Congenital Anomalies Of The Kidney And Urinary Tract Research Articles

Overexpression of Long Non-coding RNA 4933425B07Rik Causes Urinary Malformations in Mice.

Congenital anomalies of the kidney and urinary tract (CAKUT) is a common birth defect and is the leading cause of end-stage renal disease in children. The etiology of CAKUT is complex and includes mainly genetic and environmental factors. However, these factors cannot fully explain the etiological mechanism of CAKUT. Recently, participation of long non-coding RNAs (lncRNAs) in the development of the circulatory and nervous systems was demonstrated; however, the role of lncRNAs in the development of the kidney and urinary tract system is unclear. In this study, we used the piggyBac (PB) transposon-based mutagenesis to construct a mouse with lncRNA 4933425B07Rik (Rik) PB insertion (RikPB/PB) and detected overexpression of Rik and a variety of developmental abnormalities in the urinary system after PB insertion, mainly including renal hypo/dysplasia. The number of ureteric bud (UB) branches in the RikPB/PB embryonic kidney was significantly decreased in embryonic kidney culture. Only bone morphogenetic protein 4 (Bmp4), a key molecule regulating UB branching, is significantly downregulated in RikPB/PB embryonic kidney, while the expression levels of other molecules involved in the regulation of UB branching were not significantly different according to the RNA-sequencing (RNA-seq) data, and the results were verified by quantitative real-time polymerase chain reaction (RT-PCR) and immunofluorescence assays. Besides, the expression of pSmad1/5/8, a downstream molecule of BMP4 signaling, decreased by immunofluorescence. These findings suggest that abnormal expression of Rik may cause a reduction in the UB branches by reducing the expression levels of the UB branching-related molecule Bmp4, thus leading to the development of CAKUT.

Epidemiology of Chronic Kidney Disease in Children: A Report from Lithuania.

Background and Objectives: The data on the prevalence of chronic kidney disease (CKD) in the pediatric population are limited. The prevalence of CKD ranges from 56 to 74.7 cases per million of the age-related population (pmarp). The most common cause of CKD among children is congenital anomalies of the kidney and urinary tract (CAKUT). With progressing CKD, various complications occur, and end-stage renal disease (ESRD) can develop. The aim of the study was to determine the causes, stage, prevalence, and clinical signs of CKD and demand for RRT (renal replacement therapy) among Lithuanian children in 2017 and to compare the epidemiological data of CKD with the data of 1997 and 2006. Materials and Methods: The data of 172 Lithuanian children who had a diagnosis of CKD (stage 2–5) in 1997 (n = 41), in 2006 (n = 65), and in 2017 (n = 66) were retrospectively analyzed. Physical development and clinical signs of children who had CKD (stage 2–5) in 2017 were assessed. Results: The prevalence of CKD stages 2–5 was 48.0 pmarp in 1997; 88.7 in 2006; and 132.1 in 2017 (p < 0.01). Congenital and hereditary diseases of the kidney in 1997 accounted for 66% of all CKD causes; in 2006, for 70%; and in 2017, for 79%. In 2017, children with CKD stages 4 or 5 (except transplanted children) had hypertension (87.5%) and anemia (50%) (p < 0.01). Children under ≤2 years with CKD were at a 3-fold greater risk of having elevated blood pressure (OR = 3.375, 95% CI: 1.186–9.904). Conclusions: There was no change in the number of children with CKD in Lithuania; however, the prevalence of CKD increased due to reduced pediatric population. CAKUT remains the main cause of CKD at all time periods. Among children with CKD stages 4 or 5, there were more children with hypertension and anemia. In children who were diagnosed with CKD at an early age hypertension developed at a younger age.

Renal Transplants Due to Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) Have Better Graft Survival Than Non-CAKUT Controls: Analysis of Over 10,000 Patients

