Congenital Anomalies Of The Kidney And Urinary Tract Research Articles (Page 1)

Abnormalities in PBX1 represent a monogenic cause of congenital anomalies of the kidney and urinary tract (CAKUT). However, their phenotypic heterogeneity poses a challenge for timely detection, particularly in the absence of overt anomalies in the kidney and urinary tract. Here, we present a 28-year-old male diagnosed with a rare PBX1 nonsense variant identified during the evaluation of early-onset chronic kidney disease. As part of the initial workup for decreased renal function and proteinuria, a kidney biopsy was performed, revealing focal segmental glomerulosclerosis (FSGS) and acute tubular necrosis without an identifiable cause. He was initially treated with renin-angiotensin system inhibitors, followed by glucocorticoid and/or cyclosporine therapy for four years. Despite these interventions, his serum creatinine levels gradually increased without any improvement in proteinuria. Genetic testing, performed seven years after the initial visit, revealed a rare de novo heterozygous PBX1 variant, p.Arg93Ter (c.277C > T), classified as likely pathogenic. Reverse phenotyping identified cryptorchidism and dysmorphic external ears, both of which are extrarenal manifestations commonly associated with PBX1 -related CAKUT. Although this variant is predicted to be deleterious, it is flagged as escaping nonsense-mediated decay, which may explain the absence of apparent structural anomalies in the kidneys. PBX1 is prominently expressed in interstitial and endothelial cells in both fetal and adult human kidneys, and its function is not directly implicated in podocyte or tubular cell biology. Therefore, the inadvertent pathological findings in this genetic disorder may be attributed to reduced nephron endowment and/or disturbance in reciprocal cellular interactions. This case broadens the phenotypic spectrum of PBX1 -related disorders and highlights its renal manifestations, further expanding the clinical heterogeneity of FSGS.

There have been several reports on heterozygous loss of function variants in PBX1 associated with congenital anomalies of the kidney and urinary tract (CAKUT). We report three patients harboring de novo heterozygous missense variants in PBX1, who did not have CAKUT, but instead presented with respiratory failure, developmental delay, and, the most important, a unique skeletal phenotype characterized by broad and short clavicles with coracoclavicular ankylosis and broad ischia with premature fusion of the ischiopubic synchondrosis. All the variants are clustered at the last portion of the homeobox domain. This phenotype is consistent with mouse models with functional dysregulation in Pbx1 or its interacting factor, Emx2. This study highlights a previously not reported phenotype affecting the clavicles and ischia due to PBX1 variants and expands the clinical spectrum of PBX1-related disorders.

Kidney organoids, derived from stem cells, including pluripotent stem cells and adult progenitor cells, have been reported as three-dimensional in vitro models that reflect key aspects of kidney development, structure, and function. Advances in differentiation protocols and tissue engineering have enabled the generation of organoids that exhibit nephron-like structures, including glomerular and tubular structures. Kidney organoids have been widely applied in several directions, including disease modeling and therapeutic screening, drug nephrotoxicity evaluation, and regenerative medicine. In particular, kidney organoids offer a promising platform for studying genetic kidney diseases, such as polycystic kidney disease and congenital anomalies of the kidney and urinary tract (CAKUT), by allowing patient-specific modeling for the analysis of pathophysiology and therapeutic screening. Despite several current limitations, such as incomplete maturation, lack of full nephron segmentation, and variability between protocols and cell conditions, further technological innovations such as microfluidics and bioengineering may refine kidney organoid systems. This review highlights recent advances in kidney organoid research, outlines major applications, and discusses future directions to enhance their physiological relevance, functional maturity, and translational integration into preclinical and clinical nephrology.

