Congenital Anomalies Of The Kidney And Urinary Tract Patients Research Articles

Copy number variation analysis identifies MIR9-3 and MIR1299 as novel miRNA candidate genes for CAKUT.

Congenital anomalies of the kidney and urinary tract (CAKUT) represent a frequent cause of pediatric kidney failure. CNVs, as a major class of genomic variations, can also affect miRNA regions. Common CNV corresponding miRNAs (cCNV-miRNAs) are functional variants regulating crucial processes which could affect urinary system development. Thus, we hypothesize that cCNV-miRNAs are associated with CAKUT occurrence and its expressivity. The extraction and filtering of common CNVs, identified in control samples deposited in publicly available databases gnomAD v2.1 and dbVar, were coupled with mapping of miRNA sequences using UCSC Genome Browser. After verification of the mapped miRNAs using referent miRBase V22.1, prioritization of cCNV-miRNA candidates has been performed using bioinformatic annotation and literature research. Genotyping of miRNA gene copy numbers for MIR9-3, MIR511, and MIR1299, was conducted on 221 CAKUT patients and 192 controls using TaqMan™ technology. We observed significantly different MIR9-3 and MIR1299 gene copy number distribution between CAKUT patients and controls (Chi-square, P = 0.006 and P = 0.0002, respectively), while difference of MIR511 copy number distribution showed nominal significance (Chi-square, P = 0.027). The counts of less and more than two of MIR1299 copy numbers were more frequent within CAKUT patients compared to controls (P = 0.01 and P = 0.008, respectively) and also in cohort of patients with anomalies of the urinary tract compared to controls (P = 0.016 and P = 0.003, respectively). Copy number variations of miRNA genes represent a novel avenue in clarification of the inheritance complexity in CAKUT and provide potential evidence about the association of common genetic variation with CAKUT phenotypes.

Determination of the Frequency of BCL-2 Polymorphisms (c.-717C>A and c.*2364G>A) and LIF Polymorphism (c.*1414T>G) in Patients with Congenital Anomalies of the Kidney and Urinary Tract

Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) are characterized by several malformations. Its prevalence is 0.3–0.6% in live births. The B-cell lymphoma (BCL-2) gene regulates apoptosis, and the Leukemia Inhibitory Factor (LIF) gene plays a role in many biological processes, such as blastocyst growth and uterine preparation for implantation. In this study, two single nucleotide polymorphisms (SNPs) of the BCL-2 gene (rs2279115 and rs4987856) and one SNP of the LIF gene (rs929271) were investigated in CAKUT patients for the first time. Methods: Hundred and twenty-nine CAKUT patients and 105 controls were enrolled in this study. We used polymerase chain reaction-restriction fragment length polymorphism for rs2279115 and rs929271 and SNaPshot for rs4987856. The χ2 test was used to compare discrete variables, and the independent sample t test was used to compare continuous variables. Results: The allele frequencies for the rs2279115 and rs4987856 polymorphisms of BCL-2 and the rs929271 polymorphism of LIF were not significantly different between the patient and control groups (p = 0.162, p = 0.053, p = 0.635, respectively). However, the co-segregation analysis revealed a significant difference in the distribution of allele frequencies between the patient and control groups for two genetic variations: LIF rs929271 SNP and BCL-2 rs4987856 SNP (p = 0.034). The relative odds ratio was 2.444 (95% Confidence Interval (CI) 1.054–5.671). Conclusion: This study, which is the first time in the literature, showed that changes in BCL-2 and LIF genes are associated with CAKUT disease.

Diagnostic Yield and Benefits of Whole Exome Sequencing in CAKUT Patients Diagnosed in the First Thousand Days of Life

Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause of chronic kidney disease (CKD) and the need for kidney replacement therapy (KRT) in children. Although more than 60 genes are known to cause CAKUT if mutated, genetic etiology is detected, on average, in only 16% of unselected CAKUT cases, making genetic testing unproductive. Whole exome sequencing (WES) was performed in 100 patients with CAKUT diagnosed in the first 1000 days of life with CKD stages 1 to 5D/T. Variants in 58 established CAKUT-associated genes were extracted, classified according to the American College of Medical Genetics and Genomics guidelines, and their translational value was assessed. In 25% of these mostly sporadic patients with CAKUT, a rare likely pathogenic or pathogenic variant was identified in 1 or 2 of 15 CAKUT-associated genes, including GATA3, HNF1B, LIFR, PAX2, SALL1, and TBC1D1. Of the 27 variants detected, 52% were loss-of-function and 18.5% de novo variants. The diagnostic yield was significantly higher in patients requiring KRT before 3 years of age (43%, odds ratio 2.95) and in patients with extrarenal features (41%, odds ratio 3.5) compared with patients lacking these criteria. Considering that all affected genes were previously associated with extrarenal complications, including treatable conditions, such as diabetes, hyperuricemia, hypomagnesemia, and hypoparathyroidism, the genetic diagnosis allowed preventive measures and/or early treatment in 25% of patients. WES offers significant advantages for the diagnosis and management of patients with CAKUT diagnosed before 3 years of age, especially in patients who require KRT or have extrarenal anomalies.

Downregulation of fibrosis related hsa-miR-29c-3p in human CAKUT

Congenital anomalies of the kidney and urinary tract (CAKUT) represent structural and functional urinary system malformations and take place as one of the most common congenital malformations with an incidence of 1:500. Ureteral obstruction-induced hydronephrosis is associated with renal fibrosis and chronic kidney diseases in the pediatric CAKUT. We aimed to construct interaction network of previously bioinformatically associated miRNAs with CAKUT differentially expressed genes in order to prioritize those associated with fibrotic process and to experimentally validate the expression of selected miRNAs in CAKUT patients compared to control group. We constructed interaction network of hsa-miR-101-3p, hsa-miR-101-5p and hsa-miR-29c-3p that showed significant association with fibrosis. The top enriched molecular pathway was extracellular matrix-receptor interaction (adjusted p = .0000263). We experimentally confirmed expression of three miRNAs (hsa-miR-29c-3p, hsa-miR-101-3p and hsa-miR-101-5p) in obstructed ureters (ureteropelvic junction obstruction and primary obstructive megaureter) and vesicoureteral reflux. The hsa-miR-29c-3p was shown to have lower expression in both patient groups compared to controls. Relative levels of hsa-miR-101-5p and hsa-miR-101-3p showed significant positive correlations in both groups of patients. Statistically significant correlation was observed between hsa-miR-101 (-3p and -5p) and hsa-miR-29c-3p only in the obstructed group. The significant downregulation of anti-fibrotic hsa-miR-29c-3p in obstructive CAKUT could explain activation of genes involved in fibrotic processes. As miRNAs are promising candidates in therapeutic approaches our results need further measurement of fibrotic markers or assessment of extent of fibrosis and functional evaluation of hsa-miR-29c.

Outcomes of kidney transplantation in patients with congenital anomalies of the kidney and urinary tract: a propensity-score-matched analysis with case-control design.

We compared long-term outcomes after kidney transplantation (KTx) in patients with and without congenital anomalies of the kidney and urinary tract (CAKUT). KTx recipients (KTRs) with CAKUT in 1980-2016 were identified; their hard copy and electronic medical records were reviewed and compared to a propensity-score-matched control group (non-CAKUT) from the same period. The primary outcomes were graft loss or death with a functioning graft; secondary outcomes included posttransplant urinary tract infections (UTIs) and biopsy-proven rejection (BPR). : We identified 169 KTRs with CAKUT and 169 matched controls. Median follow-up was 132 (IQR: 75.0-170.0) months. UTIs were more common in CAKUT patients compared to non-CAKUT group (20.7% vs 10.7%; p = 0.01). Rates of BPR were similar between the two groups. In Kaplan-Meier analysis, 10-year graft survival rates were significantly higher in the CAKUT group than in the non-CAKUT group (87.6% vs 69.2%; p < 0.001), while patient survival rates were similar. In multivariate Cox regression analyses, CAKUT (HR: 0.469; 95% CI: 0.320-0.687; p < 0.001) and PRA positivity before transplantation (HR: 3.756; 95% CI: 1.507-9.364; p = 0.005) predicted graft loss. Graft survival in KTRs with CAKUT appears superior to KTRs without CAKUT. Transplant centers should develop multidisciplinary educational and social working groups to support and encourage CAKUT patients with kidney failure to seek for transplants.