To determine whether graft survival for patients with congenital anomalies of the kidney and urinary tract (CAKUT) is impaired compared to non-CAKUT counterparts. The United States Renal Data System (USRDS) is a national data system that has collected information about end stage renal disease (ESRD) and renal transplantation since 1995. We identified 10,635 first-time renal transplant patients with ESRD attributed to a CAKUT diagnosis transplanted between 1995 and 2018, with follow-up of 7.9 ± 5.8 years. We matched 1:1 with non-CAKUT transplant recipients, using age at transplant, sex, race, year of transplant, and donor-type. We compared renal transplant death-censored graft survival between CAKUT vs non-CAKUT controls, with further stratification for age at transplant and lower urinary tract malformations (LUTM) vs upper urinary tract malformations (UUTM). Graft survival was better in CAKUT patients with a 5-year survival of 83.3% vs 79.3% (P< .001), and CAKUT status infers a hazard ratio of 0.878 for graft failure on multivariable analysis with Cox regression. Favorability of CAKUT status persisted when stratifying for both pediatric (80.3 vs 77.6% P< .001) and adult (84.5 vs 81.4% P< .001) age groups. Looking within the CAKUT population: comparison of LUTM to UUTM yielded no difference, implying that LUTM is not a risk factor for graft failure. Examining pediatric LUTM alone, graft survival was not better than matched non-CAKUT counterparts with 5-year graft survival of 69%-75% for LUTM adolescents. Renal transplant graft survival is better overall in CAKUT patients as opposed to non-CAKUT counterparts. Pediatric LUTM patients have similar graft survival to controls.

Congenital Anomalies of the Kidney and Urinary Tract and Adulthood risk of Urinary Tract Cancer

IntroductionCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common kidney diseases in childhood. Alterations in genes governing nephrogenesis may cause CAKUT, and in some cases may contribute to development of urinary tract (UT) tumors later in life. We aimed to assess the association between CAKUT and UT cancer in adulthood.MethodsWe conducted a population-based historical cohort study encompassing 1,510,042 recruits to the Israeli army between 1967 and 1997. CAKUT exposure was determined by army medical coding of CAKUT in childhood. Incidence of UT cancer (kidney, ureter, or bladder) was available through record linkage with the Israeli Cancer Registry. Recruits were followed from the prerecruitment assessment until cancer diagnosis, death, or study termination, in 2012. Cox proportional hazards models were constructed to estimate the hazard ratios (HRs) for UT cancer in participants with vs. without CAKUT.ResultsDuring a mean follow-up of 30.4 years, 2959 participants (2573 men and 386 women) developed UT cancer. Men with CAKUT exhibited an increased risk of UT cancer compared with men without CAKUT, yielding an adjusted HR of 1.98 (95% confidence interval [CI] 1.03-3.82). Among women CAKUT was associated with a HR of 5.88 (95% CI 2.19-15.76). Notably, upon stratification according to age of cancer diagnosis, the association between CAKUT and UT cancer was statistically significant only before 45 years of age in women and only after 45 years of age in men.ConclusionCAKUT is associated with a significantly increased risk of UT cancer, although the incidence and absolute risk remained quite low.

Diagnostic Accuracy of Point-of-care Nitrite and Leukocyte Esterase Dipstick Test for the Screening of Pediatric Urinary Tract Infections.

Our study aimed to evaluate the diagnostic performance of point-of-care nitrite and leukocyte esterase (LE) dipsticks in the diagnosis of suspected urinary tract infection (UTI) in infants <6 months (young infants) versus older children. The secondary objectives were to study the dipstick efficacy in children with congenital anomalies of the kidney and urinary tract (CAKUT) versus those without CAKUT; in children with simple UTI versus complicated UTI; and to evaluate the clinico-microbiological profile of children presenting with UTI. In this prospective observational study, cases with suspected UTI were enrolled from pediatric emergency or outpatient departments. Urine was collected for performing the urine dipstick and culture. Descriptive data regarding CAKUT, age, gender, etc., were recorded in a predesigned pro forma. We screened 506 children with suspected UTI, of whom 221 had urine culture positive. Approximately 38.4% of the children with UTI had underlying CAKUT, while 7.6% had renal scars. The most common CAKUT was vesicoureteric reflux (VUR). About 12 patients (2.3%) were known to have CAKUT at the time of enrollment in the study. In infants <6 months, LE dipstick had sensitivity 92%, specificity 89.7%, positive predictive value (PPV) 86.7%, negative predictive value (NPV) 93.8%, likelihood ratio (LR) + 8.9, LR- 0.09. In infants <6 months, nitrite dipstick had sensitivity 38%, specificity 97%, PPV 90.4%, NPV 68%, LR+ 12.6 and LR-0.63. In the age group 6 months to 12 years, the efficacy was better for both dipsticks. In age group more than 6 months to 12 years, LE dipstick had sensitivity 96.4%, specificity 95.8%, PPV 94.8 %, NPV 97.2%, LR+ 22.9, LR- 0.04. In age group more than six months to 12 years, nitrite dipstick had sensitivity 94.7%, specificity 99.5%, PPV 99.3%, NPV 96%, LR+ 189.4, and LR-0.05.

