakovic M4, Antic M2. Author information Abstract BACKGROUND: Human fetal kidney development is a complex and stepwise process. The number, shape, size and distribution of glomeruli provide important information on kidney organization. The aim of this study was to quantify glomerular developing forms during human fetal kidney development using stereological methods.

METHODS: Kidney tissue specimens of 40 human fetuses with gestational ages ranging from 9 to 40 weeks were analyzed. Specimens were divided into eight groups based on gestational age, each corresponding to 1 lunar month. Stereological methods were used at the light microscopy level to estimate volume, surface and numerical density of the glomerular developing forms.

RESULTS: During gestation, nephrogenesis continually advanced, and the number of nephrons increased. Volume, surface and numerical densities of vesicular forms and S-shaped bodies decreased gradually in parallel with gradual increases in estimated stereological parameters for vascularized glomeruli. Volume density and surface density of vascularized glomeruli increased gradually during fetal kidney development, and numerical density increased until the seventh lunar month. A relative decrease in vascularized glomeruli per unit volume of cortex occurred during the last 3 lunar months. Nephrogenesis began to taper off by 32 weeks and was completed by 36 weeks of gestation. The last sample in which we observed vesicles was from a fetus aged 32 weeks, and the last sample with S-shaped bodies was from a fetus aged 36 weeks.

CONCLUSIONS: The present study is one of few quantitative studies conducted on human kidney development. Knowledge of normal human kidney morphogenesis during development could be important for future medical practice. Events occurring during fetal life may have significant consequences later in life.

KEYWORDS: Gestation age; Glomerulus; Human fetus; Kidney; Stereology PMID: 29273971 DOI: 10.1007/s00467-017-3874-2

Branching morphogenesis of the urinary collecting system in the human embryonic metanephros

Ishiyama H, Ishikawa A, Kitazawa H, Fujii S, Matsubayashi J, Yamada S & Takakuwa T. (2018). Branching morphogenesis of the urinary collecting system in the human embryonic metanephros. PLoS ONE , 13, e0203623. PMID: 30192900 DOI.

Ishiyama H1, Ishikawa A1, Kitazawa H1, Fujii S1, Matsubayashi J1, Yamada S1,2, Takakuwa T1.


An elaborate system of ducts collects urine from all nephrons, and this structure is known as the urinary collecting system (UCS). This study focused on how the UCS is formed during human embryogenesis. Fifty human embryos between the Carnegie stage (CS) 14 and CS23 were selected from the Kyoto Collection at the Congenital Anomaly Research Center of Kyoto University, Japan. Metanephroses, including the UCS, were segmented on serial digital virtual histological sections. Three-dimensional images were computationally reconstructed for morphological and quantitative analyses. A CS timeline was plotted. It consisted of the 3-D structural morphogenesis of UCS and quantification of the total amount of end-branching, average and maximum numbers of generations, deviation in the metanephros, differentiation of the urothelial epithelium in the renal pelvis, and timing of the rapid expansion of the renal pelvis. The first UCS branching generation occurred by CS16. The average branching generation reached a maximum of 8.74 ± 1.60 and was already the twelfth in CS23. The total end-branching number squared between the start and the end of the embryonic period. UCS would reach the fifteenth branching generation soon after CS23. The number of nephrons per UCS end-branch was low (0.21 ± 0.14 at CS19, 1.34 ± 0.49 at CS23), indicating that the bifid branching occurred rapidly and that the formation of nephrons followed after. The renal pelvis expanded mainly in CS23, which was earlier than that reported in a previous study. The number of nephrons connected to the UCS in the expanded group (246.0 ± 13.2) was significantly larger than that of the pre-expanded group (130.8 ± 80.1) (P < 0.05). The urothelial epithelium differentiated from the zeroth to the third generations at CS23. Differentiation may have continued up until the tenth generation to allow for renal pelvis expansion. The branching speed was not uniform. There were significantly more branching generations in the polar- than in the interpolar regions (P < 0.05). Branching speed reflects the growth orientation required to form the metanephros. Further study will be necessary to understand the renal pelvis expansion mechanism in CS23. Our CS-based timeline enabled us to map UCS formation and predict functional renal capacity after differentiation and growth. PMID: 30192900 PMCID: PMC6128595 DOI: 10.1371/journal.pone.0203623

Spatiotemporal heterogeneity and patterning of developing renal blood vessels

Daniel E, Azizoglu DB, Ryan AR, Walji TA, Chaney CP, Sutton GI, Carroll TJ, Marciano DK & Cleaver O. (2018). Spatiotemporal heterogeneity and patterning of developing renal blood vessels. Angiogenesis , 21, 617-634. PMID: 29627966 DOI.

Daniel E1, Azizoglu DB1, Ryan AR1, Walji TA1, Chaney CP1, Sutton GI1, Carroll TJ1, Marciano DK2, Cleaver O3. Author information Abstract The kidney vasculature facilitates the excretion of wastes, the dissemination of hormones, and the regulation of blood chemistry. To carry out these diverse functions, the vasculature is regionalized within the kidney and along the nephron. However, when and how endothelial regionalization occurs remains unknown. Here, we examine the developing kidney vasculature to assess its 3-dimensional structure and transcriptional heterogeneity. First, we observe that endothelial cells (ECs) grow coordinately with the kidney bud as early as E10.5, and begin to show signs of specification by E13.5 when the first arteries can be identified. We then focus on how ECs pattern and remodel with respect to the developing nephron and collecting duct epithelia. ECs circumscribe nephron progenitor populations at the distal tips of the ureteric bud (UB) tree and form stereotyped cruciform structures around each tip. Beginning at the renal vesicle (RV) stage, ECs form a continuous plexus around developing nephrons. The endothelial plexus envelops and elaborates with the maturing nephron, becoming preferentially enriched along the early distal tubule. Lastly, we perform transcriptional and immunofluorescent screens to characterize spatiotemporal heterogeneity in the kidney vasculature and identify novel regionally enriched genes. A better understanding of development of the kidney vasculature will help instruct engineering of properly vascularized ex vivo kidneys and evaluate diseased kidneys. KEYWORDS: Blood vessel; Endothelial cell heterogeneity; Endothelium; Epithelium; Nephron; Vascular patterning

DOI: 10.1007/s10456-018-9612-y

Conserved and Divergent Features of Human and Mouse Kidney Organogenesis

Lindström NO, McMahon JA, Guo J, Tran T, Guo Q, Rutledge E, Parvez RK, Saribekyan G, Schuler RE, Liao C, Kim AD, Abdelhalim A, Ruffins SW, Thornton ME, Baskin L, Grubbs B, Kesselman C & McMahon AP. (2018). Conserved and Divergent Features of Human and Mouse Kidney Organogenesis. J. Am. Soc. Nephrol. , 29, 785-805. PMID: 29449453 DOI.

Lindström NO1, McMahon JA1, Guo J1, Tran T1, Guo Q1, Rutledge E1, Parvez RK1, Saribekyan G1, Schuler RE2, Liao C1, Kim AD1, Abdelhalim A1, Ruffins SW1, Thornton ME3, Baskin L4, Grubbs B3, Kesselman C2,5, McMahon AP6.