Overlap of vitamin A and vitamin D target genes with CAKUT-related processes

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are a group of abnormalities affecting the kidneys and their outflow tracts. CAKUT patients display a large clinical variability as well as a complex aetiology. Only 5% to 20% of the cases have a monogenic origin. It is thereby suspected that interactions of both genetic and environmental factors contribute to the disease. Vitamins are among the environmental factors that are considered for CAKUT aetiology. In this study, we aimed to investigate whether vitamin A or vitamin D could have a role in CAKUT aetiology. For this purpose we collected vitamin A and vitamin D target genes and computed their overlap with CAKUT-related gene sets. We observed limited overlap between vitamin D targets and CAKUT-related gene sets. We however observed that vitamin A target genes significantly overlap with multiple CAKUT-related gene sets, including CAKUT causal and differentially expressed genes, and genes involved in renal system development. Overall, these results indicate that an excess or deficiency of vitamin A might be relevant to a broad range of urogenital abnormalities.

POS-787 LONG-TERM OUTCOMES OF KIDNEY TRANSPLANTATION IN CHILDREN WITH CAKUT VERSUS NON-CAKUT CAUSES OF CHRONIC KIDNEY DISEASE

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of end stage renal disease in children. Little is known about long-term outcomes after kidney transplantation in this group. The aim of this study is to evaluate the clinical characteristics of pediatric kidney transplantation (KTx) in CAKUT children and its outcomes. We conducted a retrospective study, from December 2007 to December 2020, including living donor kidney transplant recipients ≤17 years transplanted in our center. Patients were divided into those with CAKUT and those with non-CAKUT as the cause of chronic kidney disease (CKD). Our aim was to compare delayed graft function (DGF) rate, acute rejection, complication’s rates, and graft loss between groups. A total of 259 living donor kidney transplants were done till 2019. 38 (15%) were ≤17 years, The cause of CKD was CAKUT in 13 patients (34,2%) and non-CAKUT in 25 patients. Of the latter, 15 (60%) had glomerular disease. The most common CAKUT-related cause of CKD was primary vesicoureteral reflux (84,6%). There was no difference in age between the groups, with a mean age of 13,4 +/- 2,9 years in the CAKUT group and 12,7 +/- 3,4 years in the non-CAKUT group (p=0,542). Recipients with CAKUT showed female preponderance, and were more likely to be seropositive for both CMV and EBV (all p<0,05). A nephrectomy is most often performed in patients with CAKUT (53,8%) versus 4,3% in the non CAKUT patients (p=0,001). For both groups, there was no difference in cytotoxic PRA (15,4 % vs 16%, p=0,331) or mean number of compatibilities (3,53 vs 2,92, p=0,314). The post transplant hypertension was significantly higher in non CAKUT recipients than in those with CAKUT (p=0,049). . Compared to non CAKUT-group, CAKUT patients had more urinary tract infection (p=0,043). There was no difference in DGF (7,7% vs 8%, p=0,734), Acute rejection (7,7% vs 20%, p=0,141) or graft loss (7,7% vs 8%, p=0,784). Graft survival of the transplant in children with CAKUT is favourable. However, they have an increased risk of urinary tract infections.

MO029CLINICAL CHARACTERISTICS AND PATHOGENIC GENES OF CONGENITAL SOLITARY KIDNEY WITH REPRODUCTIVE SYSTEM MALFORMATION*

Abstract Background and Aims Congenital solitary kidney – one category of congenital anomalies of the kidney and urinary tract (CAKUT) may combine with other system malformations such as reproductive, cardiac, skeletal system, and so on. Our study analysed the clinical characteristics among congenital solitary kidney patients and their reproductive system malformations. And further work about probable pathogenic genes was explored. Method The information of CAKUT patients who were indicated by Doppler ultrasound was collected. The clinical and imaging features including reproductive system abnormalities were retrospectively reviewed in patients with congenital solitary kidney. In patients with Mayer-Rokitansky- Küster-Hauser (MRKH) syndrome, a disorder of congenital agenesis of uterus and vagina, whole exome sequencing was performed. Rare variants in CAKUT-related genes were analysed. Trio analysis was conducted to identify de novo mutations. Results We identified 209 patients with congenital solitary kidney from July 20, 2017 to July 19, 2020 among 1160 CAKUT patients in Peking Union Medical College Hospital. There were 152 females. The average age of congenital solitary kidney patients was 35.26±18.42 years when they were diagnosed. 53.2% showed different degrees of proteinuria and hematuria. Serum creatinine elevating was proved 13.1% and 40% in women and men separately. Among 81 females who also had a gynecological ultrasound report, 88.9% combined with genital malformation, oblique vaginal septum syndrome 48.7%, the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome 22.2%, malformed uterus 23.5%, vaginal atresia and other genital malformation 7%. Congenital heart disease, complete transposition of viscera, and scoliosis were also found in some patients with congenital solitary kidney. Furthermore, based on the whole exome data of 443 patients with MRKH syndrome, seven function-lost mutations were confirmed. And also two De nove mutations (NOTCH2 (NM_024408.3: c.703A&amp;gt;T(p.Thr235Ser), ESRRG (NM_001243512.1:c.-169-8delT)), one homozygous patients with parents heterozygous (NM_133433.3:c.8084C&amp;gt;T(p.Thr2695Me) were identified as possible pathogenic genes caused CAKUT. Conclusion We should be aware of reproductive system malformations in CAKUT patients. Whole exome sequencing may suggest common pathogenic genes between the two kinds of diseases.

Overlap of vitamin A and vitamin D target genes with CAKUT-related processes

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are a group of abnormalities affecting the kidneys and their outflow tracts, which include the ureters, the bladder, and the urethra. CAKUT patients display a large clinical variability as well as a complex aetiology, as only 5% to 20% of the cases have a monogenic origin. It is thereby suspected that interactions of both genetic and environmental factors contribute to the disease. Vitamins are among the environmental factors that are considered for CAKUT aetiology. In this study, we collected vitamin A and vitamin D target genes and computed their overlap with CAKUT-related gene sets. We observed significant overlaps between vitamin A target genes and CAKUT causal genes, or with genes involved in renal system development, which indicates that an excess or deficiency of vitamin A might be relevant to a broad range of urogenital abnormalities.

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.

Inflammation-like changes in the urothelium of Lifr-deficient mice and LIFR-haploinsufficient humans with urinary tract anomalies.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of end-stage kidney disease in children. While the genetic aberrations underlying CAKUT pathogenesis are increasingly being elucidated, their consequences on a cellular and molecular level commonly remain unclear. Recently, we reported rare heterozygous deleterious LIFR variants in 3.3% of CAKUT patients, including a novel de novo frameshift variant, identified by whole-exome sequencing, in a patient with severe bilateral CAKUT. We also demonstrated CAKUT phenotypes in Lifr-/- and Lifr+/- mice, including a narrowed ureteric lumen due to muscular hypertrophy and a thickened urothelium. Here, we show that both in the ureter and bladder of Lifr-/- and Lifr+/- embryos, differentiation of the three urothelial cell types (basal, intermediate and superficial cells) occurs normally but that the turnover of superficial cells is elevated due to increased proliferation, enhanced differentiation from their progenitor cells (intermediate cells) and, importantly, shedding into the ureteric lumen. Microarray-based analysis of genome-wide transcriptional changes in Lifr-/- versus Lifr+/+ ureters identified gene networks associated with an antimicrobial inflammatory response. Finally, in a reverse phenotyping effort, significantly more superficial cells were detected in the urine of CAKUT patients with versus without LIFR variants indicating conserved LIFR-dependent urinary tract changes in the murine and human context. Our data suggest that LIFR signaling is required in the epithelium of the urinary tract to suppress an antimicrobial response under homeostatic conditions and that genetically induced inflammation-like changes underlie CAKUT pathogenesis in Lifr deficiency and LIFR haploinsufficiency.

