GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are prevalent birth defects. Although pathogenic CAKUT genes are known, they are insufficient to reveal the causes for all patients. Our previous studies indicated GEN1 as a pathogenic gene of CAKUT in mice, and this study further investigated the correlation between GEN1 and human CAKUT. METHODS: In this study, DNA from 910 individuals with CAKUT was collected; 26 GEN1 rare variants were identified, and two GEN1 (missense) variants in a non-CAKUT group were found. Mainly due to the stability results of the predicted mutant on the website, in vitro, 10 variants (eight CAKUT, two non-CAKUT) were selected to verify mutant protein stability. In addition, mainly based on the division of the mutation site located in the functional region of the GEN1 protein, 8 variants (six CAKUT, two non-CAKUT) were selected to verify enzymatic hydrolysis, and the splice variant GEN1 (c.1071 + 3(IVS10) A > G) was selected to verify shear ability. Based on the results of in vitro experiments and higher frequency, three sites with the most significant functional change were selected to build mouse models. RESULTS: Protein stability changed in six variants in the CAKUT group. Based on electrophoretic mobility shift assay of eight variants (six CAKUT, two non-CAKUT), the enzymatic hydrolysis and DNA-binding abilities of mutant proteins were impaired in the CAKUT group. The most serious functional damage was observed in the Gen1 variant that produced a truncated protein. A mini-gene splicing assay showed that the variant GEN1 (c.1071 + 3(IVS10) A > G) in the CAKUT group significantly affected splicing function. An abnormal exon10 was detected in the mini-gene splicing assay. Point-mutant mouse strains were constructed (Gen1: c.1068 + 3 A > G, p.R400X, and p.T105R) based on the variant frequency in the CAKUT group and functional impairment in vitro study and CAKUT phenotypes were replicated in each. CONCLUSION: Overall, our findings indicated GEN1 as a risk factor for human CAKUT.

PAX2/Renal Coloboma Syndrome Expresses Extreme Intrafamilial Phenotypic Variability.

Renal coloboma syndrome (RCS) is a disease characterized by kidney and ocular anomalies (kidney hypodysplasia and coloboma). RCS is caused, in half of the cases, by mutations in the paired box 2 (PAX2) gene, a critical organogenesis transcriptional factor. We report the case of a newborn with kidney hypodysplasia in a negative parental context where mother and father were phenotypically unaffected at the initial evaluation. The maternal family presented an important history of kidney disease with undefined diagnosis. Molecular characterization identified a PAX2 variant, classified as likely pathogenic. This variant segregates with the disease, and it was also found in the newborn, explaining his severe symptoms. It is noteworthy that the mother shows the same PAX2 variant, with an apparently negative kidney phenotype, displaying the possibility of an extreme variable expressivity of the disease. This feature suggests extreme caution in segregation analysis and family counseling of PAX2 pedigrees.

Sonographic differential diagnosis of duplex kidneys.

Duplex kidneys have two renal pelvises and two ureters, which can join on the way to the urinary bladder but can also enter the bladder separately. A distinction must be made between normal and pathological duplex kidneys. In normal duplex kidneys, both renal pelvises are normal in width, and the upper and lower poles are approximately the same size. Furthermore, ureters are not dilated, and the upper and lower poles of the kidneys are not cystically altered. In contrast, pathological duplex kidneys, occurring in about 50 % of cases, are characterized by dilation of one or both renal pelvises. Additionally, one or both ureters may be dilated. Megaureters may be obstructive or refluxive. If a megaureter is present, a ureterocele must be ruled out, as well as an ectopically opening ureter. A pathological duplex kidney must always be assumed if one pole of the kidney is hypoplastic. Hypoplasia of the upper renal pole is often associated with an obstructive megaureter. Vesicoureteral reflux into the lower pyelon is common in hypoplasia of the lower pole. In the presence of vesicoureteral reflux, the associated (lower) pyelon is dilated when the bladder is full or during micturition. In addition, there is a dilated ureter. On the other hand, the pyelon can have a normal width when the bladder is empty. In rare cases, one pole may be cystically altered in pathological duplex kidneys. In this instance, segmental multicystic dysplastic duplex kidney must be differentiated from segmental multicystic nephroma.