Abstract Human kidney function is underpinned by approximately 1,000,000 nephrons, although the number varies substantially, and low nephron number is linked to disease. Human kidney development initiates around 4 weeks of gestation and ends around 34-37 weeks of gestation. Over this period, a reiterative inductive process establishes the nephron complement. Studies have provided insightful anatomic descriptions of human kidney development, but the limited histologic views are not readily accessible to a broad audience. In this first paper in a series providing comprehensive insight into human kidney formation, we examined human kidney development in 135 anonymously donated human kidney specimens. We documented kidney development at a macroscopic and cellular level through histologic analysis, RNA in situ hybridization, immunofluorescence studies, and transcriptional profiling, contrasting human development (4-23 weeks) with mouse development at selected stages (embryonic day 15.5 and postnatal day 2). The high-resolution histologic interactive atlas of human kidney organogenesis generated can be viewed at the GUDMAP database ( together with three-dimensional reconstructions of key components of the data herein. At the anatomic level, human and mouse kidney development differ in timing, scale, and global features such as lobe formation and progenitor niche organization. The data also highlight differences in molecular and cellular features, including the expression and cellular distribution of anchor gene markers used to identify key cell types in mouse kidney studies. These data will facilitate and inform in vitro efforts to generate human kidney structures and comparative functional analyses across mammalian species. KEYWORDS: human genetics; kidney development; nephron PMID: 29449453 PMCID: PMC5827606 [Available on 2019-03-01] DOI: 10.1681/ASN.2017080887

Zebrafish Pronephros Development

Results Probl Cell Differ. 2017;60:27-53. doi: 10.1007/978-3-319-51436-9_2.

Naylor RW1, Qubisi SS1, Davidson AJ2.

Abstract The pronephros is the first kidney type to form in vertebrate embryos. The first step of pronephrogenesis in the zebrafish is the formation of the intermediate mesoderm during gastrulation, which occurs in response to secreted morphogens such as BMPs and Nodals. Patterning of the intermediate mesoderm into proximal and distal cell fates is induced by retinoic acid signaling with downstream transcription factors including wt1a, pax2a, pax8, hnf1b, sim1a, mecom, and irx3b. In the anterior intermediate mesoderm, progenitors of the glomerular blood filter migrate and fuse at the midline and recruit a blood supply. More posteriorly localized tubule progenitors undergo epithelialization and fuse with the cloaca. The Notch signaling pathway regulates the formation of multi-ciliated cells in the tubules and these cells help propel the filtrate to the cloaca. The lumenal sheer stress caused by flow down the tubule activates anterior collective migration of the proximal tubules and induces stretching and proliferation of the more distal segments. Ultimately these processes create a simple two-nephron kidney that is capable of reabsorbing and secreting solutes and expelling excess water-processes that are critical to the homeostasis of the body fluids. The zebrafish pronephric kidney provides a simple, yet powerful, model system to better understand the conserved molecular and cellular progresses that drive nephron formation, structure, and function. PMID: 28409341 DOI: 10.1007/978-3-319-51436-9_2 [Indexed for MEDLINE]

Reciprocal Spatiotemporally Controlled Apoptosis Regulates Wolffian Duct Cloaca Fusion

J Am Soc Nephrol. 2018 Mar;29(3):775-783. doi: 10.1681/ASN.2017040380. Epub 2018 Jan 11.

Hoshi M1, Reginensi A2, Joens MS3, Fitzpatrick JAJ3,4,5, McNeill H2, Jain S6,7.


The epithelial Wolffian duct (WD) inserts into the cloaca (primitive bladder) before metanephric kidney development, thereby establishing the initial plumbing for eventual joining of the ureters and bladder. Defects in this process cause common anomalies in the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). However, developmental, cellular, and molecular mechanisms of WD-cloaca fusion are poorly understood. Through systematic analysis of early WD tip development in mice, we discovered that a novel process of spatiotemporally regulated apoptosis in WD and cloaca was necessary for WD-cloaca fusion. Aberrant RET tyrosine kinase signaling through tyrosine (Y) 1062, to which PI3K- or ERK-activating proteins dock, or Y1015, to which PLCγ docks, has been shown to cause CAKUT-like defects. Cloacal apoptosis did not occur in RetY1062F mutants, in which WDs did not reach the cloaca, or in RetY1015F mutants, in which WD tips reached the cloaca but did not fuse. Moreover, inhibition of ERK or apoptosis prevented WD-cloaca fusion in cultures, and WD-specific genetic deletion of YAP attenuated cloacal apoptosis and WD-cloacal fusion in vivo Thus, cloacal apoptosis requires direct contact and signals from the WD tip and is necessary for WD-cloacal fusion. These findings may explain the mechanisms of many CAKUT. KEYWORDS: CAKUT; Wolffian duct; apoptosis; kidney development; nephric duct; ureteric bud PMID: 29326158 DOI: 10.1681/ASN.2017040380

Lightsheet fluorescence microscopy of branching human fetal kidney

Kidney Int. 2018 Feb;93(2):525. doi: 10.1016/j.kint.2017.09.010.

Isaacson D1, Shen J2, McCreedy D3, Calvert M3, McDevitt T3, Cunha G2, Baskin L4.

PMID: 29389399 PMCID: PMC5797994 [Available on 2019-02-01] DOI: 10.1016/j.kint.2017.09.010


Morphologic and morphometric study on microvasculature of developing mouse kidneys

Am J Physiol Renal Physiol. 2018 Feb 21. doi: 10.1152/ajprenal.00615.2017. [Epub ahead of print]

Zhang J1, Cong J2, Yang J3, Thomsen JS4, Andreasen A5, Chang SJ3, Wang KY3, Gu L1, Zhai XY1.


A proper morphogenesis of the renal microvasculature is crucial not only for fulfilling the renal function, but also to slow down the progression of chronic kidney disease in adulthood. However, the current description of the developing microvasculature is incomplete. The present study investigated the morphogenesis and volume densities of the renal microvasculature using computer-assisted tubular tracing, immunohistochemistry for CD34, and unbiased stereology. The earliest glomerular capillaries were observed at the lower cleft of the S-shape nephrons, as simple loops connecting the afferent and efferent arterioles. In parallel with this the peritubular capillaries were established. Noticeably, from the early nephrogenesis on, the efferent arterioles of the early-formed glomeruli ran in close proximity to their own thick ascending limbs. In addition, the ascending vasa recta arising from the arcuate or interlobular veins also ran in close proximity to the thick descending limb. Thus, the tubules and vessels formed the typical countercurrent relation in the medulla. No loop bends were observed between descending and ascending vasa recta. The volume density of the cortical and medullary peritubular capillary increased 3.3- and 2.6-fold respectively, from 2.34 {plus minus} 0.13% and 7.03 {plus minus} 0.09% at E14.5 to 7.71 {plus minus} 0.44% and 18.27 {plus minus} 1.17% at P40. In contrast, the volume density of glomeruli changed only slightly during kidney development, from 4.61 {plus minus} 0.47% at E14.5 to 6.07 {plus minus} 0.2% at P7 to 4.19 {plus minus} 0.47% at P40. These results reflect that the growth and formation of the renal microvasculature closely correspond to functional development of the tubules. KEYWORDS: glomeruli; peritubular capillary; renal microvasculature; volume density

PMID: 29465303 DOI: 10.1152/ajprenal.00615.2017

New structural insights into podocyte biology

Cell Tissue Res. 2017 Mar 10. doi: 10.1007/s00441-017-2590-3. [Epub ahead of print]

Grahammer F


The last 5 years have witnessed tremendous advances in both light- and electron-microscopic techniques in the biomedical sciences. Application of these new cutting-edge methods to glomerular biology has advanced considerably and, in part, completed our endeavor to draw a detailed map of the glomerular tuft. The scope of this review is to illustrate these new insights within both the morphometry of podocyte cells and the architecture of the glomerular filtration barrier and to assess whether these findings have indeed had an impact on our biological understanding of glomerular function. KEYWORDS: Glomerular basement membrane; Glomerulum; Podocyte; Renal filtration; Slit diaphragm

PMID 28283912 DOI: 10.1007/s00441-017-2590-3

© The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.


Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis

Nature. 2015 Oct 7. doi: 10.1038/nature15695. [Epub ahead of print]

Takasato M1,2, Er PX1, Chiu HS2, Maier B2, Baillie GJ2, Ferguson C2, Parton RG2, Wolvetang EJ3, Roost MS4, Chuva de Sousa Lopes SM4, Little MH1,2,5.


The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells. Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.

PMID 26444236

The yin and yang of kidney development and Wilms' tumors

Genes Dev. 2015 Mar 1;29(5):467-82. doi: 10.1101/gad.256396.114.

Hohenstein P1, Pritchard-Jones K2, Charlton J2.


Wilms' tumor, or nephroblastoma, is the most common pediatric renal cancer. The tumors morphologically resemble embryonic kidneys with a disrupted architecture and are associated with undifferentiated metanephric precursors. Here, we discuss genetic and epigenetic findings in Wilms' tumor in the context of renal development. Many of the genes implicated in Wilms' tumorigenesis are involved in the control of nephron progenitors or the microRNA (miRNA) processing pathway. Whereas the first group of genes has been extensively studied in normal development, the second finding suggests important roles for miRNAs in general-and specific miRNAs in particular-in normal kidney development that still await further analysis. The recent identification of Wilms' tumor cancer stem cells could provide a framework to integrate these pathways and translate them into new or improved therapeutic interventions. © 2015 Hohenstein et al.; Published by Cold Spring Harbor Laboratory Press. KEYWORDS: Wilms’ tumor; Wt1; kidney development; miRNA; nephron progenitor cells; β-catenin

PMID 25737276

© 2015 Hohenstein et al.; Published by Cold Spring Harbor Laboratory Press This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at

Histone deacetylase 1 and 2 regulate Wnt and p53 pathways in the ureteric bud epithelium

Development. 2015 Mar 15;142(6):1180-92. doi: 10.1242/dev.113506.

Chen S1, Yao X1, Li Y1, Saifudeen Z1, Bachvarov D2, El-Dahr SS3.


Histone deacetylases (HDACs) regulate a broad range of biological processes through removal of acetyl groups from histones as well as non-histone proteins. Our previous studies showed that Hdac1 and Hdac2 are bound to promoters of key renal developmental regulators and that HDAC activity is required for embryonic kidney gene expression. However, the existence of many HDAC isoforms in embryonic kidneys raises questions concerning the possible specificity or redundancy of their functions. We report here that targeted deletion of both the Hdac1 and Hdac2 genes from the ureteric bud (UB) cell lineage of mice causes bilateral renal hypodysplasia. One copy of either Hdac1 or Hdac2 is sufficient to sustain normal renal development. In addition to defective cell proliferation and survival, genome-wide transcriptional profiling revealed that the canonical Wnt signaling pathway is specifically impaired in UB(Hdac1,2-/-) kidneys. Our results also demonstrate that loss of Hdac1 and Hdac2 in the UB epithelium leads to marked hyperacetylation of the tumor suppressor protein p53 on lysine 370, 379 and 383; these post-translational modifications are known to boost p53 stability and transcriptional activity. Genetic deletion of p53 partially rescues the development of UB(Hdac1,2-/-) kidneys. Together, these data indicate that Hdac1 and Hdac2 are crucial for kidney development. They perform redundant, yet essential, cell lineage-autonomous functions via p53-dependent and -independent pathways. © 2015. Published by The Company of Biologists Ltd. KEYWORDS: Branching morphogenesis; Histone; Kidney; Mouse; Ureteric bud; Wnt; p53 (Trp53)

PMID 25758227

Node retraction during patterning of the urinary collecting duct system

J Anat. 2015 Jan;226(1):13-21. doi: 10.1111/joa.12239. Epub 2014 Oct 8.

Lindström NO1, Chang CH, Valerius MT, Hohenstein P, Davies JA.


This report presents a novel mechanism for remodelling a branched epithelial tree. The mouse renal collecting duct develops by growth and repeated branching of an initially unbranched ureteric bud: this mechanism initially produces an almost fractal form with young branches connected to the centre of the kidney via a sequence of nodes (branch points) distributed widely throughout the developing organ. The collecting ducts of a mature kidney have a different form: from the nephrons in the renal cortex, long, straight lengths of collecting duct run almost parallel to one another through the renal medulla, and open together to the renal pelvis. Here we present time-lapse studies of E11.5 kidneys growing in culture: after about 5 days, the collecting duct trees show evidence of 'node retraction', in which the node of a 'Y'-shaped branch moves downwards, shortening the stalk of the 'Y', lengthening its arms and narrowing their divergence angle so that the 'Y' becomes a 'V'. Computer simulation suggests that node retraction can transform a spread tree, like that of an early kidney, into one with long, almost-parallel medullary rays similar to those seen in a mature real kidney. © 2014 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society. KEYWORDS: branching morphogenesis; collecting duct; development; embryonic kidney; modelling; organogenesis; pattern formation; ureteric bud

PMID 25292187;jsessionid=B63AAD445BB49952BDFFD1407ADD0B85.f03t04

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© 2014 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.


The regulation of apoptosis in kidney development: implications for nephron number and pattern?

Front Pediatr. 2014 Nov 18;2:128. doi: 10.3389/fped.2014.00128. eCollection 2014.

Ho J1.


Apoptosis is essential to remodel developing structures and eliminate superfluous cells in a controlled manner during normal development, and continues to be an important component of tissue remodeling and regeneration during an organism's lifespan, or as a response to injury. This mini review will discuss recent studies that have provided insights into the roles of apoptosis in the determination of nephron number and pattern, during normal and abnormal kidney development. The regulation of congenital nephron endowment has implications for risk of chronic kidney disease in later life, whereas abnormalities in nephron pattern are associated with congenital anomalies of the kidney and urinary tract (the leading cause of renal disease in children). Tight regulation of apoptosis is required in normal renal morphogenesis, although many questions remain regarding the regulation of apoptosis by genetic, epigenetic, and environmental factors, in addition to the functional requirement of different components of the apoptotic pathway. KEYWORDS: apoptosis; cystic kidney disease; kidney development; nephron number; nephron pattern

PMID 25478553

Non-canonical Wnt5a/Ror2 signaling regulates kidney morphogenesis by controlling intermediate mesoderm extension

Hum Mol Genet. 2014 Jul 31. pii: ddu397. [Epub ahead of print]

Yun K1, Ajima R1, Sharma N1, Costantini F2, Mackem S1, Lewandoski M1, Yamaguchi TP1, Perantoni AO3.