Targeted Exome Sequencing Provided Comprehensive Genetic Diagnosis of Congenital Anomalies of the Kidney and Urinary Tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. The search for genetic causes of CAKUT has led to genetic diagnosis in approximately 5–20 % of CAKUT patients from Western countries. In this study, genetic causes of CAKUT in Korean children were sought using targeted exome sequencing (TES) of 60 genes reported to cause CAKUT in human or murine models. We identified genetic causes in 13.8% of the 94 recruited patients. Pathogenic single nucleotide variants of five known disease-causing genes, HNF1B, PAX2, EYA1, UPK3A, and FRAS1 were found in 7 cases. Pathogenic copy number variations of 6 patients were found in HNF1B, EYA1, and CHD1L. Genetic abnormality types did not significantly differ according to CAKUT phenotypes. Patients with pathogenic variants of targeted genes had syndromic features more frequently than those without (p < 0.001). This is the first genetic analysis study of Korean patients with CAKUT. Only one-seventh of patients were found to have pathogenic mutations in known CAKUT-related genes, indicating that there are more CAKUT-causing genes or environmental factors to discover.

The Frequency of Familial Congenital Anomalies of the Kidney and Urinary Tract: Should We Screen Asymptomatic First-Degree Relatives Using Urinary Tract Ultrasonography?

Introduction: The objectives of this study were to determine the incidence of congenital anomalies of the kidney and urinary tract (CAKUT) in asymptomatic first-degree relatives of patients with a CAKUT diagnosis and to evaluate the benefits of such screening. Methods: Files of patients who were followed up at Cerrahpaşa Faculty of Medicine, Pediatric Nephrology Outpatient Clinic, Istanbul University-Cerrahpaşa between 1998 and 2016 were examined retrospectively and those with CAKUT were identified. These patients, and their asymptomatic first-degree relatives, were invited to participate in this study. Ultrasonography of the urinary tract was performed in siblings and parents of 145 CAKUT patients (index cases) who could be reached by phone and agreed to participate. Results: A total of 412 asymptomatic first-degree relatives of 145 index patients were screened by ultrasound. CAKUT was diagnosed in 23 individuals among the family members of 21 index subjects. Anomalies detected in asymptomatic first-degree relatives were renal agenesis (RA) and grade 3 hydronephrosis (n = 1), RA (n = 7), renal hypodysplasia (n = 7), grade 2 hydronephrosis (n = 1), and grade 1 hydronephrosis (n = 7). The frequency of familial CAKUT was 14.4%. Familial RA was found in 3 of the 5 families of index cases with RA. Conclusion: The ratio of familial CAKUT was 14.4%. The findings of the present study could not support a systematic family screening to all asymptomatic first-degree relatives; however, family screening with ultrasonography can be considered for children with RA.

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

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. 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. 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. 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.

Glomerular disease patients have higher odds not to reach quality targets in chronic dialysis compared with CAKUT patients: analyses from a nationwide German paediatric dialysis registry.

Paediatric dialysis patients still suffer from high morbidity rates. To improve this, quality assurance programs like the German QiNKid (Quality in Nephrology for Children)-Registry have been developed. In our study, the significance of underlying renal disease on a range of clinical and laboratory parameters impacting morbidity and mortality was analysed. Our aim was to evaluate whether or not disease-specific dialysis strategies should be considered in planning dialysis for a patient. Inclusion criteria were defined as follows: (1) CAKUT (congenital anomalies of the kidney and urinary tract) or glomerular disease patient, (2) < 18years of age, (3) haemodialysis or peritoneal dialysis patient. Only measurements obtained from day 90 to 365 after the date of the first dialysis in the registry were analysed. Laboratory (serum albumin, haemoglobin, ferritin, calcium, phosphate, parathyroid hormone) and clinical parameters (height, blood pressure) were analysed using mixed effects models accounting for the correlation of repeated measures in individual patients. The study cohort comprised n = 167 CAKUT and n = 55 glomerular disease patients. Glomerular disease patients had significantly higher odds of hypoalbuminemia (OR 13.90, 95% CI 1.35-159.99; p = 0.0274), anaemia (OR 3.31, 95% CI 1.22-9.13; p = 0.0197), hyperphosphatemia (OR 9.69, 95% CI 2.65-37.26; p = 0.0006) and diastolic hypertension (OR 3.38, 95% CI 1.20-9.79; p = 0.0212). Glomerular disease patients might require more intensive dialysis regimens. The evaluation of hydration status should be given more attention, since conditions differing between the cohorts can be linked to overhydration. The QiNKid-Registry allows monitoring of the quality of paediatric dialysis in a nationwide cohort.

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

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. 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. 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). 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.

Transcriptome-driven integrative exploration of functional state of ureter tissue affected by CAKUT

Aims(1) to identify the most dysregulated genes in ureter tissue affected by congenital anomalies of the kidney and urinary tract (CAKUT) and to extract the biological meaning of these markers; (2) to describe the key molecular networks in CAKUT and to provide expression validation of the genes selected from these networks. Main methodsTranscriptome data was obtained from ureter samples of CAKUT patients and controls by Illumina iScan microarray. Identification of differentially expressed genes was coupled with subsequent bioinformatics analyses. Expression of candidate genes was validated by qRT-PCR. Key findingsAnalysis of the transcriptome led to the identification of 78 commonly dysregulated genes in CAKUT tissue compared to controls. Integrative bioinformatic analyses of differentially expressed genes identified 7 major networks. The targets for qRT-PCR validation were selected as members of the major molecular networks in CAKUT, which had both, the significant high fold change and biological relevance for CAKUT. By qRT-PCR the substantial increase of LCN2, PROM1, SOSTDC1, and decrease of INA, RASD1 and TAC3 mRNA levels was confirmed. SignificanceSince CAKUT is a leading cause of end-stage renal disease in children, the search for molecular targets for postnatal therapy is of particular interest. Data described in this study represents the gene expression profile and significant molecular networks specific to human ureter affected by CAKUT. The discovery of impaired molecular factors and processes is the step towards the uncovering of the key mechanisms that reflect CAKUT postnatally and could lead to the affected tissue deterioration and end organ damage.

Prevalence of recurrent urinary tract infection in children with congenital anomalies of the kidney and urinary tract (CAKUT)

Prevalence of congenital abnormalities varies from 3.5% up to 43% in pediatrics.This wide interval is due to limited numbers of research. Limitation of data on recurrent urinary tract infection in CAKUT infants as well as symptoms which resemble other diseases makes it quite a challenge. A study of the prospective cohort was established to analyze the prevalence of recurrent UTI among CAKUT in children at Neonatal and Nephrology Paediatric Department of H.Adam Malik Hospital from 2016 to 2017.Urinalysis and urine culture were used to assess the presence of UTI. The result showed that the prevalence of UTI in CAKUT patients reached 64% in which 52% is the obstructive type and 12% non-obstructive type. Pelvic ureteric junction obstruction is the most common cause. Children with known urinary tract problems such as CAKUT are very prone to developing recurrent UTI. Due to a low survival rate of children with ESKD, new strategies are needed to prevent CAKUT, preserve renal function, and reduce associated cardiovascular morbidity. Meanwhile, children with CAKUT requires a multi-disciplinary and longer follow up.

Genetic basis of human congenital anomalies of the kidney and urinary tract.

The clinical spectrum of congenital anomalies of the kidney and urinary tract (CAKUT) encompasses a common birth defect in humans that has significant impact on long-term patient survival. Overall, data indicate that approximately 20% of patients may have a genetic disorder that is usually not detected based on standard clinical evaluation, implicating many different mutational mechanisms and pathogenic pathways. In particular, 10% to 15% of CAKUT patients harbor an unsuspected genomic disorder that increases risk of neurocognitive impairment and whose early recognition can impact clinical care. The emergence of high-throughput genomic technologies is expected to provide insight into the common and rare genetic determinants of diseases and offer opportunities for early diagnosis with genetic testing.

Antibiotics Prophylaxis in Patients with CAKUT, Does It Actually Prevent UTI? A Single Center Experience at South Africa

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are a well-documented risk factor for the development of urinary tract infection (UTI) in children. Prevention of UTI in this group of patients is advocated due to their increased risk of renal scarring, hypertension and end stage kidney failure. Methods: A 10-year retrospective review of CAKUT patients at the Johannesburg Academic Hospital, who were placed on prophylactic antibiotics over a certain period was done. The rate of UTI, the types of causative organisms isolated and the efficacy of prophylactic antibiotics in preventing UTI were documented. Results: Thirty-six (36) out of 134 patients had been started on prophylactic antibiotics after the diagnosis of CAKUT was made. There was a statistically significant association between the use of prophylactic antibiotics and the rate of UTI (p Conclusion: Antibiotic prophylaxis was very effective in decreasing the rate of UTI in our cohort of patients with CAKUT.