Dexamethasone to prevent kidney scarring in acute pyelonephritis: a randomized clinical trial.

BACKGROUND: Urinary tract infection (UTI) is one of the most common bacterial infections in childhood and is associated with long-term complications. We aimed to assess the effect of adjuvant dexamethasone treatment on reducing kidney scarring after acute pyelonephritis (APN) in children. METHODS: Multicenter, prospective, double-blind, placebo-controlled, randomized clinical trial (RCT) where children from 1 month to 14 years of age with proven APN were randomly assigned to receive a 3-day course of either an intravenous corticosteroid (dexamethasone 0.30 mg per kg/day) twice daily or placebo. The late technetium 99 m-dimercaptosuric acid scintigraphy (> 6 months after acute episode) was performed to assess kidney scar persistence. Kidney scarring risk factors (vesicoureteral reflux, kidney congenital anomalies, or urinary tract dilatation) were also assessed. RESULTS: Ninety-one participants completed the follow-up and were finally included (dexamethasone n = 49 and placebo n = 42). Both groups had similar baseline characteristics. Twenty participants showed persistent kidney scarring after > 6 months of follow-up without differences in incidence between groups (22% and 21% in the dexamethasone and placebo groups, p = 0.907). Renal damage severity in the early DMSA (ß = 0.648, p = 0.023) and procalcitonin values (ß = 0.065 p = 0.027) significantly modulated scar development. Vesicoureteral reflux grade showed a trend towards significance (ß = 0.545, p = 0.054), but dexamethasone treatment showed no effect. CONCLUSION: Dexamethasone showed no effect on reducing the risk of scar formation in children with APN. Hence, there is no evidence for an adjuvant corticosteroid treatment recommendation in children with APN. However, the study was limited by not achieving the predicted sample size and the expected scar formation. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02034851. Registered in January 14, 2014. "A higher resolution version of the Graphical abstract is available as Supplementary information."

Expanding the KIF4A-associated phenotype.

Kinesin super family (KIF) genes encode motor kinesins, a family of evolutionary conserved proteins, involved in intracellular trafficking of various cargoes. These proteins are critical for various physiological processes including neuron function and survival, ciliary function and ciliogenesis, and cell-cycle progression. Recent evidence suggests that alterations in motor kinesin genes can lead to a variety of human diseases, including monogenic disorders. Neuropathies, impaired higher brain functions, structural brain abnormalities and multiple congenital anomalies (i.e., renal, urogenital, and limb anomalies) can result from pathogenic variants in many KIF genes. We expand the phenotype associated with KIF4A variants from developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of phenotypic manifestations. Additional anomalies of the kidneys and urinary tract, congenital lymphedema, eye, and dental anomalies seem to be variably associated and overlap with clinical signs observed in other kinesinopathies. Caution still applies to missense variants, but hopefully, future work will further establish genotype-phenotype correlations in a larger number of patients and functional studies may give further insights into the complex function of KIF4A.

A Homozygous Dab1-/- Is a Potential Novel Cause of Autosomal Recessive Congenital Anomalies of the Mice Kidney and Urinary Tract.

This study aimed to explore morphology changes in the kidneys of Dab1-/- (yotari) mice, as well as expression patterns of reelin, NOTCH2, LC3B, and cleaved caspase3 (CASP3) proteins, as potential determinants of normal kidney formation and function. We assumed that Dab1 functional inactivation may cause disorder in a wide spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). Animals were sacrificed at postnatal days P4, P11, and P14. Paraffin-embedded kidney tissues were sectioned and analyzed by immunohistochemistry using specific antibodies. Kidney specimens were examined by bright-field, fluorescence, and electron microscopy. Data were analyzed by two-way ANOVA and t-tests. We noticed that yotari kidneys were smaller in size with a reduced diameter of nephron segments and thinner cortex. TEM microphotographs revealed foot process effacement in the glomeruli (G) of yotari mice, whereas aberrations in the structure of proximal convoluted tubules (PCT) and distal convoluted tubules (DCT) were not observed. A significant increase in reelin expression, NOTCH2, LC3B and cleaved CASP3 proteins was observed in the glomeruli of yotari mice. Renal hypoplasia in conjunction with foot process effacement and elevation in the expression of examined proteins in the glomeruli revealed CAKUT phenotype and loss of functional kidney tissue of yotari.