Congenital anomalies of the kidney and urinary tract (CAKUT) affect about 1 in 500 births and are a major cause of morbidity in infants. Duplex collecting systems rank among the most common abnormalities of CAKUT, but the molecular basis for this defect is poorly understood. In mice, conditional deletion of Wnt5a in mesoderm results in bilateral duplex kidney and ureter formation. The ureteric buds (UB) in mutants emerge as doublets from the intermediate mesoderm (IM)-derived nephric duct (ND) without anterior expansion of the Gdnf expression domain in the surrounding mesenchyme. Wnt5a is normally expressed in a graded manner at the posterior end of the IM, but its expression is down regulated prior to UB outgrowth at E10.5. Furthermore, ablation of Wnt5a in mesoderm with an inducible Cre at E7.5 results in duplex UBs; whereas, ablation at E8.5 yields normal UB outgrowth, demonstrating that Wnt5a functions in IM development well before formation of the metanephros. In mutants, the posterior ND is duplicated and surrounding Pax2-positive mesenchymal cells persist in the nephric cord, suggesting that disruption of normal ND patterning prompts the formation of duplex ureters and kidneys. Ror2 homozygous mutants, which infrequently yield duplex collecting systems, show a dramatic increase in incidence with the additional deletion of one copy of Wnt5a, implicating this receptor in non-canonical Wnt5a signaling during IM development. This work provides the first evidence of a role for Wnt5a/Ror2 signaling in IM extension and offers new insight into the etiology of CAKUT and possible involvement of Wnt5a/Ror2 mutations. Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

PMID 25082826

Renal branching morphogenesis: Morphogenetic and signaling mechanisms

Semin Cell Dev Biol. 2014 Jul 28. pii: S1084-9521(14)00222-5. doi: 10.1016/j.semcdb.2014.07.011. [Epub ahead of print] Blake J1, Rosenblum ND2.


The human kidney is composed of an arborized network of collecting ducts, calyces and urinary pelvis that facilitate urine excretion and regulate urine composition. The renal collecting system is formed in utero, completed by the 34th week of gestation in humans, and dictates final nephron complement. The renal collecting system arises from the ureteric bud, a derivative of the intermediate-mesoderm derived nephric duct that responds to inductive signals from adjacent tissues via a process termed ureteric induction. The ureteric bud subsequently undergoes a series of iterative branching and remodeling events in a process called renal branching morphogenesis. Altered signaling that disrupts patterning of the nephric duct, ureteric induction, or renal branching morphogenesis leads to varied malformations of the renal collecting system collectively known as congenital anomalies of the kidney and urinary tract (CAKUT) and is the most frequently detected congenital renal aberration in infants. Here, we describe critical morphogenetic and cellular events that govern nephric duct specification, ureteric bud induction, renal branching morphogenesis, and cessation of renal branching morphogenesis. We also highlight salient molecular signaling pathways that govern these processes, and the investigative techniques used to interrogate them. Copyright © 2014. Published by Elsevier Ltd. KEYWORDS: Branching morphogenesis; CAKUT; Kidney; Signaling; Ureteric bud

PMID 25080023

Glomerular development--shaping the multi-cellular filtration unit

Semin Cell Dev Biol. 2014 Dec;36:39-49. doi: 10.1016/j.semcdb.2014.07.016. Epub 2014 Aug 18.

Schell C1, Wanner N2, Huber TB3.

Abstract The glomerulus represents a highly structured filtration unit, composed of glomerular endothelial cells, mesangial cells, podocytes and parietal epithelial cells. During glomerulogenesis an intricate network of signaling pathways involving transcription factors, secreted factors and cell-cell communication is required to guarantee accurate evolvement of a functional, complex 3-dimensional glomerular architecture. Here, we want to provide an overview on the critical steps and relevant signaling cascades of glomerular development. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved. KEYWORDS: Endothelial cell; Glomerular development; Mesangial cell; Parietal epithelial cell; Podocyte; WT1

PMID 25153928

Renal development: a complex process dependent on inductive interaction

Curr Pediatr Rev. 2014;10(2):107-14.

Upadhyay KK, Silverstein DM1.


Renal development begins in-utero and continues throughout childhood. Almost one-third of all developmental anomalies include structural or functional abnormalities of the urinary tract. There are three main phases of in-utero renal development: Pronephros, Mesonephros and Metanephros. Within three weeks of gestation, paired pronephri appear. A series of tubules called nephrotomes fuse with the pronephric duct. The pronephros elongates and induces the nearby mesoderm, forming the mesonephric (Woffian) duct. The metanephros is the precursor of the mature kidney that originates from the ureteric bud and the metanephric mesoderm (blastema) by 5 weeks of gestation. The interaction between these two components is a reciprocal process, resulting in the formation of a mature kidney. The ureteric bud forms the major and minor calyces, and the collecting tubules while the metanephrogenic blastema develops into the renal tubules and glomeruli. In humans, all of the nephrons are formed by 32 to 36 weeks of gestation. Simultaneously, the lower urinary tract develops from the vesico urethral canal, ureteric bud and mesonephric duct. In utero, ureters deliver urine from the kidney to the bladder, thereby creating amniotic fluid. Transcription factors, extracellular matrix glycoproteins, signaling molecules and receptors are the key players in normal renal development. Many medications (e.g., aminoglycosides, cyclooxygenase inhibitors, substances that affect the renin-angiotensin aldosterone system) also impact renal development by altering the expression of growth factors, matrix regulators or receptors. Thus, tight regulation and coordinated processes are crucial for normal renal development.

PMID 25088264


Generation of the podocyte and tubular components of an amniote kidney: timing of specification and a role for Wnt signaling

Development. 2013 Nov;140(22):4565-73. doi: 10.1242/dev.097063. Epub 2013 Oct 23.

Grinstein M1, Yelin R, Herzlinger D, Schultheiss TM.


Kidneys remove unwanted substances from the body and regulate the internal body environment. These functions are carried out by specialized cells (podocytes) that act as a filtration barrier between the internal milieu and the outside world, and by a series of tubules and ducts that process the filtrate and convey it to the outside. In the kidneys of amniote vertebrates, the filtration (podocyte) and tubular functions are tightly integrated into functional units called nephrons. The specification of the podocyte and tubular components of amniote nephrons is currently not well understood. The present study investigates podocyte and tubule differentiation in the avian mesonephric kidney, and presents several findings that refine our understanding of the initial events of nephron formation. First, well before the first morphological or molecular signs of nephron formation, mesonephric mesenchyme can be separated on the basis of morphology and the expression of the transcription factor Pod1 into dorsal and ventral components, which can independently differentiate in culture along tubule and podocyte pathways, respectively. Second, canonical Wnt signals, which are found in the nephric duct adjacent to the dorsal mesonephric mesenchyme and later in portions of the differentiating nephron, strongly inhibit podocyte but not tubule differentiation, suggesting that Wnt signaling plays an important role in the segmentation of the mesonephric mesenchyme into tubular and glomerular segments. The results are discussed in terms of their broader implications for models of nephron segmentation. KEYWORDS: Chick embryo; Kidney; Mesonephros; Podocyte; Renal vesicle; Wnt signaling

PMID 24154527


Glomerulogenesis: Can it predict the gestational age? A study of 176 fetuses

Indian J Pathol Microbiol. 2012 Jul;55(3):303-7. doi: 10.4103/0377-4929.101734.