Renal developmental genes are differentially regulated after unilateral ureteral obstruction in neonatal and adult mice

Congenital obstructive nephropathy hinders normal kidney development. The severity and the duration of obstruction determine the compensatory growth of the contralateral, intact opposite kidney. We investigated the regulation of renal developmental genes, that are relevant in congenital anomalies of the kidney and urinary tract (CAKUT) in obstructed and contralateral (intact opposite) kidneys after unilateral ureteral obstruction (UUO) in neonatal and adult mice. Newborn and adult mice were subjected to complete UUO or sham-operation, and were sacrificed 1, 5, 12 and 19 days later. Quantitative RT-PCR was performed in obstructed, intact opposite kidneys and sham controls for Gdnf, Pax2, Six4, Six2, Dach1, Eya1, Bmp4, and Hnf-1β. Neonatal UUO induced an early and strong upregulation of all genes. In contrast, adult UUO kidneys showed a delayed and less pronounced upregulation. Intact opposite kidneys of neonatal mice revealed a strong upregulation of all developmental genes, whereas intact opposite kidneys of adult mice demonstrated only a weak response. Only neonatal mice exhibited an increase in BMP4 protein expression whereas adult kidneys strongly upregulated phosphatidylinositol 3 kinase class III, essential for compensatory hypertrophy. In conclusion, gene regulation differs in neonatal and adult mice with UUO. Repair and compensatory hypertrophy involve different genetic programs in developing and adult obstructed kidneys.

Pattern of pediatric renal diseases in a rural tertiary care hospital

Background: Spectrum of renal disease varies in different population, geographical location, and by environmental factors. The purpose of this study was to find out the occurrence of different pediatric renal diseases at a teaching hospital in the rural part of Maharashtra, India.Methods: All cases of renal diseases from one month to 12 years of age, admitted to the wards during the period of July 2018 to December 2019, were included in the study. Detailed clinical and laboratory evaluations were performed on all patients. Diseases were categorized as per standard definitions and managed with hospital protocols.Results: Renal diseases accounted to be 235 cases (2.8%) of total pediatric admissions during study period, of which (61.3%) were male and (38.7%) female. Nephrotic syndrome (NS), was the most common disorder (34%) followed by congenital anomalies of the kidney and the urinary tract (CAKUT) (24.7%), urolithiasis (11%), urinary tract infection (10.63%), chronic kidney disease (CKD) (7.66%) and acute kidney injury (AKI) (3.83%). The causes of AKI were dehydration, urosepsis, septicemia, and acute glomerulonephritis (AGN). Mortality was found in 3.4% of cases and the etiologies were AKI, NS and CKD.Conclusions: A substantial number of children are hospitalized with renal and urinary tract diseases. NS and congenital defects were the leading renal disorders in this study. These patients need comprehensive services for early identification and management.

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT): An Emerging Relationship With Pregestational Diabetes Mellitus Among First Nations and Non-First Nations People in Saskatchewan—Results From the DIP: ORRIIGENSS Project

ObjectivesBecause congenital anomalies of the kidneys and urinary tract (CAKUT) represent a frequent cause of end stage renal disease (ESRD) in the young, we explored the epidemiology of CAKUT and the role of diabetes in pregnancy. MethodsThis was a retrospective cohort study of CAKUT, by maternal diabetes status, from among all 1980‒2009 births in Saskatchewan First Nations (FN) and non-First Nations (non-FN) people. We determined frequencies, predictors and complications of CAKUT, as well as cumulative survival (to 2014) of affected persons until ESRD and death. ResultsOf the 411,055 babies (204,167 mothers) in the Saskatchewan maternal-infant database, 2,540 had CAKUT (391 FN and 2,149 non-FN). Overall annual CAKUT incidence was 0.63% for non-FN and 0.57% for FN (p=0.082), but 5-year CAKUT incidence only increased among FN (0.40% in 1980‒1984 and 0.76% in 2005‒2009, p<0.0001) and was highest among offspring of FN mothers with pregestational diabetes (pre-G/DM) (0% before 1995, 2.51% in 2000‒2004 and 1.66% in 2005–2009). Pre-G/DM, but not gestational diabetes mellitus (GDM), was an independent predictor of CAKUT in non-FN (odds ratio, 1.79; 95% confidence interval, 1.20 to 2.69), and in FN interacting with maternal history of stillbirth (odds ratio, 7.90; 95% confidence interval, 1.14 to 54.6). ESRD was >100-fold more likely among offspring with CAKUT compared with all other offspring and was responsible for 40% of ESRD cases in young FN and non-FN people. ConclusionsIn Saskatchewan, pre-G/DM is an emerging cause of CAKUT, accounting for 40% of ESRD cases in FN/non-FN children and young adults. Because pre-G/DM‒related CAKUT is potentially preventable with optimal glycemic management, increased recognition of this serious complication is required.