Abstract Background and Aims Congenital anomalies of the kidney and urinary tract (CAKUT) are a group of disorders responsible for the majority of pediatric end-stage renal disease cases. CAKUT is phenotypically variable and can affect the kidney(s) alone and/or the lower urinary tract. The spectrum includes more common anomalies such as vesicoureteral reflux and, rarely, more severe malformations such as bilateral renal agenesis. The aim of the study was to assess the risk factors for the onset of chronic kidney disease (CKD) and the progression to kidney failure (KF, i.e. the need of dialysis or kidney transplantation) in a cohort of patients with CAKUT. Method We conducted a retrospective, observational study at the Nephrology, Dialysis and Transplantation Units of Annunziata Hospital of Cosenza. We enrolled consecutive patients with CAKUT from 2005 to 2020 Risk factors of CKD and KF were assessed via Logistic Regression. Stepwise selection method (p value of 0.100) was used the most related risk factors for each endpoint. Results We studied 51 patients with CAKUT, 17 females and 34 males. The most frequent causes of CAKUT were renal agenesis (13.7%), renal dysplasia (17.6%), vesicoureteral reflux (31.4%). Cystic diseases, renal hypoplasia, and more rare causes such as Prune-Belly syndrome or Beckwith-Wiedemann syndrome were also reported. When testing the risk factors for CKD we found that irregular growth (odds ratio, OR 97.4, P = <0.001) and arterial hypertension (OR 73.2, P = 0.001) were independently associated with CKD. Risk factors for KF were arterial hypertension (OR 10.9, P = 0.022), proteinuria (OR 6.5, P = 0.040), and body weight at birth (OR 0.1, P = 0.005). Body weight at birth was significantly lower in patients who developed KF (Fig. 1). Conclusion The long follow-up in these children with CAKUT allowed us to find traditional and non-traditional predictive risk factors for CKD and progression of kidney damage to ESRD. Early and appropriate treatment of these risk factors could improve the prognosis of renal disease. In addition, the correlation between low birth weight and renal failure may be explained by lower functional renal activity at birth. Indeed, the number of nephrons correlates with birth weight.

Abstract Background and Aims Cardiovascular (CV) complications represent the main cause of mortality among kidney transplanted patients (KTRs). Despite this well-known CV burden, post-transplant CV prevention in KTRs remains overlooked in the clinical practice. Therefore, with the aim of better stratifying the CV risk after transplantation, we analysed if the underlying nephropathy has an impact on the post-transplant CV risk. Method Our retrospective analysis includes 240 prevalent adult KTRs in follow-up at the outpatient Nephrology Clinic of San Martino Hospital, Genoa from 2016 to 2021. The cohort includes patients affected by 5 different underlying nephropathies: autoimmune diseases (AID) (n = 20), primary glomerulonephritis (GN) (n = 73), diabetic nephropathy (DN) (n = 32), autosomic polycystic kidney disease (ADPKD) (n = 88) and congenital anomalies of the kidney and urinary tract (CAKUT) (n = 27). The outcomes are: 1. development of major CV events (MACE, defined as myocardial infarction, lower limbs revascularization, stroke and hospitalization for heart failure), 2. all-cause mortality and 3. a composite endpoint represented by MACE and all-cause mortality. Continuous variables are presented as means with standard deviations, while categorical variables are presented as the number of patients with a proportion. Differences between the subpopulations were analysed with ANOVA test or Fischer's test, as appropriate. Kaplan Meier analysis with log-rank test was carried out to compare the event-free survival curves. The relationship between baseline characteristics and time to the occurrence of the three analysed outcomes was assessed by univariate and multivariate Cox regression analysis. A p-value less than 0.05 was considered statistically significant. Results Baseline characteristics of the 5 subgroups are reported in Table 1: the cohorts differed significantly in terms of age, gender, previous history of MACE, dyslipidemia, number of transplants and maximum panel reactive antibody test (PRA) titer. We observed a significant lower event free survival in AID and DN for the three analysed events, while CAKUT showed better survival curves (Fig. 1). Among the evaluated nephropathies, only AID and DN were statistically significant predictors of time to outcomes’ occurrence, but only AID maintained its significance in the multivariate regression analysis (Table 2). For what concerns other analysed covariates, it is interesting to point out that significance was maintained in the multivariate analysis for the following variables: a previous history of MACE for MACE occurrence, (HR 4.85, IC 95% 2.22–10.60, P = 0.0001), pre-transplant diabetes for overall mortality (HR 6.69, IC 95% 0.92–22.67, P = 0.002) and pre-transplant MACE and diabetes and previous transplants for the composite endpoint (respectively HR 2.61 IC 95% 1.25–5.42 p 0.01; HR 4.36 IC 95% 1.37–13.81 P = 0.01; HR 2.63 IC 95% 1.32–5.26 P = 0.006). Observing the role of previous immunosuppressive treatments among the 91 patients affected by AID and GN, a prior therapy with steroids was associated with a six-fold (HR 6.17, IC 95% 1.10–34.58, P = 0.04) higher risk in overall mortality and prior use of cyclophosphamide with a three-fold increased risk in developing the composite outcome (HR 3.06, IC 95% 1.07–8.74, P = 0.04). Conclusion Underlying nephropathies influence the CV risk even after transplantation. Surprisingly, AID have a similar or even higher risk than DN. This finding could lead to a more tailored CV follow up and thus to an improvement in post-transplantation CV outcomes in these patients.

Hypertension (HT) is an important risk factor in patients with congenital anomalies of the kidney and urinary tract (CAKUT), independent of the existing anomaly in childhood. This study aimed to investigate masked hypertension and/or blood pressure profiles in different subgroups with a normal glomerular filtration rate (GFR). The study included participants from seven different pediatric nephrology centers in Türkiye. Ambulatory blood pressure monitoring (ABPM) was performed on patients aged 5-18years, diagnosed with CAKUT, with a GFR above 100ml/min/m2, and normal office blood pressure measurements. Validated Mobil-O-Graph or Spacelabs devices were used in all centers. In total, 118 healthy control data and 322 patients with CAKUT were evaluated, consisting of 73 (22.7%) with agenesis, 79 (24.5%) with cystic dysplasia, 92 (28.6%) with vesicoureteral reflux, 18 (5.6%) with UPJ (ureteropelvic junction) obstruction, and 60 (18.6%) with other conditions. In all CAKUT patients, daytime systolic blood pressure (SBP) and both day and nighttime diastolic blood pressure (DBP) loads were significantly higher compared to the healthy control group (p < 0.05). Nocturnal hypertension was identified in 58 (18%) of 322 children, whereas none of the control group presented hypertension. Children with cystic dysplasia had the highest nighttime hypertension proportions (22.7%) when compared to other subgroups. All data revealed higher total systolic-diastolic SDS and total mean SDS in the cystic dysplasia subgroup (p < 0.05). The findings underscore the importance of blood pressure monitoring in the follow-up of patients with CAKUT, especially those with cystic dysplasia, even in the absence of GFR decline.

Renal hypodysplasia (RHD) is a common and severe form of congenital anomalies of the kidney and urinary tract (CAKUT), often leading to chronic kidney disease (CKD) in children. This study, leveraging a 10-year single-center cohort, aims to elucidate clinical and prognostic characteristics as well as genetic causes in pediatric RHD. We enrolled 322 patients diagnosed with primary RHD by ultrasound at Wuhan Children's Hospital in the past decade. Baseline and follow-up data were collected. Kidney outcomes were investigated using Kaplan-Meier curves and Cox regression model to assess risk factors for early CKD event (eGFR < 75mL/min/1.73 m2). Whole Exome Sequencing and copy number variation analysis were performed to identify genetic causes. Among 322 RHD patients, 281 (87.3%) had unilateral kidney involvement, and 41 (12.7%) had bilateral involvement. Patients with bilateral RHD exhibited worse kidney function and CKD stage (P < 0.001), while unilateral RHD was more frequently associated with additional CAKUT. After median follow-up of 4.5years, 72 (22.4%) patients reached the early CKD endpoint. Bilateral kidney involvement (HR = 4.40, 95% CI 2.31-8.39, P < 0.001), urine ACR levels (3-30mg/mmol: HR = 2.24, 95% CI 1.02-4.92, P = 0.044; > 30mg/mmol: HR = 2.55, 95% CI 1.32-4.93, P = 0.005), and extra-urogenital malformations (HR = 2.28, 95% CI 1.26-4.10, P = 0.006) were independent risk factors. Genetic testing revealed PAX2, WT1 variants, and 17q12 deletion as the most prevalent pathogenic variations. This study reveals distinct clinical and prognostic characteristics between unilateral and bilateral RHD. Bilateral kidney lesions, albuminuria, and extra-urogenital malformations are independent risk factors for kidney function decline. PAX2, WT1 variants, and 17q12 deletion are the most common genetic causes.

Expression of Fibroblast Growth Factor 23 (FGF-23) and α-KLOTHO in Normal Human Kidney Development and Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)

Congenital anomalies of the kidney and urinary tract (CAKUT) represent 15-20% of prenatally diagnosed congenital anomalies, often presenting unilaterally. This study aimed to describe sonographic features of fetuses with unilateral renal anomalies and evaluate their postnatal outcomes. Additionally, we assessed whether specific prenatal ultrasound findings predicted postnatal complications. This was a retrospective, observational study including singleton pregnancies referred to our center from 2008 to 2023 for unilateral renal anomalies identified in second or third trimester ultrasounds. Sequential prenatal ultrasound evaluations were conducted to monitor disease progression and associated anomalies. Postnatal outcomes were retrieved from delivery records and pediatric follow-ups. Statistical analyses included Chi-square tests, t-tests, and ROC curve analysis to assess the predictive value of the antero-posterior diameter (DAP) of the renal pelvis for postnatal complications. A total of 226 cases were included: 116 (51.3%) pyelectases, 51 (22.6%) hydroureteronephroses, 48 (21.2%) multicystic kidneys, and 11 (4.9%) renal dysplasias. Diagnosis occurred at an average gestational age of 25 weeks, with 19.3% showing progression during pregnancy and 23% having associated anomalies detected during ultrasound examinations. Of 135 children with follow-up data, 47.4% required surgery, 1.5% developed hypertension, and 1.5% developed chronic kidney disease (CKD). Associated anomalies significantly correlated with unfavorable outcomes, such as need for intervention (P=0.001), risk of developing postnatal recurrent urinary infections (P=0.025), vesicoureteral reflux (P=0.001) and CKD (P=0.010). Progression during pregnancy correlated with vesicoureteral reflux (P=0.002) and development of anomalies in the contralateral kidney (P=0.012). DAP measurement did not reliably predict postnatal complications (AUC=0.590, P=0.191). Unilateral renal anomalies are often associated with other congenital anomalies, influencing postnatal outcomes. DAP measurement was not a significant predictor of postnatal complications. Comprehensive prenatal ultrasound assessments are critical for guiding parental counseling, pregnancy management, and postnatal care.

Solitary functioning kidney (SFK) is linked to chronic kidney disease (CKD) in children, particularly when associated with congenital anomalies of the kidney and urinary tract (CAKUT). Pelvi-ureteric junction obstruction (PUJO) is the most frequent obstructive uropathy in SFK. This study aimed to evaluate long-term kidney function in children operated on for PUJO in an SFK. Among a retrospective cohort study of children with an SFK, a subgroup analysis was performed: primary SFK with operated PUJO (n = 35); primary SFK without CAKUT (n = 108); primary SFK with CAKUT other than PUJO (n = 24). Markers of CKD and measured glomerular filtration rate were assessed during follow-up. Surgery was indicated because of neonatal acute kidney injury (AKI) (n = 21), worsening renal pelvis dilation (n = 10). The median age at surgery was 15 months (1.2-30 months). At a median age of 13 years at last follow-up, the proportion of CKD was higher in primary SFK with PUJO compared to primary SFK without CAKUT (43% vs. 12%, p = 0.0008). In SFK/PUJO, neonatal AKI was predictive of subsequent CKD (OR 4.8, p = 0.04). PUJO in an SFK is associated with a high rate of CKD during childhood, particularly when neonatal AKI is present.

Increased mTOR signaling secondary to a human ILK missense variant inhibits nephrogenesis with decreased metabolism.

Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant disorder that increases the risk of various types of cancer. It is primarily caused by inherited mutations in the TP53 gene. While the tumor suppressor function of p53 is well established, its role in embryonic development, particularly in the formation of the kidney and urinary tract, remains poorly understood. Moreover, its contribution to human congenital anomalies has not been clearly defined. Here, we report that pathogenic TP53 variants can lead to congenital anomalies of the kidney and urinary tract (CAKUT), as well as genital defects (GD), in individuals with LFS. Among 28 unrelated TP53 mutation carriers, 28% (8/28) exhibited CAKUT and/or GD, with a higher frequency observed in individuals carrying structurally disruptive or dominant-negative mutations. We focused on two clinically observed variants: R242W, which destabilizes protein structure, and R282W, a dominant-negative hotspot mutation. AlphaFold modeling showed that both variants cluster within the DNA-binding domain and are predicted to disrupt tetramer formation. In Xenopus laevis, tp53 is expressed in developing nephric structures, consistent with findings from mouse models of nephrogenesis. Expression of either mutant TP53 mRNA in Xenopus embryos disrupted kidney morphogenesis in vivo , supporting a developmental loss-of-function effect. These findings indicate that pathogenic TP53 variants contribute to renal and urogenital defects in LFS. They reveal a previously unrecognized developmental role for p53 and expand the phenotypic spectrum associated with this cancer predisposition syndrome.

ABSTRACTBackground:Congenital anomalies of the kidney and urinary tract (CAKUT) are frequently detected on the prenatal ultrasonography, but their postnatal outcomes vary widely. Accurate diagnosis and early postnatal evaluation are essential for guiding prognosis and management.Objective:To assess the clinical spectrum and postnatal outcomes of renal anomalies detected during prenatal screening.Methods:A prospective observational study was conducted over 18 months on 40 neonates with prenatal renal anomalies detected via ultrasonography. Postnatal evaluation included serial ultrasounds, micturating cystourethrogram (MCU), and diuretic renography (DTPA) scans as indicated. Outcomes were analyzed based on anomaly type, laterality, and severity of hydronephrosis.Results:Hydronephrosis was the most common finding (67.5%), followed by polycystic kidney disease and multicystic dysplastic kidney. Postnatal resolution occurred in 37.5% of cases. Surgical intervention was required in 27.5%, predominantly for ureteropelvic junction obstruction and posterior urethral valves. Bilateral anomalies and high-grade hydronephrosis were associated with poorer outcomes.Conclusion:Prenatally detected renal anomalies warrant structured postnatal follow-up. Severity, laterality, and anomaly type significantly influence clinical outcomes.

Pediatric Renal Transplantation: A 10-Year Single-Center Experience.

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are the leading cause of pediatric kidney failure (KF) and a significant contributor to KF in adults. Progression to KF varies widely. Early renal risk stratification is challenging, due to a lack of data on long-term kidney outcomes during adulthood. This multicenter study, therefore, aims to correlate progression to KF with CAKUT phenotypes, including the extent of extrarenal involvement and genetic findings. Observational, retrospective cohort study. 229 adult CAKUT patients with KF either before or after the age of 18 were recruited at two tertiary care centers. Genetic testing was performed in 117 patients. Genetic testing identified pathogenic variants in 14 patients (12.0%), spanning 10 genes. Extrarenal manifestations were more common in genetically resolved cases (9/14, 64.3%), primarily affecting the genital (3/14, 21.4%) and gastrointestinal systems (5/14, 35.7%). Syndromic patients experienced significantly earlier KF-onset (median age: 22.0 years [14.0; 31.0]; n=81) compared to those with isolated CAKUT (28.0 years [21.0-38.0]; n=145). Among CAKUT subtypes, multicystic dysplastic kidneys presented with the fastest rate of progression to KF (median age at KF-onset 18.0 years [5.0; 23.0]; n=9), whereas horseshoe or ectopic kidneys showed more attenuated outcomes (55.5 years [47.3-62.5]; n=4). Bilateral kidney and urinary tract involvement was associated with a significantly worse prognosis (median age at KF-onset 22.0 years [15.5-30.0]; n=143) compared to unilateral involvement (37.0 years [28.0-47.0]; n=71). CAKUT is genetically heterogeneous, and the majority of cases remain genetically unresolved. Among patients on kidney replacement therapy, the rate of progression to KF is influenced by extrarenal presentation, bilateral kidney and urinary tract involvement, as well as CAKUT subtypes. Comprehensive interdisciplinary phenotypic characterization is essential and also contributes to a more accurate determination of kidney prognosis.

Background: Thrombospondin-1 (TSP-1) is a matricellular protein involved in kidney fibrosis, potentially influencing the progression of proteinuria. However, its potential as a predictive biomarker for proteinuria events in children with chronic kidney disease (CKD), particularly across different etiological subgroups, such as congenital anomalies of the kidney and urinary tract (CAKUT) and non-CAKUT, has not been fully explored. Methods: In this prospective study of 60 children with CKD, we assessed baseline plasma TSP-1 and tracked proteinuria events over one year. Participants were stratified into CAKUT and non-CAKUT groups. Results: In total, 5 of 60 participants had proteinuria events. Plasma TSP-1 was significantly lower in patients with events (21.18 vs. 36.28 μg/mL, p = 0.0364). In multivariable analysis, TSP-1 lost significance overall but remained predictive in the non-CAKUT subgroup (AUC = 0.79, p = 0.064; OR = 0.93, p = 0.028). Conclusions: Plasma TSP-1 may serve as an etiology-specific biomarker for proteinuria events in pediatric CKD, particularly among non-CAKUT patients, and warrants further investigation for personalized risk assessment.

We aimed to investigate predictive factors associated with perinatal and neonatal mortality in cases with congenital anomalies of the kidney and urinary tract (CAKUT). This study included a cohort of neonates with CAKUT born at a tertiary hospital between 1996 and 2021. Controls were matched with CAKUT cases by sex, time, and place of birth at a ratio of approximately 2:1. The covariates included in the analysis were sex, gestational age, birth weight, neonatal classification, and birth order. CAKUT was categorized into four phenotypes: urinary tract dilatation, lower urinary tract obstruction (LUTO), cystic diseases, and agenesis/hypodysplasia. The primary outcome was perinatal and neonatal mortality. Survival analysis was performed using the Cox proportional hazards model. 857 cases and 1,755 controls were included in the analysis. The overall early mortality rate was 7.2%. After controlling for confounding factors, CAKUT cases exhibited a higher risk of perinatal and neonatal mortality than controls (hazard ratio [HR], 25.1; 95%CI, 14.0-45.2). The following covariates were independently associated with mortality: prematurity (HR, 1.7; 95%CI, 1.2-2.5), LBW (HR, 2.4; 95%CI, 1.6-2.5), VLBW (HR, 2.9; 95%CI, 1.1-1.7), oligohydramnios (HR, 3.2; 95%CI, 2.2-4.8), cystic diseases (HR, 3.8; 95%CI, 2.3-6.4), LUTO (HR, 5.1; 95%CI, 3.0-8.5), kidney agenesis/hypodysplasia (HR, 5.1; 95%CI, 2.9-8.7), and extra-renal malformations (HR, 2.6; 95% CI, 1.7-3.9). CAKUT was associated with elevated stillbirth and neonatal mortality rates compared with controls. Prematurity, LBW, oligohydramnios, extra-renal malformations, and specific CAKUT phenotypes with kidney involvement were associated with increased mortality risk.

Congenital anomalies of the kidneys and urinary tract (CAKUT) are developmental disorders that commonly cause pediatric chronic kidney disease and mortality. We examine here rare coding variants in 248 CAKUT trios and 1742 singleton CAKUT cases and compare them to 22,258 controls. Diagnostic and candidate diagnostic variants are detected in 14.1% of cases. We find a significant enrichment of rare damaging variants in constrained genes expressed during kidney development and in genes associated with other developmental disorders, suggesting phenotype expansion. Consistent with these data, 18% of CAKUT patients with diagnostic variants have neurodevelopmental or cardiac phenotypes. We identify 40 candidate genes, including CELSR1, SSBP2, XPO1, NR6A1, and ARID3A. Two are confirmed as CAKUT genes: ARID3A and NR6A1. This study suggests that many yet-unidentified syndromes would be discoverable with larger cohorts and cross-phenotype analysis, leading to clarification of the genetic and phenotypic spectrum of developmental disorders.

There is a paucity of information and data on congenital anomalies of the kidney and urinary tract (CAKUT) in the African setting. The aim of this study was to determine the prevalence, pattern and distribution of CAKUT as observed from computed tomography (CT) scans in a black African population. This was a retrospective study carried out in Enugu, Southeast Nigeria. The study population was drawn from subjects who had an abdominopelvic CT scan or CT urography for either urological or non-urological conditions. Data was pulled from three large-volume referral centers for CT scans in the city center, and study period extended from January 2015 to December 2024. Analysis was performed using Statistical Package for Social Sciences (IBM Corp., Armonk, NY, USA) for Windows, version 27.0. Data were described using frequencies and proportions in tables and charts. The records of 3507 subjects were retrieved for this study. A total number of 122 subjects had congenital anomalies of the kidneys or the urinary tract, which gave a prevalence of 3.5% (95% confidence interval: 2.9-4.1%). The mean age of subjects was 39 ± 19.8 years and the majority of them were males (57.4%). The most prevalent anomaly was pelviureteric junction (PUJ) obstruction (1.28%), followed by duplex collecting system. The prevalence of CAKUT from this study was 3.5%. Pelvic ureteric junction obstruction was the most prevalent congenital anomaly of the urinary tract in our setting.

Introduction:Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of chronic kidney disease in children and young adults. Although over 50 monogenic causes have been identified, many remain unresolved. PRPF8 is a core spliceosome component, essential for pre-mRNA splicing, and further localizes to the distal mother centriole to promote ciliogenesis.Methods:We performed trio exome sequencing in 208 CAKUT families and identified strong variants in PRPF8 and the EDD-DYRK2-DDB1VprBP complex. Functional validation included splicing assays in yeast (Saccharomyces cerevisiae), Sonic hedgehog (Shh) signaling in RPE-1 cells, co-immunoprecipitation for protein complex assembly, and in situ hybridization in mouse embryos. Protein interactions were modeled using AlphaFold.Results:We identified heterozygous de novo or inherited variants in PRPF8, DYRK2, DDB1, EDD and CEP78. Yeast assays revealed that while most PRPF8 variants preserved growth and splicing at consensus splice sites, the de novo PRPF8R1681W variant impaired splicing of non-consensus splice sites and was inviable at elevated temperature. CAKUT variants failed to rescue prp28–1 and U4-cs1 alleles but showed variant-specific synthetic interactions with brr2–1, including weak suppression or synthetic sickness at elevated temperatures. Shh signaling was reduced in ~50% of PRPF8 variants expressed in RPE-1 cells. CEP78 truncating variants abrogated binding to CEP350 and VPRBP. Two DYRK2 variants disrupted EDD-DYRK2-DDB1VprBP complex formation without affecting kinase activity. In situ hybridization revealed strong Prpf8 expression in the developing collecting duct and urothelium.Conclusion:Variants in PRPF8 and components of the EDD-DYRK2-DDB1VprBP complex may contribute to CAKUT through impaired pre-mRNA splicing and defective ciliogenesis. These findings uncover an entirely new functional network of candidate genes for CAKUT and ciliopathies, significantly broadening our understanding of disease mechanisms and offering novel entry points for mechanistic studies.