Chikkannaiah P, Roy M, Kangle R, Patil PV. Source Department of Pathology, KLE University's Jawaharlal Nehru Medical College, Belgaum, Karnataka, India.


Background: Accurate assessment of gestational age of fetuses is essential from both clinical and medico-legal point of view. Crown-rump length, crown-heel length, foot length, and the weight of the fetus are the commonly used parameters for fetal age assessment. However, this estimate often lacks accuracy and sometimes is necessary to combine other data. An analysis of the embryological development of nephrons in the kidney can assist in this determination. Objective : To correlate the gestational age with the histological study of sequential development of nephrons in fetal kidney. Materials and Methods: This study included 176 fetuses delivered between June 2009 and June 2011 and aged from 12 to 40 weeks. The number of glomerular generations counted in hematoxylin and eosin-stained microscopic sections of the kidneys were correlated with the reported period of gestation based on obstetrical methods. Regression analysis was used to determine the statistical significance of the correlation. Results: A high degree of statistically significant correlation was observed between the period of gestation and the number of glomerular generations (P value < 0.0001). Conclusion: The histological assessment of the number of glomerular generations in kidney can be used as a reliable method of estimating fetal age.

PMID 23032821;year=2012;volume=55;issue=3;spage=303;epage=307;aulast=Chikkannaiah

Pathway in Kidney Development: Implications for Nephrogenesis

Citation: Saifudeen Z, Liu J, Dipp S, Yao X, Li Y, et al. (2012) A p53-Pax2 Pathway in Kidney Development: Implications for Nephrogenesis. PLoS ONE 7(9): e44869. doi:10.1371/journal.pone.0044869

Copyright: © 2012 Saifudeen et al. 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 author and source are credited.

Bmp7 functions via a polarity mechanism to promote cloacal septation

PLoS One. 2012;7(1):e29372. Epub 2012 Jan 13.

Xu K, Wu X, Shapiro E, Huang H, Zhang L, Hickling D, Deng Y, Lee P, Li J, Lepor H, Grishina I. Source Department of Urology, School of Medicine, New York University, New York, New York, United States of America.


BACKGROUND: During normal development in human and other placental mammals, the embryonic cloacal cavity separates along the axial longitudinal plane to give rise to the urethral system, ventrally, and the rectum, dorsally. Defects in cloacal development are very common and present clinically as a rectourethral fistula in about 1 in 5,000 live human births. Yet, the cellular mechanisms of cloacal septation remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We previously detected Bone morphogenetic protein 7 (Bmp7) expression in the urorectal mesenchyme (URM), and have shown that loss of Bmp7 function results in the arrest of cloacal septation. Here, we present evidence that cloacal partitioning is driven by Bmp7 signaling in the cloacal endoderm. We performed TUNEL and immunofluorescent analysis on cloacal sections from Bmp7 null and control littermate embryos. We found that loss of Bmp7 results in a dramatic decrease in the endoderm survival and a delay in differentiation. We used immunological methods to show that Bmp7 functions by activating the c-Jun N-terminal kinase (JNK) pathway. We carried out confocal and 3D imaging analysis of mitotic chromosome bundles to show that during normal septation cells in the cloacal endoderm divide predominantly in the apical-basal direction. Loss of Bmp7/JNK signaling results in randomization of mitotic angles in the cloacal endoderm. We also conducted immunohistochemical analysis of human fetal sections to show that BMP/phospho-SMAD and JNK pathways function in the human cloacal region similar as in the mouse. CONCLUSION/SIGNIFICANCE: Our results strongly indicate that Bmp7/JNK signaling regulates remodeling of the cloacal endoderm resulting in a topological separation of the urinary and digestive systems. Our study points to the importance of Bmp and JNK signaling in cloacal development and rectourethral malformations.

PMID 22253716

Expression of Bcl-2 and Bax in Mouse Renal Tubules during Kidney Development

PLoS One. 2012;7(2):e32771. Epub 2012 Feb 28.

Song XF, Ren H, Andreasen A, Thomsen JS, Zhai XY. Source Department of Histology and Embryology, Institute of Pathology and Pathophysiology, China Medical University, Shen Yang, Liao Ning, China.


Bcl-2 and Bax play an important role in apoptosis regulation, as well as in cell adhesion and migration during kidney morphogenesis, which is structurally and functionally related to mitochondria. In order to elucidate the role of Bcl-2 and Bax during kidney development, it is essential to establish the exact location of their expression in the kidney. The present study localized their expression during kidney development. Kidneys from embryonic (E) 16-, 17-, 18-day-old mouse fetuses, and postnatal (P) 1-, 3-, 5-, 7-, 14-, 21-day-old pups were embedded in Epon. Semi-thin serial sections from two E17 kidneys underwent computer assisted 3D tubule tracing. The tracing was combined with a newly developed immunohistochemical technique, which enables immunohistochemistry on glutaraldehyde fixated plastic embedded sections. Thereby, the microstructure could be described in detail, and the immunochemistry can be performed using exactly the same sections. The study showed that Bcl-2 and Bax were strongly expressed in mature proximal convoluted tubules at all time points, less strongly expressed in proximal straight tubules, and only weakly in immature proximal tubules and distal tubules. No expression was detected in ureteric bud and other earlier developing structures, such as comma bodies, S shaped bodies, glomeruli, etc. Tubules expressing Bcl-2 only were occasionally observed. The present study showed that, during kidney development, Bcl-2 and Bax are expressed differently in the proximal and distal tubules, although these two tubule segments are almost equally equipped with mitochondria. The functional significance of the different expression of Bcl-2 and Bax in proximal and distal tubules is unknown. However, the findings of the present study suggest that the mitochondrial function differs between mature proximal tubules and in the rest of the tubules. The function of Bcl-2 and Bax during tubulogenesis still needs to be investigated.

PMID 22389723


Kidney development: two tales of tubulogenesis

Curr Top Dev Biol. 2010;90:193-229.

Little M, Georgas K, Pennisi D, Wilkinson L. Source Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia.


The mammalian kidney may well be one of the most complex organs of postnatal life. Each adult human kidney contains on average more than one million functional filtration units, the nephrons, residing within a specialized cellular interstitium. Each kidney also contains over 25 distinct cell types, each of which must be specifically aligned with respect to each other to ensure both normal development and ultimately, normal renal function. Despite this complexity, the development of the kidney can be simplistically described as the coordinate formation of two distinct sets of tubules. These tubules develop cooperatively with each other in time and space, yet represent two distinct but classical types of tubulogenesis. The first of these tubules, the ureteric bud, forms as an outgrowth of another epithelial tube, the nephric duct, and undergoes extensive branching morphogenesis to create the collecting system of the kidney. The second tubules are the nephrons themselves which arise via a mesenchyme-to-epithelial transition induced by the first set of tubules. These tubules never branch, but must elongate to become intricately patterned and functionally segmented tubules. The molecular drivers for these two tales of tubulogenesis include many gene families regulating tubulogenesis and branching morphogenesis in other organs; however, the individual players and codependent interrelationships between a branched and non-branched tubular network make organogenesis in the kidney unique. Here we review both what is known and remains to be understood in kidney tubulogenesis.

Copyright 2010 Elsevier Inc. All rights reserved.

PMID: 20691850

Kidney development in the absence of Gdnf and Spry1 requires Fgf10

PLoS Genet. 2010 Jan 15;6(1):e1000809.

Michos O, Cebrian C, Hyink D, Grieshammer U, Williams L, D'Agati V, Licht JD, Martin GR, Costantini F.

Department of Genetics and Development, Columbia University, New York, New York, USA.

Abstract GDNF signaling through the Ret receptor tyrosine kinase (RTK) is required for ureteric bud (UB) branching morphogenesis during kidney development in mice and humans. Furthermore, many other mutant genes that cause renal agenesis exert their effects via the GDNF/RET pathway. Therefore, RET signaling is believed to play a central role in renal organogenesis. Here, we re-examine the extent to which the functions of Gdnf and Ret are unique, by seeking conditions in which a kidney can develop in their absence. We find that in the absence of the negative regulator Spry1, Gdnf, and Ret are no longer required for extensive kidney development. Gdnf-/-;Spry1-/- or Ret-/-;Spry1-/- double mutants develop large kidneys with normal ureters, highly branched collecting ducts, extensive nephrogenesis, and normal histoarchitecture. However, despite extensive branching, the UB displays alterations in branch spacing, angle, and frequency. UB branching in the absence of Gdnf and Spry1 requires Fgf10 (which normally plays a minor role), as removal of even one copy of Fgf10 in Gdnf-/-;Spry1-/- mutants causes a complete failure of ureter and kidney development. In contrast to Gdnf or Ret mutations, renal agenesis caused by concomitant lack of the transcription factors ETV4 and ETV5 is not rescued by removing Spry1, consistent with their role downstream of both RET and FGFRs. This shows that, for many aspects of renal development, the balance between positive signaling by RTKs and negative regulation of this signaling by SPRY1 is more critical than the specific role of GDNF. Other signals, including FGF10, can perform many of the functions of GDNF, when SPRY1 is absent. But GDNF/RET signaling has an apparently unique function in determining normal branching pattern. In contrast to GDNF or FGF10, Etv4 and Etv5 represent a critical node in the RTK signaling network that cannot by bypassed by reducing the negative regulation of upstream signals.

PMID 20084103

Hs2st mediated kidney mesenchyme induction regulates early ureteric bud branching

Dev Biol. 2010 Mar 15;339(2):354-65. Epub 2010 Jan 6.

Shah MM, Sakurai H, Sweeney DE, Gallegos TF, Bush KT, Esko JD, Nigam SK.

Department of Medicine, University of California, San Diego, CA 92093-0693, USA.


Heparan sulfate proteoglycans (HSPGs) are central modulators of developmental processes likely through their interaction with growth factors, such as GDNF, members of the FGF and TGFbeta superfamilies, EGF receptor ligands and HGF. Absence of the biosynthetic enzyme, heparan sulfate 2-O-sulfotransferase (Hs2st) leads to kidney agenesis. Using a novel combination of in vivo and in vitro approaches, we have reanalyzed the defect in morphogenesis of the Hs2st(-)(/)(-) kidney. Utilizing assays that separately model distinct stages of kidney branching morphogenesis, we found that the Hs2st(-/-) UB is able to undergo branching and induce mesenchymal-to-epithelial transformation when recombined with control MM, and the isolated Hs2st null UB is able to undergo branching morphogenesis in the presence of exogenous soluble pro-branching growth factors when embedded in an extracellular matrix, indicating that the UB is intrinsically competent. This is in contrast to the prevailing view that the defect underlying the renal agenesis phenotype is due to a primary role for 2-O sulfated HS in UB branching. Unexpectedly, the mutant MM was also fully capable of being induced in recombination experiments with wild-type tissue. Thus, both the mutant UB and mutant MM tissue appear competent in and of themselves, but the combination of mutant tissues fails in vivo and, as we show, in organ culture. We hypothesized a 2OS-dependent defect in the mutual inductive process, which could be on either the UB or MM side, since both progenitor tissues express Hs2st. In light of these observations, we specifically examined the role of the HS 2-O sulfation modification on the morphogenetic capacity of the UB and MM individually. We demonstrate that early UB branching morphogenesis is not primarily modulated by factors that depend on the HS 2-O sulfate modification; however, factors that contribute to MM induction are markedly sensitive to the 2-O sulfation modification. These data suggest that key defect in Hs2st null kidneys is the inability of MM to undergo induction either through a failure of mutual induction or a primary failure of MM morphogenesis. This results in normal UB formation but affects either T-shaped UB formation or iterative branching of the T-shaped UB (possibly two separate stages in collecting system development dependent upon HS). We discuss the possibility that a disruption in the interaction between HS and Wnts (e.g. Wnt 9b) may be an important aspect of the observed phenotype. This appears to be the first example of a defect in the MM preventing advancement of early UB branching past the first bifurcation stage, one of the limiting steps in early kidney development.

Copyright 2010 Elsevier Inc. All rights reserved.

PMID 20059993

A novel, low-volume method for organ culture of embryonic kidneys that allows development of cortico-medullary anatomical organization.

Sebinger DD, Unbekandt M, Ganeva VV, Ofenbauer A, Werner C, Davies JA. PLoS One. 2010 May 10;5(5):e10550.

PMID 20479933

Jacob M. Yusuf F. and Jacob HJ. Development, Differentiation and Derivatives of the Wolffian and Müllerian Ducts. (2012) The Human Embryo, Dr. Shigehito Yamada (Ed.), ISBN: 978-953-51-0124-6, InTech, Available from:

Monika Jacob, Faisal Yusuf and Heinz Jürgen Jacob (2012). Development, Differentiation and Derivatives of the Wolffian and Müllerian Ducts, The Human Embryo, Dr. Shigehito Yamada (Ed.), ISBN: 978-953-51-0124-6, InTech, Available from: derivatives-of-the-wolffian-and-m-llerian-ducts

The Wolffian ducts (pro- and mesonephric ducts) are the most important and earliest structures formed during the development of the urogenital system in vertebrates including humans. The Wolffian ducts originate in the prospective cervical region of the young embryo but later migrate caudally inducing the development of the pronephric and mesonephric tubules along their migratory route. In addition to being the inducers of the first two generations of the kidney, namely the pronephros and mesonephros, the Wolffian ducts also give rise to the ureteric buds which drive the growth and differentiation of the permanent kidneys, the metanephroi. The paired ureteric bud arises as outpouching from the caudal end of the Wolffian duct and induces the epithelialisation of the metanephric blastema leading to the formation of the renal corpuscles and tubular part of the nascent metanephric kidney, while the entire collecting system consisting of the ureter, the renal pelvis, the calyces and the collecting ducts take their origin from the ureteric bud.

© 2012 The Author(s). Licensee IntechOpen. This is an open access article distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Size and volume charts of fetal kidney, renal pelvis and adrenal gland

Ultrasound Obstet Gynecol. 2012 Dec;40(6):659-64. doi: 10.1002/uog.11169.

van Vuuren SH1, Damen-Elias HA, Stigter RH, van der Doef R, Goldschmeding R, de Jong TP, Westers P, Visser GH, Pistorius LR.


OBJECTIVE: To establish reference curves for size and volume of the fetal kidney, renal pelvis and adrenal gland, as measured using ultrasound from the 15(th) week of gestation. METHODS: This was a prospective, longitudinal study of 96 fetuses in low-risk singleton pregnancies, in which we performed serial ultrasound examinations at 4-week intervals. The length and anteroposterior and transverse diameters of both kidneys, the anteroposterior and transverse diameters of the renal pelvises and the length of the adrenal glands were measured three times at each examination, with the average being used for further analysis. Reference charts were constructed using multilevel statistical analysis and comparisons were made with previously published charts derived from cross-sectional data. RESULTS: We present nomograms for fetal kidney dimensions and volume, renal pelvis dimensions and adrenal gland length. The new charts show differences in shape and have narrower percentile bands in comparison to previously published reference ranges. CONCLUSIONS: These new charts of measurements of the fetal kidney, renal pelvis and adrenal gland, from a prospective, longitudinal study, may be useful in the diagnosis and assessment of pathology of the kidney and adrenal gland. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

PMID 22581671

Good graphs of US renal growth.

The kidney from prenatal to adult life: perinatal programming and reduction of number of nephrons during development

Am J Nephrol. 2009;30(2):162-70. Epub 2009 Apr 2.

Puddu M, Fanos V, Podda F, Zaffanello M. Source Department of Pediatrics and Clinical Medicine, NICU, University of Cagliari, Cagliari, Italy.


Modified embryonic-fetal development resulting in low birth weight may lead to a reduced nephron endowment, hypertension and renal diseases in adulthood. Regarding the involvement of genetic factors, several environmental conditions may also contribute towards reducing the number of nephrons in the fetus and infant, subsequently constituting a health burden in later life. To date no methods of investigation for the early detection of a reduced nephron reserve are available. However, more structured studies should be implemented to investigate the role of angiotensin-converting enzyme inhibitors in managing proteinurias and glomerulosclerosis in children with renal conditions characterized by reduce nephron number and glomerular hypertrophic changes. In view of the current lack of specific methods of investigation and management, close monitoring of children and young adults at risk of reduced renal reserve should be carried out to enhance the early detection of potential changes in renal function.

  • humans the overall number of nephrons ranges be- tween 617,000 and 1,075,000 (mean 850,000 nephrons).
  • hypertensive adults mean of about 702,000 nephrons.
  • normotensive subjects with a mean of 1,429,000 nephrons.

Copyright 2009 S. Karger AG, Basel.

PMID 19339773

Human renal function maturation: a quantitative description using weight and postmenstrual age

Pediatr Nephrol. 2009 Jan;24(1):67-76. Epub 2008 Oct 10.

Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut E, Grubb A, Veal GJ, Keir MJ, Holford NH. Source Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden.


This study pools published data to describe the increase in glomerular filtration rate (GFR) from very premature neonates to young adults. The data comprises measured GFR (using polyfructose, (51)Cr-EDTA, mannitol or iohexol) from eight studies (n = 923) and involved very premature neonates (22 weeks postmenstrual age) to adulthood (31 years). A nonlinear mixed effects approach (NONMEM) was used to examine the influences of size and maturation on renal function. Size was the primary covariate, and GFR was standardized for a body weight of 70 kg using an allometric power model. Postmenstrual age (PMA) was a better descriptor of maturational changes than postnatal age (PNA). A sigmoid hyperbolic model described the nonlinear relationship between GFR maturation and PMA. Assuming an allometric coefficient of 3/4, the fully mature (adult) GFR is predicted to be 121.2 mL/min per 70 kg [95% confidence interval (CI) 117-125]. Half of the adult value is reached at 47.7 post-menstrual weeks (95%CI 45.1-50.5), with a Hill coefficient of 3.40 (95%CI 3.03-3.80). At 1-year postnatal age, the GFR is predicted to be 90% of the adult GFR. Glomerular filtration rate can be predicted with a consistent relationship from early prematurity to adulthood. We propose that this offers a clinically useful definition of renal function in children and young adults that is independent of the predictable changes associated with age and size.

PMID 18846389

Kidney development: from ureteric bud formation to branching morphogenesis

Curr Opin Genet Dev. 2009 Oct;19(5):484-90. Epub 2009 Oct 14.

Michos O.

Department of Genetics and Development, Columbia University Medical Center, HHSC1416, New York, NY 10032, USA.

Abstract Epithelial branching morphogenesis is critical to the formation of various organs such as the vasculature, mammary glands, lungs, and kidneys in vertebrate embryos. One fascinating aspect of branching morphogenesis is to understand how a simple epithelial tube grows by reiterative branching to form a complex epithelial tree structure. Recent studies combining mouse genetics and chimeric analysis with live imaging have uncovered the molecular networks and interactions that govern kidney branching morphogenesis. This review focuses on ureteric bud (UB) formation and epithelial branching during kidney development. The invasion of the metanephric mesenchyme by the UB is a fundamental step toward establishing the cyto-architecture of the kidney and determining the number of nephrons, which form the filtration units of the adult kidney.

PMID 19828308

--Mark Hill 07:20, 8 April 2011 (EST) Good molecular development overview figures.

Cell and molecular biology of kidney development

Reidy KJ, Rosenblum ND. Semin Nephrol. 2009 Jul;29(4):321-37. Review. PMID: 19615554

Semin Nephrol. 2009 Jul;29(4):321-37. Cell and molecular biology of kidney development. Reidy KJ, Rosenblum ND.

Department of Pediatrics/Division of Pediatric Nephrology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, 3415 Bainbridge Ave, Bronx, NY 10467, USA. Abstract Abnormalities of kidney and urinary tract development are the most common cause of end-stage kidney failure in childhood in the United States. Over the past 20 years, the advent of mutant and transgenic mice and the manipulation of gene expression in other animal models has resulted in major advances in identification of the cellular and molecular mechanisms that direct kidney morphogenesis, providing insights into the pathophysiology of renal and urologic anomalies. This review focuses on the molecular mechanisms that define kidney progenitor cell populations, induce nephron formation within the metanephric mesenchyme, initiate and organize ureteric bud branching, and participate in terminal differentiation of the nephron. Highlighted are common signaling pathways that function at multiple stages during kidney development, including signaling via Wnts, bone morphogenic proteins, fibroblast growth factor, sonic hedgehog, RET/glial cell-derived neurotrophic factor, and notch pathways. Also emphasized are the roles of transcription factors Odd1, Eya1, Pax2, Lim1, and WT-1 in directing renal development. Areas requiring future investigation include the factors that modulate signaling pathways to provide temporal and site-specific effects. The evolution of our understanding of the cellular and molecular mechanisms of kidney development may provide methods for improved diagnosis of renal anomalies and, hopefully, targets for intervention for this common cause of childhood end-stage kidney disease.

PMID 19615554

How does the ureteric bud branch?

J Am Soc Nephrol. 2009 Jul;20(7):1465-9. Epub 2008 Dec 3.

Nigam SK, Shah MM.

Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, USA. Abstract Many genes that modulate kidney development have been identified; however, the molecular interactions that direct arborization of the ureteric bud (UB) remain incompletely understood. This article discusses how "systems" approaches may shed light on the structure of the gene network during UB branching morphogenesis and the mechanisms involved in the formation of a branched collecting system from a straight epithelial tube in the context of a stage model. In vitro and genetic studies suggest that the stages seem to be governed by a conserved network of genes that establish a "tip-stalk generator"; these genes sustain iterative UB branching tubulogenesis through minimal alterations in the network architecture as a budding system shifts to one that autocatalytically branches through budding. The differential expression of stage-specific positive and inhibitory factors in the mesenchyme, likely presented in the context of heparan sulfate proteoglycans, and effector molecules in the epithelium seems to regulate advancement between stages; similar principles may apply to other branching epithelia such as the lung, salivary gland, pancreas, mammary gland, and prostate. Active mesenchymal interactions with the UB seem to govern vectorial arborization and tapering of the collecting system and its terminal differentiation. Cessation of branching correlates with induction of mesenchyme as well as local extracellular matrix changes. Perturbations of these mechanisms and/or single-nucleotide polymorphisms in genes regulating UB branching may predispose to a variety of renal diseases (e.g., hypertension and chronic kidney disease) by altering nephron number. Decentralization of the gene-protein interaction network may explain the relative paucity of branching phenotypes in mutant mice and in human disease.

PMID 19056872


The spectrum of podocytopathies: a unifying view of glomerular diseases

Kidney Int. 2007 Jun;71(12):1205-14. Epub 2007 Apr 4.

Wiggins RC. Source Nephrology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-0676, USA.


Glomerular diseases encompass a broad array of clinicopathologically defined syndromes which together account for 90% of end-stage kidney disease costing $20 billion per annum to treat in the United States alone. Recent insights have defined the central role of the podocyte as both the regulator of glomerular development as well as the determinant of progression to glomerulosclerosis. We can now place all glomerular diseases within this spectrum of podocytopathies with predictable outcomes based on podocyte biology impacted by temporal, genetic, and environmental cues. This simplified construct is particularly useful to rationalize clinical effort toward podocyte preservation and prevention of progression as well as to focus basic research effort on understanding podocyte biology and for clinical research toward development of practical monitoring strategies for podocyte injury, dysfunction, and loss.

PMID 17410103


Quantitative analysis of the nephron during human fetal kidney development

Vojnosanit Pregl. 2005 Apr;62(4):281-6.

Daković-Bjelaković M, Vlajković S, Cukuranović R, Antić S, Bjelaković G, Mitić D. Source University of Nis, Medical Faculty, Institute of Anatomy, Clinical Centre, Nis. Abstract BACKGROUND: The development of human kidney is a complex process. The number, shape, size, and distribution of nephrons as functional units in a kidney, provide some important information about the organization of the kidney. The aim of this study was to extend the knowledge of the developing human kidney by studying nephrons in the kidney's cortex during gestation. METHODS: Kidney tissue specimens of 32 human fetuses, the gestational age from IV lunar month (LM IV) to LM X, were analysed. Specimens were divided in ten groups based on gestational age. Stereological methods were used at the light microscopic level to estimate the volume densities of the corpuscular and tubular components of the nephron in the cortex of the developing human kidney. RESULTS: Nephron polymorphism was the main characteristic of the human fetal kidney during development. In younger fetuses, just below the renal capsule, there was a wide nephrogenic zone. It contained the condensed mesenchyme and terminal ends of the ureteric bud. Nephrons, in the different stages of development, were located around the ureteric bud which branched in the cortical nephrogenic zone and induced nephrogenesis. More mature nephrons were located in the deeper part of the cortex, close to the juxta-medullary junction. During gestation, nephrogenesis continually advanced, and the number of nephrons increased. Glomeruli changed their size and shape, while the tubules changed their length and convolution. Renal cortex became wider and contained the more mature glomeruli and the more convoluted tubules. The volume density of the tubular component of the nephron increased continually from 10.53% (LM IVa) to 27.7% (LM X). Renal corpuscles changed their volume density irregularly during gestation, increasing from 13% (LM IVa) to 15.5% (LM IVb). During the increase of gestational age, the volume density of corpuscular component of the nephron decreased to 11.7% (LM VIII), then went on increasing until the end of the intrauterine development (LM X) when corpuscles occupied 16.73% of the cortical volume. The volume density of the developing nephrons (corpuscular and tubular portion) showed the significant positive correlation (r = 0.85; p<0.01) with gestational age. CONCLUSION: The present study was one of few quantitative studies of the human developing nephron. Knowledge about the normal development of the human kidney should be important for the future medical practice. PMID 15889592


Endodermal origin of bladder trigone inferred from mesenchymal-epithelial interaction

J Urol. 2010 Jan;183(1):386-91.

Tanaka ST, Ishii K, Demarco RT, Pope JC 4th, Brock JW 3rd, Hayward SW.

Department of Urologic Surgery, Monroe Carell, Jr Children's Hospital at Vanderbilt, Nashville, Tennessee 37232-9820, USA.

Abstract PURPOSE: In the classic view of bladder development the trigone originates from the mesoderm derived wolffian ducts while the remainder of the bladder originates from the endoderm derived urogenital sinus. Recent molecular developmental studies have questioned the veracity of this received wisdom, suggesting an endodermal origin for the trigone. To shed further light on this issue we observed mesenchymal-epithelial interactions between trigone epithelium and fetal urogenital sinus mesenchyma to infer the trigonal germ layer of origin.

MATERIALS AND METHODS: Mouse trigone epithelium was recombined with fetal rat urogenital sinus mesenchyma in tissue recombinant grafts that were placed beneath the renal capsule of athymic mouse hosts. Grafts were harvested at 4 weeks. Control grafts with bladder dome and ureteral epithelium were also examined. Tissues were evaluated with hematoxylin and eosin, and Hoechst dye 33258 to confirm cell species origin. Immunohistochemistry was done with androgen receptor, broad spectrum uroplakin, dorsolateral prostate secretions and seminal vesicle secretions to differentiate prostatic and seminal vesicle differentiation.

RESULTS: Grafts of mouse trigone epithelium with fetal rat urogenital sinus mesenchyma yielded epithelial tissue that stained for dorsolateral prostate secretions but not for seminal vesicle secretions. Control grafts of bladder dome epithelium yielded the expected endodermal prostate differentiation. Control grafts of ureteral epithelium yielded the expected mesodermal seminal vesicle differentiation.

CONCLUSIONS: The consistent finding of prostatic epithelium in tissue recombinants of trigone epithelium and fetal urogenital sinus mesenchyma reinforces the hypothesis that the trigone is derived from the endoderm and not from the mesoderm, as commonly accepted.

PMID: 19914648


Human embryo (12 mm) with mesohydronephrosis and ureterohydronephrosis

Ruano-Gil D & Tejedo-Mateu A. (1975). Human embryo (12 mm) with mesohydronephrosis and ureterohydronephrosis. Acta Anat (Basel) , 93, 135-40. PMID: 1189894

Abstract This report describes a human embryo with a length of 12 mm (horizon XVII Streeterm 35 +/- 1 day old), in which the following malformations appear: Dilation on both sides of the Wolffian ducts, and the more caudal mesonephritic glomerules (mesohydronephrosis). Dilatation of both ureters and renal pelvis (uretero-hydronephrosis). These malformations are the result of the accumulation of liquid secreted by the mesonephros in a cloaca which is dilated, unwalled and blocked by an epithelial plug which is continuous with the cloacal membrane.