Variable Expressivity of HNF1B Nephropathy, From Renal Cysts and Diabetes to Medullary Sponge Kidney Through Tubulo-interstitial Kidney Disease

IntroductionIn humans, heterozygous mutations of hepatocyte nuclear factor 1beta (HNF1B) are responsible for a dominant inherited disease with both renal and extrarenal phenotypes. HNF1B nephropathy is the umbrella term that includes the various kidney phenotypes of the disease, ranging from congenital anomalies of the kidney and urinary tract (CAKUT), to tubular transport abnormalities, to chronic tubulointerstitial and cystic renal disease.MethodsWe describe 7 families containing 13 patients with ascertained HNF1B nephropathy. All patients underwent genetic testing and clinical, laboratory, and instrumental assessment, including renal imaging and evaluation of extrarenal HNF1B manifestations.ResultsSignificant inter- and intrafamilial variability of HNF1B nephropathy has been observed. In our cohort, HNF1B pathogenic variants presented with renal cysts and diabetes syndrome (RCAD); renal cystic phenotype mimicking autosomal dominant polycystic kidney disease (ADPKD); autosomal dominant tubulointerstitial kidney disease (ADTKD) with or without hyperuricemia and gout; CAKUT; and nephrogenic diabetes insipidus (NDI). Of note, for the first time, we describe the occurrence of medullary sponge kidney (MSK) in a family harboring the HNF1B whole-gene deletion at chromosome 17q12. Genotype characterization led to the identification of an additional 6 novel HNF1B pathogenic variants, 3 frameshift, 2 missense, and 1 nonsense.ConclusionHNF1B nephropathy may present with a highly variable renal phenotype in adult patients. We expand the HNF1B renal clinical picture to include MSK as a potential new finding. Finally, we expand the allelic repertoire of the disease by adding novel HNF1B pathogenic variants.

Biallelic Pathogenic GFRA1 Variants Cause Autosomal Recessive Bilateral Renal Agenesis.

Congenital anomalies of the kidney and urinary tract (CAKUT) are one of the most common malformations identified in the fetal stage. Bilateral renal agenesis (BRA) represents the most severe and fatal form of CAKUT. Only three genes have been confirmed to have a causal role in humans (ITGA8, GREB1L, and FGF20). Genome sequencing within a diagnostic setting and combined data repository analysis identified a novel gene. Two patients presented with BRA, detected during the prenatal period, without additional recognizable malformations. They had parental consanguinity and similarly affected, deceased siblings, suggesting autosomal recessive inheritance. Evaluation of homozygous regions in patient 1 identified a novel, nonsense variant in GFRA1 (NM_001348097.1:c.676C>T, p.[Arg226*]). We identified 184 patients in our repository with renal agenesis and analyzed their exome/genome data. Of these 184 samples, 36 were from patients who presented with isolated renal agenesis. Two of them had loss-of-function variants in GFRA1. The second patient was homozygous for a frameshift variant (NM_001348097.1:c.1294delA, p.[Thr432Profs*13]). The GFRA1 gene encodes a receptor on the Wolffian duct that regulates ureteric bud outgrowth in the development of a functional renal system, and has a putative role in the pathogenesis of Hirschsprung disease. These findings strongly support the causal role of GFRA1-inactivating variants for an autosomal recessive, nonsyndromic form of BRA. This knowledge will enable early genetic diagnosis and better genetic counseling for families with BRA.

Kidney transplantation in children with CAKUT and non-CAKUT causes of chronic kidney disease: Do they have the same outcomes?