Types of Parenchymal Changes Diagnosed on DMSA Scans of Kidneys Affected by Different Grades of Vesicoureteral Reflux.

BACKGROUND Renal parenchymal damage and scarring usually is associated with urinary tract infection (UTI), whereas the impact of vesicoureteral reflux (VUR) on the kidneys is unclear. We aimed to compare kidneys with all grades of VUR (grades Io-V) and those without VUR by using direct radionuclide cystography, voiding cystourethrography, and findings from 99mTc-DMSA scintigraphy (DMSA scan). MATERIAL AND METHODS The present analysis included 253 renal ureteral units (RUU) from 129 children with VUR and recurrent UTI and children with a single febrile UTI associated with abnormal ultrasonographic findings. The 6 grades of VUR (Io, I, II, III, IV, and V) and 35 RUUs without VUR were divided into 4 groups: 1. Non-dilated VUR (grades Io-II); 2. Mildly dilated VUR (grade III); 3. Dilated VUR (grades IV-V); and 4. The control group. RESULTS DMSA scanning showed significant differences between the groups with non-dilated VUR, grade III VUR, grades IV-V VUR, and the control group in kidney width (χ²=30.5; P<0.001); position and shape (χ²=30.6; P<0.001); intensity of activity (χ²=38.1; P<0.001); distribution of activity (χ²=34.5; P<0.001); and existence of scars (χ²=16; P<0.001). The probability of abnormalities on DMSA scans increased with the VUR grade. However, inside the groups of dilated and non-dilated VUR we found no significant statistical differences between those characteristics. CONCLUSIONS Our results indicate that kidneys without VUR or with non-dilated lateral VUR and dilated VUR on the contralateral side represent 2 different categories of parenchymal changes.

Inherited intragenic PBX1 deletion: Expanding the phenotype.

PBX1 encodes the pre-B cell leukemia homeobox transcription factor, a three amino acid loop extension (TALE) homeodomain transcription factor, which forms nuclear complexes with other TALE class homeodomain proteins that ultimately regulate target genes controlling organ patterning during embryogenesis. Heterozygous de novo pathogenic variants in PBX1 resulting in haploinsufficiency are associated with congenital anomalies of the kidneys and urinary tract, most commonly renal hypoplasia, as well as anomalies involving the external ear, branchial arch, heart, and genitalia, and they cause intellectual disability and developmental delay. Affected individuals described thus far have had de novo variants. Here, we report three related individuals with an inherited pathogenic intragenic PBX1 deletion with variable clinical features typical for this syndrome.

Relationship between Vesicoureteral Reflux and Glomerular Filtration Rate in Children.

Vesicoureteral reflux (VUR) is one of the most common urinary tract anomalies in children and causes renal damage and studies focusing on the effect of VUR on renal function are rare. We recruited 35 primary VUR patients with recurrent urinary tract infection (UTI) and 10 non-VUR patients with recurrent UTI. Contrast-enhanced voiding urosonography (ceVUS) was performed for VUR grading, and renal dynamic imaging was used for evaluating glomerular filtration rate (GFR, mL/min). Standardized GFR (sGFR), namely GFR/BSA (mL·min-1·m-2), was calculated based on the body surface area (BSA). Total sGFR (tsGFR, mL·min-1·m-2) was obtained from the sum of sGFR on the left and right sides of all the children. The risk of renal regurgitation was equal in the unilateral reflux group. The sGFR of children with grade IV (45.74±18.05 mL·min-1·m-2) and grade V (49.67±23.63 mL·min-1·m-2) reflux was significantly lower than that in children with grade III (77.69 ±22.21 mL·min-1·m-2). The renal function compensation of contralateral non-reflux kidney increased in unilateral reflux group, which was higher than that in the control group and level II, IV and V of reflux group respectively. In VUR group of the same grade, sGFR decreased with the age at diagnosis. In unilateral grade V reflux group, the tsGFR was lower than that in the unilateral grade III reflux group (133.51±48.21 vs. 186.87±53.49 mL·min-1·m-2). The patients with VUR of unilateral grade II were significantly older than those with VUR of unilateral grades III and IV. This study indicates that severe VUR is significantly associated with decreased renal function. Therefore, VUR should be diagnosed early and managed individually.

Metabolic acidosis exacerbates pyelonephritis in mice prone to vesicoureteral reflux.

Acute pyelonephritis is a common, serious bacterial infection in children. The prevalence of acute pyelonephritis is due at least in part to vesicoureteral reflux (VUR). Although an association between abnormalities in electrolyte and acid-base balance and pyelonephritis is common in young children, the impact of metabolic acidosis (MA) on progression of acute pyelonephritis is not fully understood. In this study, the effect of MA on pyelonephritis was studied in C3H mouse strains prone to VUR. MA induced by ammonium chloride supplementation in food specifically impaired clearance of urinary tract infection with uropathogenic Escherichia. coli (UPEC-UTI) in innate immune competent C3H strains (HeOuJ, HeN), whereas kidney UPEC burden in Tlr-4-deficient HeJ mice was unaffected. Antibody-mediated depletion of myeloid cells (monocytes, neutrophil) markedly increased UPEC burden in the bladder and kidney confirming the pivotal role of neutrophils and tissue-resident macrophages in clearance of UPEC-UTI. MA concurrent with UPEC-UTI markedly increased expression of cytokine (TNFα, IL-1ß, IL-6) and chemokine (CXCL 1, 2, and 5) mRNA in isolated kidney CD cells and kidney neutrophil infiltrates were increased four- to fivefold compared to normal, UPEC-infected mice. Thus, MA intensified pyelonephritis and increased the risk of kidney injury by impairing clearance of UPEC-UTI and potentiating renal inflammation characterized by an elevated kidney neutrophil infiltrate.

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

BACKGROUND: In 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. METHODS: Forty-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). RESULTS: The 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. CONCLUSION: This 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.

Rare heterozygous GDF6 variants in patients with renal anomalies.

Although over 50 genes are known to cause renal malformation if mutated, the underlying genetic basis, most easily identified in syndromic cases, remains unsolved in most patients. In search of novel causative genes, whole-exome sequencing in a patient with renal, i.e., crossed fused renal ectopia, and extrarenal, i.e., skeletal, eye, and ear, malformations yielded a rare heterozygous variant in the GDF6 gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, GDF6 variants were reported to cause pleiotropic defects including skeletal, e.g., vertebral, carpal, tarsal fusions, and ocular, e.g., microphthalmia and coloboma, phenotypes. To assess the role of GDF6 in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare GDF6 variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, gdf6 was expressed in the pronephric tubule of Xenopus laevis, and Gdf6 expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development. Altogether, we identified rare heterozygous GDF6 variants in 1.6% of all renal anomaly patients and 5.4% of renal anomaly patients additionally manifesting skeletal, ocular, or auricular abnormalities, adding renal hypodysplasia and fusion to the phenotype spectrum of GDF6 variant carriers and suggesting an involvement of GDF6 in nephrogenesis.

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.

Urinary biomarkers of latent inflammation and fibrosis in children with vesicoureteral reflux.

PURPOSE: To investigate the urinary levels of TGF-ß1, VEGF, and MCP-1 as potential biomarkers of latent inflammation and fibrosis in the kidney before and 6 months after correction of vesicoureteral reflux (VUR) in children. METHODS: A total of 88 patients (mean age 26 months) with VUR were divided into three groups: group A-patients with grades II-III VUR, conservative treatment; group B-patients with grades III-V VUR, endoscopic correction of VUR; group C-patients with grades III-V VUR, ureteral reimplantation after failed endoscopic correction. Control group included 20 healthy children. Biomarker levels were measured by ELISA. 99mTc-DMSA scintigraphy and renal histology were performed if possible. RESULTS: At admission, TGF-ß1 was close to control in all study groups, VEGF increased with severity of the disease, and MCP-1 increased in group C. Six months after correction of VUR, despite clinical and laboratory improvement, TGF-ß1 and MCP-1 increased while VEGF decreased compared to the admission values in all groups; no amelioration of renal scarring was detected either by 99mTc-DMSA scintigraphy or renal histology. CONCLUSION: The results support our hypothesis that successful correction of VUR is not sufficient to stop or reduce the latent inflammatory and fibrotic processes that have already started in the kidney regardless of the reflux grade and treatment option. Measuring the urinary levels of TGF-ß1, VEGF, and MCP-1 may aid in the development of non-invasive, pathophysiologically relevant approach to diagnosis and monitoring of kidney injury and fibrosis in children with VUR.

Generation of infant- and pediatric-derived urinary induced pluripotent stem cells competent to form kidney organoids.

BACKGROUND: Human induced pluripotent stem cells (iPSCs) are a promising tool to investigate pathogenic mechanisms underlying human genetic conditions, such as congenital anomalies of the kidney and urinary tract (CAKUT). Currently, iPSC-based research in pediatrics is limited by the invasiveness of cell collection. METHODS: Urine cells (UCs) were isolated from pediatric urine specimens, including bag collections, and reprogrammed using episomal vectors into urinary iPSCs (UiPSCs). Following iPSC-quality assessment, human kidney organoids were generated. RESULTS: UCs were isolated from 71% (12/17) of single, remnant urine samples obtained in an outpatient setting (patients 1 month-17 years, volumes 10-75 ml). Three independent UCs were reprogrammed to UiPSCs with early episome loss, confirmed pluripotency and normal karyotyping. Subsequently, these UiPSCs were successfully differentiated into kidney organoids, closely resembling organoids generated from control fibroblast-derived iPSCs. Importantly, under research conditions with immediate sample processing, UC isolation was successful 100% for target pediatric CAKUT patients and controls (11/11) after at most two urine collections. CONCLUSIONS: Urine in small volumes or collected in bags is a reliable source for reprogrammable somatic cells that can be utilized to generate kidney organoids. This constitutes an attractive approach for patient-specific iPSC research involving infants and children with wide applicability and a low threshold for participation.

Diverse phenotypes in children with PAX2-related disorder.

BACKGROUND: The aim of this study was to analyze the diverse phenotypes of children with PAX2-related disorder so as to improve our understanding of this disease. METHODS: The clinical data of ten children with PAX2 mutations, detected by targeted region capture sequencing or whole-exome sequencing, were retrospectively analyzed. Family members of index cases were verified by Sanger sequencing and family segregation analysis was performed. RESULTS: The age of first symptom of 10 unrelated children (six girls and four boys) was 6.4 (ranged from postnatal day to 14.8) years old. Proteinuria, abnormal renal function, and structure were found in all patients. Renal hypoplasia and renal cysts were found in 10 of 10 and five of 10 cases, respectively. Three patients progressed to chronic kidney disease stage 5 and the onset age of end-stage renal disease was 9.8-16.4 years old. PAX2-related ocular abnormalities were found in five of seven cases and three patients were observed to have more than one ocular findings involved. In addition to diverse renal and ocular findings, new phenotypes including congenital ventricular septal defect, skeletal deformity (fourth metatarsal microsomia), ovarian teratoma, and relatively rare extrarenal manifestations such as growth retardation, gout, and microcephaly were also found. Three novel mutations were reported for the first time. De novo mutations occurred in all patients who were carried out segregation analysis. Patients with the same mutation had different manifestations. PAX2-related disorder showed remarkable clinical variability and phenotypic heterogeneity. CONCLUSION: We firstly reported skeletal deformity (fourth metatarsal microsomia), ovarian teratoma, and congenital ventricular septal defect as new phenotypes of PAX2-related disorder which enlarged the phenotypic spectrum. Gout was firstly reported as the onset symptom of PAX2-related disorder. The diagnosis of PAX2-related disorder should be considered without family history due to a much higher percentage of De novo mutations.

Development of the urogenital system is regulated via the 3'UTR of GDNF.

Mechanisms controlling ureter lenght and the position of the kidney are poorly understood. Glial cell-line derived neurotrophic factor (GDNF) induced RET signaling is critical for ureteric bud outgrowth, but the function of endogenous GDNF in further renal differentiation and urogenital system development remains discursive. Here we analyzed mice where 3' untranslated region (UTR) of GDNF is replaced with sequence less responsive to microRNA-mediated regulation, leading to increased GDNF expression specifically in cells naturally transcribing Gdnf. We demonstrate that increased Gdnf leads to short ureters in kidneys located in an abnormally caudal position thus resembling human pelvic kidneys. High GDNF levels expand collecting ductal progenitors at the expense of ureteric trunk elongation and result in expanded tip and short trunk phenotype due to changes in cell cycle length and progenitor motility. MEK-inhibition rescues these defects suggesting that MAPK-activity mediates GDNF's effects on progenitors. Moreover, Gdnf   hyper mice are infertile likely due to effects of excess GDNF on distal ureter remodeling. Our findings suggest that dysregulation of GDNF levels, for example via alterations in 3'UTR, may account for a subset of congenital anomalies of the kidney and urinary tract (CAKUT) and/or congenital infertility cases in humans and pave way to future studies.

Interleukin-10-1082A/G polymorphism is associated with renal parenchymal damage in congenital anomalies of the kidney and urinary tract.

AIM: The aim of the study was to investigate whether the functional IL10-1082A/G polymorphism exert a role in congenital anomalies of the kidney and urinary tract (CAKUT) in children. Also, the serum IL-10 and its association with genotype and renal parenchymal damage in CAKUT were explored. METHODS: In the current case-control study, 134 paediatric cases of CAKUT and 382 unrelated controls were included. The genotyping of IL10-1082A/G polymorphism was performed by amplification refractory mutation system-PCR and IL-10 serum level was determined by ELISA. RESULTS: Although, the genotype and allelic frequencies of IL10-1082 A/G polymorphism in cases and controls were similar (χ2 = 0.459; P = 0.79 and χ2 = 0.426; P = 0.51, respectively), significant different genotype distribution between patients with or without parenchymal damage/reduction was observed (χ2 = 6.9; P = 0.032). The GG-genotype was more frequent in cases with renal parenchymal damage/reduction compared to patients with preserved parenchyma (22% vs. 9%; OR = 2.987; 95% CI = 0.979-9.468; P = 0.031). On the contrary, the heterozygous genotype was less frequent among cases with parenchymal damage/reduction compared to cases with preserved parenchyma (39% vs. 59%; OR = 0.453; 95% CI = 0.214-0.958; P = 0.024). Additionally, the serum IL-10 was significantly higher in CAKUT patients compared to age-sex-matched controls (median 11.98; IQR: 7.14-31.6 vs. 5.92; IQR: 4.68-14.8; P = 0.0057). Among carriers of GG-genotype significantly higher IL-10 level was detected in cases with parenchymal damage/reduction, than cases with preserved parenchyma (P = 0.028). CONCLUSION: Our results suggested that the functional -1082A/G polymorphism in IL10 is associated with risk of renal parenchymal damage/reduction rather than genetic predisposition to CAKUT. Additionally, our study supposes that immunoregulatory cytokine IL-10 might have a significant role in CAKUT.