Almost half the children who undergo kidney transplantation (KTx) have congenital abnormalities of the kidney and urinary tract (CAKUT). We compared patient, graft survival, and kidney function at last follow-up between CAKUT and non-CAKUT patients after KTx. We divided the analysis into two eras: 1988-2000 and 2001-2019. Of 923 patients, 52% had CAKUT and 48% non-CAKUT chronic kidney disease (CKD). Of the latter, 341 (77%) had glomerular disease, most frequently typical HUS (32%) and primary FSGS (27%); 102 had non-glomerular disease. CAKUT patients were more often boys, younger at KTx, transplanted more frequently preemptively, but with longer time on chronic dialysis. They had less delayed graft function (DGF) and better eGFR, but higher incidence of urinary tract infection (1 year post-KTx). In both eras, 1-, 5-, and 10-year patient survival was similar in the groups, but graft survival was better in CAKUT recipients vs those with primary glomerular and primary recurrent glomerular disease: Era 1, 92.3%, 80.7%, and 63.6% vs 86.9%, 70.6%, and 49.5% (P=.02), and 76.7%, 56.6%, and 34% (P=.0003); Era 2, 96.2%, 88%, and 73.5% vs 90.3%, 76.1%, and 61% (P=.0075) and 75.4%, 54%, and 25.2% (P<.0001), respectively. Main predictors of graft loss were DGF, late acute rejection (AR), and age at KTx in CAKUT group and disease relapse, DGF, early AR, and number of HLA mismatches in recipients with glomerular disease. Graft survival was better in CAKUT patients. DGF was the main predictor of graft loss in all groups. Disease recurrence and early AR predicted graft failure in patients with glomerular disease.

Phenotype expansion of heterozygous FOXC1 pathogenic variants toward involvement of congenital anomalies of the kidneys and urinary tract (CAKUT)

PurposeCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in childhood and adolescence. We aim to identify novel monogenic causes of CAKUT. MethodsExome sequencing was performed in 550 CAKUT-affected families. ResultsWe discovered seven FOXC1 heterozygous likely pathogenic variants within eight CAKUT families. These variants are either never reported, or present in <5 alleles in the gnomAD database with ~141,456 controls. FOXC1 is a causal gene for Axenfeld–Rieger syndrome type 3 and anterior segment dysgenesis 3. Pathogenic variants in FOXC1 have not been detected in patients with CAKUT yet. Interestingly, mouse models for Foxc1 show severe CAKUT phenotypes with incomplete penetrance and variable expressivity. The FOXC1 variants are enriched in the CAKUT cohort compared with the control. Genotype–phenotype correlations showed that Axenfeld–Rieger syndrome or anterior segment dysgenesis can be caused by both truncating and missense pathogenic variants, and the missense variants are located at the forkhead domain. In contrast, for CAKUT, there is no truncating pathogenic variant, and all variants except one are located outside the forkhead domain. ConclusionWe thereby expanded the phenotype of FOXC1 pathogenic variants toward involvement of CAKUT, which can potentially be explained by allelism.

Additional Mutations in NRIP1 in Families with Congenital Anomalies of the Kidneys and Urinary Tract (CAKUT)

Additional Mutations in NRIP1 in Families with Congenital Anomalies of the Kidneys and Urinary Tract (CAKUT)

Copy Number Variation Analysis Increases Diagnostic Yield of Exome Sequencing and Facilitates the Identification of Genetic Causation for Congenital Anomalies of the Kidneys and Urinary Tract (CAKUT)

Copy Number Variation Analysis Increases Diagnostic Yield of Exome Sequencing and Facilitates the Identification of Genetic Causation for Congenital Anomalies of the Kidneys and Urinary Tract (CAKUT)

2020 update on the renin-angiotensin-aldosterone system in pediatric kidney disease and its interactions with coronavirus.

The last decade was crucial for our understanding of the renin–angiotensin–aldosterone system (RAAS) as a two-axis, counter-regulatory system, divided into the classical axis, formed by angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the angiotensin type 1 receptor (AT1R), and the alternative axis comprising angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) (Ang-(1-7)), and the Mas receptor. Breakthrough discoveries also took place, with other RAAS endopeptides being described, including alamandine and angiotensin A. In this review, we characterize the two RAAS axes and the role of their components in pediatric kidney diseases, including childhood hypertension (HTN), pediatric glomerular diseases, congenital abnormalities of the kidney and urinary tract (CAKUT), and chronic kidney disease (CKD). We also present recent findings on potential interactions between the novel coronavirus, SARS-CoV-2, and components of the RAAS, as well as potential implications of coronavirus disease 2019 (COVID-19) for pediatric kidney diseases.

A homozygous HOXA11 variation as a potential novel cause of autosomal recessive congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) is the leading cause of end-stage kidney disease in children. Until now, more than 50 monogenic causes for CAKUT have been described, all of which only explain 10% to 20% of all patients with CAKUT, suggesting the presence of additional genes that cause CAKUT when mutated. Herein, we report two siblings of a consanguineous family with CAKUT, both of which rapidly progressed to chronic kidney disease in early childhood. Whole-exome sequencing followed by homozygosity mapping identified a homozygous variation in HOXA11. We therefore showed for the first time an association between a homozygous HOXA11 variation with CAKUT in humans, expanding the genetic spectrum of the disease.

Chronic Kidney Disease in Iran: First Report of the National Registry in Children and Adolescences.

Knowing the epidemiological aspects of chronic kidney disease (CKD) in children is crucial for early recognition, identification of reversible causes, and prognosis. Here, we report the epidemiological characteristics of childhood CKD in Iran. This cross-sectional study was conducted during 1991 - 2009. The data were collected using the information in the Iranian Pediatric Registry of Chronic Kidney Disease (IPRCKD) core dataset. A total of 1247 children were registered. The mean age of the children at registration was 0.69 ± 4.72 years (range, 0.25 -18 years), 7.79 ± 3.18 years for hemodialysis (HD), 4.24 ± 1.86 years for continuous ambulatory peritoneal dialysis (CAPD), and 3.4±1.95 years for the children who underwent the renal transplantation (RT) (P < .001). The mean year of follow-up was 7.19 ± 4.65 years. The mean annual incidence of CKD 2-5 stages was 3.34 per million age-related population (pmarp). The mean prevalence of CKD 2-5 stages was 21.95 (pmarp). The cumulative 1-, 5-, and 10-year patients' survival rates were 98.3%, 90.7%, and 84.8%, respectively. The etiology of the CKD included the congenital anomalies of the kidney and urinary tract (CAKUT) (40.01%), glomerulopathy (19.00%), unknown cause (18.28%), and cystic/hereditary/congenital disease (11.14%). The incidence and prevalence rate of pediatric CKD in Iran is relatively lower than those reported in Europe and other similar studies. CAKUT was the main cause of the CKD. Appropriate management of CAKUT including early urological intervention is required to preserve the renal function. Herein, the long-term survival rate was higher among the children with CKD than the literature.

Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X.tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

Molecular diagnostic in fetuses with isolated congenital anomalies of the kidney and urinary tract by whole-exome sequencing.

BackgroundIn prenatal care, accumulating evidences has demonstrated that whole‐exome sequencing (WES) expedites the genetic diagnosis of fetal structural anomalies. However, the clinical value of WES in the diagnosis of prenatal isolated congenital anomalies of the kidney and urinary tract (CAKUT) is unknown.MethodsForty‐one fetuses with unexplained isolated CAKUT, normal karyotype and negative chromosomal microarray analysis (CMA) results, underwent WES and were accordingly grouped as (a) Group 1: complex cases with bilateral renal abnormalities (N = 19); and (b) Group 2: cases with isolated unilateral fetal renal abnormalities (N = 22).ResultsThe detection rate of WES for pathogenic variants and incidental variants was 7.32% (3/41) and 2.4% (1/41), respectively. The three pathogenic variants were identified in the genes ACTA2 (multisystem smooth muscle dysfunction syndrome), PKHD1 (autosomal recessive form of polycystic kidney disease), and PKD1 (autosomal dominant polycystic kidney disease type 1). The incidental variants were detected in genes PPM1D (syndromic neurodevelopmental disorders). Furthermore, all above fetuses carrying pathogenic variants came from bilateral kidney anomalies. Thus, the detection rate was 0 for fetuses with unilateral fetal renal abnormalities and 15.7% (3/19) for bilateral renal abnormalities.ConclusionThis cohort shows that prenatal WES is a supplementary approach for the etiologic diagnosis of unexplained isolated CAKUT with negative CMA, especially for fetuses with bilateral renal abnormality.

Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease

Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-β4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-β4 abundance was confirmed with ELISA. Knockout of thymosin-β4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin β4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable.