Congenital Anomalies Of Kidneys Research Articles

Duplex collecting system with renal malrotation: an unusual combination

Both duplex collecting system and renal malrotation are congenital developmental anomalies of kidney. They usually present asymptomatic and accidentally diagnosed while patients undergo radiology examinations. We are reporting a case of a 33-year-old-male with a combination of duplex and malrotation kidney. Although these two are common anomalies of kidney, their combination is extremely rare. We found only two reports that had similar combined cases, so our case is the third reported.

Amniotic fluid content in children with kidney and urinary tract anomalies determines pre- and postnatal development

BackgroundRenal oligohydramnios (ROH) describes an abnormally low volume of amniotic fluid (AF) during pregnancy. ROH is mostly caused by congenital fetal kidney anomalies. The ROH diagnosis frequently implies an increased risk of peri- and postnatal fetal mortality and morbidity. The present study aimed to evaluate the impact of ROH on pre-and postnatal development in children with congenital kidney anomalies.MethodsThis retrospective study included 168 fetuses with anomalies in the kidney and urinary tract. Based on the amount of AF measured by ultrasound, patients were divided into three groups: normal amniotic fluid (NAF), amniotic fluid in the lower normal range (LAF), and ROH. These groups were compared with respect to prenatal sonographic parameters, perinatal outcomes, and postnatal outcomes.ResultsAmong the 168 patients with congenital kidney anomalies, 26 (15%) had ROH, 132 (79%) had NAF, and 10 (6%) had LAF. Of the 26 families affected by ROH, 14 (54%) decided to terminate pregnancy. Of 10 live-born children in the ROH group, 6 (60%) survived the observation time; of these, 5/6 presented with chronic kidney disease, stages I–III, at their last examination. The main differences in postnatal development between the ROH group and the NAF and LAF groups were: restricted height and weight gain, respiratory issues, complicated feeding, and the presence of extrarenal malformations.ConclusionsROH is not a mandatory indicator of severe postnatal kidney function impairment. However, children with ROH have complicated peri-and postnatal periods, due to the presence of concomitant malformations, which must be considered in prenatal care.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Disturbances in Switching between Canonical and Non-Canonical Wnt Signaling Characterize Developing and Postnatal Kidneys of Dab1-/- (yotari) Mice.

This study aims to determine the protein expression patterns of acetylated α-tubulin, inversin, dishevelled-1, Wnt5a/b, and β-catenin in developing (E13.5 and E15.5) and early postnatal (P4 and P14) kidneys of Dab1-/- (yotari) mice, their role in regulating the Wnt signaling pathway, and the possible relation to congenital anomalies of kidney and urinary tract (CAKUT). The analysis of target protein co-expression, observed in the renal vesicles/immature glomeruli, ampullae/collecting ducts, convoluted tubules, metanephric mesenchyme of developing kidneys, but proximal convoluted tubules, distal convoluted tubules and glomeruli of postnatal kidneys, was performed using double immunofluorescence and semi-quantitative methods. The overall expression of acetylated α-tubulin and inversin during normal kidney development increases with higher expression in yotari mice as the kidney acquires mature morphology. An increase in β-catenin and cytosolic DVL-1 levels, indicating a switch from non-canonical to canonical Wnt signaling, is found in the postnatal kidney of yotari mice. In contrast, healthy mouse kidney expresses inversin and Wnt5a/b in the postnatal period, thus activating non-canonical Wnt signaling. Target protein expression patterns in kidney development and the early postnatal period observed in this study could indicate that switching between canonical and non-canonical Wnt signaling is crucial for normal nephrogenesis, while the defective Dab1 gene product in yotari mice may promote CAKUT due to interfering with this process.

Predictive factors of advanced chronic kidney disease in children with congenital anomalies of kidney and urinary tract

Background Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (CKD) in children. Delayed diagnosis of CAKUT due to lack of universal screening (such as prenatal ultrasound screening or postnatal ultrasound screening in neonates with risk of CAKUT) has led to more cases of advanced CKD in children. CKD has high morbidity and mortality, and early detection is required to prevent the progression of CKD.
 Objective To determine the factors that predict the development of advanced CKD in children with CAKUT.
 Methods This retrospective cohort study included children with CAKUT at Dr. Sardjito Hospital, Yogyakarta, Indonesia from January 2016 to February 2021. Patients who were diagnosed with CAKUT were followed up to 5 years or until the onset of advanced CKD. Advanced CKD was defined as a decreased estimated glomerular filtration rate (eGFR) of less than 30mL/min/1.73m2 based on the revised Schwartz formula. CKD progression-free survival was determined with Kaplan-Meier and Cox regression analyses.
 Results Among 62 subjects with CAKUT, 7 (11.3%) subjects progressed to advanced CKD. The mean time of advanced CKD progression was 52.2 (95%CI 46.9 to 57.5) months. The overall incidence rate was 22 per 1,000 person-years. Based on Kaplan-Meier analysis, children with eGFR <60 mL/min/1.73m2 at the time of diagnosis had more rapid progression to advanced CKD than patients with eGFR ?60 mL/min/1.73m2 [40.2 (95%CI 33.4 to 46.6) months vs. 58.2 95%CI 46.9 to 57.5) months; P=0.02, respectively].
 Conclusion Reduced eGFR at the time of diagnosis showed rapid progression to advanced CKD.

Subclinical C1q Nephropathy Combined with Possible Donor-Derived IgA Deposition in a 1-Year Kidney Allograft Biopsy: A Case Report

Few previous studies have reported immune-complex nephropathy that has not been classified as a specific phenotype in kidney allografts. We report a case of a de novo subclinical "full-house" pattern of deposition in a pediatric transplantation recipient with possible donor-derived IgA deposition. A five-year-old boy underwent living kidney transplantation due to congenital kidney and urinary tract anomalies. A one-hour implantation biopsy revealed IgA deposition. A four-month protocol biopsy finding showed less intense IgA deposition, in contrast with the one-hour biopsy, and trace para-mesangial deposits. A one-year protocol biopsy demonstrated a full-house deposition pattern and massive electron-dense deposits with minor glomerular changes. At the time of the one-year biopsy, kidney function was stable, with no urinalysis abnormalities. No evidence of systemic lupus erythematosus was observed in clinical and serologic examinations. Mesangial IgG, IgM, C3, and C1q deposition was codominant, and IgA deposition was weaker. We diagnosed this case as C1q nephropathy combined with remaining donor-derived IgA deposition. Few studies have reported C1q nephropathy in kidney allograft; further accumulation of cases is required. To distinguish between donor-derived and de novo glomerular lesions, it is important to assess the serial histologic findings of immunofluorescence and electron microscopy. Here, we report a rare case of subclinical C1q nephropathy with possible donor-derived IgA nephropathy.

PD37-01 THE CADHERIN-CATENIN COMPLEX IS CRUCIAL FOR THE INITIAL STEP OF NEPHRON FORMATION

You have accessJournal of UrologyCME1 Apr 2023PD37-01 THE CADHERIN-CATENIN COMPLEX IS CRUCIAL FOR THE INITIAL STEP OF NEPHRON FORMATION Balint Der, Helena Bugacov, Muskaan Singh, and Andrew P. McMahon Balint DerBalint Der More articles by this author , Helena BugacovHelena Bugacov More articles by this author , Muskaan SinghMuskaan Singh More articles by this author , and Andrew P. McMahonAndrew P. McMahon More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003335.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Congenital anomalies of the kidney and urinary tract contribute to a significant share of pre- and neonatal developmental abnormalities. In nephron formation, canonical Wnt-signaling induces mesenchymal nephron progenitor cells (NPCs) to aggregate and epithelialize forming the renal vesicle (RV), the nephron precursor. β-catenin is essential for the inductive process though the mechanism of morphological transition is not well understood (Park et al., 2007). We hypothesized that ß-catenin also directs RV formation through its critical role in cadherin mediated cell adhesion, the potential redundancy amongst cadherin members confounding earlier genetic studies (Dahl et al., 2002). METHODS: Using a chemically defined culture medium replicating in vivo NPC signaling, we examined the requirement for multiple cadherin adhesion complex components in the canonical Wnt signaling induced aggregation of induced NPCs in vitro. RESULTS: Removal of extracellular calcium, an essential ion in cadherin complexes, resulted in reversible loss of cell-cell contacts, consistent with a role for cadherin adhesion in the aggregation process. In vitro knockout of β-catenin inhibited the induction and aggregation of NPCs replicating the findings of the in vivo loss-of-function mouse experiments. Interestingly, the deletion of α-catenin phenocopied the results of β-catenin knockout experiments blocking cell aggregation providing further evidence for the role of the cadherin-catenin complex in the aggregation. To identify the cadherin members of the adhesion complex, we screened in vitro bulk RNA-seq. dataset and validated the presence of four cadherin proteins by immunofluorescent staining. The quadruple removal of in vitro expressed cadherins replicated the previously characterized phenomenon of inhibited aggregation of the NPCs. CONCLUSIONS: The aggregation of NPCs in vitro is exclusively mediated via the cadherin-catenin complex which models the initial step of nephrogenesis in vivo. A mechanistic insight into NPC aggregation fits within the larger framework of how a healthy kidney is formed and might explain the genetic background of certain congenital kidney anomalies. Source of Funding: National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK054364 Cell Interaction in Development of the Mammalian Kidney) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e986 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Balint Der More articles by this author Helena Bugacov More articles by this author Muskaan Singh More articles by this author Andrew P. McMahon More articles by this author Expand All Advertisement PDF downloadLoading ...

A decrease in the incidence of Shiga toxin-related hemolytic uremic syndrome as a cause of kidney transplantation at an argentine referral center.

In Argentina, Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC HUS), is the main cause of acute kidney injury and the second cause of end-stage renal disease (ESRD) in children. In recent decades, strategies have been implemented to reduce progression to ESRD, but it is not known whether the cumulative incidence of HUS requiring kidney transplantation (KTx) has decreased. We aimed to determine whether the cumulative incidence of STEC HUS in children undergoing KTx decreased and compared outcomes of HUS-related KTx vs. those related to other etiologies. All patients who underwent KTx at our institution were evaluated. The cohort was divided into quintiles (Q), and we compared the cumulative incidence of HUS-related KTx vs KTx due to other etiologies. A total of 1000 consecutive KTx were included. The cumulative incidence of HUS-related KTx was 11%. HUS was the second cause of KTx in Q1: 17% (1988-1995); Q2: 13.5% (1996-2003); Q3: 11.5% (2004-2009) and third cause in Q4: 10% (2010-2015) and Q5: 3% (2016-2021). The cumulative incidence of HUS-related KTx decreased in Q4 and Q5 compared to Q1, Q2, and Q3 and the decline was even steeper when comparing Q4 to Q5 (p:0.019). There was no difference in graft survival in patients with HUS vs. congenital anomalies of kidney and urinary tract (CAKUT) but better than in those with focal segmental glomerulosclerosis (FSGS). In this cohort, the cumulative incidence of HUS-related KTx decreased, which may have been due to the implementation of nephroprotective strategies.

Early-in-Life Serum Aldosterone Levels Could Predict Surgery in Patients with Obstructive Congenital Anomalies of the Kidney and Urinary Tract: A Pilot Study.

The aim of the study was to evaluate whether serum aldosterone levels or plasmatic renin activity (PRA) measured early in life (1-3 months) could predict a future surgical intervention for obstructive congenital anomalies of kidney and urinary tract (CAKUT). Twenty babies aged 1-3 months of life with suspected obstructive CAKUT were prospectively enrolled. The patients underwent a 2-year follow-up and were classified as patients needing or not needing surgery. In all of the enrolled patients, PRA and serum aldosterone levels were measured at 1-3 months of life and were evaluated as predictors of surgery by receiver-operating characteristic (ROC) curve analysis. Patients undergoing surgery during follow-up showed significantly higher levels of aldosterone at 1-3 months of life compared to those who did not require surgery (p = 0.006). The ROC curve analysis of the aldosterone for obstructive CAKUT needing surgery showed an area under the ROC curve of 0.88 (95%CI = 0.71-0.95; p = 0.001). The aldosterone cut-off of 100 ng/dL presented 100% sensitivity and 64.3% specificity and predicted surgery in 100% of cases. The PRA at 1-3 months of life was not a predictor of surgery. In conclusion, serum aldosterone levels at 1-3 months could predict the need for surgery during obstructive CAKUT follow-up.

CAKUT: A Pediatric and Evolutionary Perspective on the Leading Cause of CKD in Childhood

The global prevalence of chronic kidney disease (CKD) is increasing rapidly, due to increasing environmental stressors through the life cycle. Congenital anomalies of kidney and urinary tract (CAKUT) account for most CKD in children, with a spectrum that can lead to kidney failure from early postnatal to late adult life. A stressed fetal environment can impair nephrogenesis, now recognized as a significant risk factor for the development of adult CKD. Congenital urinary tract obstruction is the leading cause of CKD due to CAKUT and can itself impair nephrogenesis as well as contribute to progressive nephron injury. Early diagnosis by ultrasonography in fetal life by an obstetrician/perinatologist can provide important information for guiding prognosis and future management. This review focuses on the critical role played by the pediatrician in providing timely evaluation and management of the patient from the moment of birth to the transfer to adult care. In addition to genetic factors, vulnerability of the kidney to CKD is a consequence of evolved modulation of nephron number in response to maternal signaling as well as to susceptibility of the nephron to hypoxic and oxidative injury. Future advances in the management of CAKUT will depend on improved biomarkers and imaging techniques.

Renal-hepatic-pancreatic dysplasia type 2: Perinatal lethal condition or a multisystemic disorder with variable expressivity.

Renal-hepatic-pancreatic dysplasia type 2 (RHPD2) is a rare condition that has been described in the literature disproportionately in perinatal losses. The main features of liver and kidney involvement are well described, with cardiac malformations and cardiomyopathy adding additional variation to the phenotype. Many patients reported are within larger cohorts of congenital anomalies of kidney and urinary tract (CAKUT) or liver failure, and with minimal phenotypic and clinical course data. An independent series of phenotypes and prognosis was aggregated from the literature. In this literature review, we describe an additional patient with RHPD2, provide a clinical update on the oldest known living patient, and report the cumulative phenotypes from the existing published patients. With now examining the 17 known patients in the literature, 13 died within the perinatal period-pregnancy to one year of life. Of the four cases living past the first year of life, one case died at 5 years secondary to renal failure, the other at 30 months secondary to liver and kidney failure. Two are currently alive and well at one year and 13 years. Two cases have had transplantation with one resulting in long-term survival. These patients serve to expand the existing phenotype of RHPD2 as a perinatal lethal condition into a pediatric disorder with variable expressivity. Additionally, we introduce the consideration of transplantation and outcomes within this cohort and future patients.

Prevalence of and risk factors for chronic kidney disease in ten metropolitan areas of China: a cross-sectional study using three kidney damage markers

Introduction To estimate the up-to-date prevalence of chronic kidney disease among the health check-up population in economically developed areas of China using estimated glomerular filtration rate, urinary albumin creatinine ratio, and kidney ultrasound. Methods Healthcare data from 38,093 subjects in 10 megalopolises of China who had an annual health check-up in 2021 were used. The overall and stratified prevalence of chronic kidney disease by sex, age, region and comorbidity group was reported. The association between chronic kidney disease and covariates of demographics, and comorbidities were analyzed in the multivariable-adjusted logistic regression model. Results A total of 3837 CKD cases were detected meeting any of the three CKD diagnostic criteria, with a crude prevalence of 10.1% in the study population. Using one criterion of decreased glomerular filtration rate, albuminuria and kidney structural abnormalities alone detected 204 (5.3%), 3289 (85.7%) and 563 (14.7%) cases, respectively. The addition of kidney ultrasound detected 427 (11.1%) structural abnormality cases without decreased GFR and albuminuria. The most common abnormalities were renal masses, hydronephrosis due to obstruction and congenital anomalies of kidney and urinary tract. Female, older age, low city-tier, hypertension, diabetes, obesity, hypertriglyceridemia as well as early disease stages such as pre-hypertension, impaired fasting glucose and overweight were significantly associated with chronic kidney disease. Conclusion Kidney ultrasound helps to amplify the detection of CKD patients, which is a supplement to kidney function and urine protein.

An unexpected case of neonatal compartment syndrome associated with congenital anomalies of kidney and urinary tract

Abstract Objectives Neonatal compartment syndrome (NCS) occurs when increased pressure within the fasciocutaneous compartment decreases capillary perfusion, causing irreversible tissue damage from ischemia. NCS is a rare condition that requires prompt diagnosis and treatment. Diagnosing NCS is highly dependent on the examination, which can be difficult in newborns. Prompt recognition provides the best chance for good outcomes. Case presentation We present a case of NCS diagnosed and treated based on physical examination findings. Fetal ultrasonography showed bladder distension, bilateral hydroceles, urethra dilation, and abdominal urinary ascites concerning for lower urinary tract obstruction and possible bladder rupture. At 1 h after birth, examination of the infant’s left upper extremity showed no spontaneous movement, the hand and forearm appeared dusky, and the hand had a large blister with desquamation. No pulse distal to the antecubital fossa was detected via Doppler ultrasonography. The infant was diagnosed with NCS and underwent urgent fasciotomy. The clinical appearance and perfusion of the left upper extremity gradually improved. At four months of age, the wounds were healed and the patient had full passive range of motion of the left upper extremity. Recovery of active motion is ongoing. Conclusions The presence of blistering and desquamation should provoke suspicion for NCS. Once NCS is diagnosed, prompt intervention is necessary to reduce the risk of poor functional outcomes. This case highlights the need for increased awareness of the risk developing compartment syndrome in utero as part of the rare sequalae in infants with congenital anomalies of kidney and urinary tract.

The Importance of a Healthy Lifestyle in Patients with Congenital Anomalies of Kidney and Urinary Tract.

The Importance of a Healthy Lifestyle in Patients with Congenital Anomalies of Kidney and Urinary Tract.

Genetic Susceptibility to Chronic Kidney Disease: Links, Risks and Management.

Chronic kidney disease (CKD) is associated with significant morbidity and mortality worldwide. In recent years, our understanding of genetic causes of CKD has expanded significantly with several renal conditions having been identified. This review discusses the current landscape of genetic kidney disease and their potential treatment options. This review will focus on cystic kidney disease, glomerular disease with genetic associations, congenital anomalies of kidneys and urinary tract (CAKUT), autosomal dominant-tubulointerstitial kidney disease (ADTKD), inherited nephrolithiasis and nephrocalcinosis.

Prenatal diagnosis and molecular cytogenetic analyses of a paternal inherited deletion of 1q23.3 encompassing PBX1 gene

BackgroundPatients with deletions involving the long arm of chromosome 1 are rare. The PBX1 gene is located on chromosome 1q23.3. PBX1 encodes a transcription factor which promotes protein–protein interaction and plays a crucial role in several developmental processes. PBX1 haploinsufficiency had been reported to lead syndromic congenital anomalies of kidney and urinary tract (CAKUT) in humans.Case presentationIn this research, a 24-year-old woman (gravida 1, para 0) underwent amniocentesis at 22 weeks’ gestation because of a horseshoe kidney of the fetus on prenatal ultrasound.ResultsChromosomal microarray analysis (CMA) from this family revealed a 1.14 Mb paternal inherited deletion on chromosome 1q23.3, spanning from position 163,620,000 to 164,760,000 (hg19). Trio whole-exome sequencing (WES) showed heterozygous deletions in exons 1–2 of the PBX1 in fetal and paternal samples. At the 3-year follow-up, the baby did not have an abnormal phenotype except a horseshoe kidney.ConclusionWe provide a detailed description of the phenotype in a family with paternal inherited deletion of 1q23.3 encompassing exons 1–2 of the PBX1 gene. Combination of karyotype analysis, CMA, WES, prenatal ultrasound and genetic counseling is helpful for the prenatal diagnosis of chromosomal microdeletions/microduplications.

Renal Genetics Clinic: 3-Year Experience in the Cleveland Clinic

There has been an increasing demand for the expertise provided by a renal genetics clinic. Such programs are limited in the United States and typically operate in a genomics research setting. Here we report a 3-year, real-world, single-center renal genetics clinic experience. Retrospective cohort. Outpatient cases referred to the renal genetics clinic of the Cleveland Clinic between January 2019 and March 2022 were reviewed. Clinical and laboratory characteristics were analyzed. All genetic testing was performed in clinical labs. 309 new patients referred from 15 specialties were evaluated, including 118 males and 191 females aged 35.1±20.3 years. Glomerular diseases were the leading presentation followed by cystic kidney diseases, electrolyte disorders, congenital anomalies of kidneys and urinary tract, nephrolithiasis, and tubulointerstitial kidney diseases. Dysmorphic features were noted in 27 (8.7%) patients. Genetic testing was recommended in 292 (94.5%) patients including chromosomal microarray (8.9%), single-gene tests (19.5%), multigene panels (77.3%), and exome sequencing (17.5%). 80.5% of patients received insurance coverage for genetic testing. 45% (115/256) of patients had positive results, 25% (64/256) had variants of unknown significance, and 22.3% (57/256) had negative results. 43 distinct monogenic disorders were diagnosed. Family history of kidney disease was present in 52.8% of patients and associated with positive genetic findings (OR, 2.28; 95% CI, 1.40-3.74). 69% of patients with positive results received a new diagnosis and/or a change in the diagnosis. Among these, 39.7% (31/78) of patients received a significant change in disease management. Retrospective and single-center study. The renal genetics clinic plays important roles in the diagnosis and management of patients with genetic kidney diseases. Multigene panels are the most frequently used testing modality with a high diagnostic yield. Family history of kidney disease is a strong indication for renal genetics clinic referral.

Aberrations in FGFR1, FGFR2, and RIP5 Expression in Human Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).

This study aimed to explore the spatio-temporal expression patterns of congenital anomalies of kidney and urinary tract (CAKUT) candidate genes, Fibroblast Growth Factor Receptor 1 (FGFR1), Fibroblast Growth Factor Receptor 2 (FGFR2) and Receptor-Interacting Protein Kinase 5 (RIP5), in human fetal kidney development (CTRL) and kidneys affected with CAKUT. Human fetal kidneys from the 22nd to 41st developmental week (duplex, hypoplastic, dysplastic, and controls) were stained with antibodies and analyzed by epifluorescence microscopy and RT-qPCR. The effect of CAKUT candidate genes on kidney nephrogenesis and function is confirmed by statistically significant variations in the spatio-temporal expression patterns of the investigated markers. The nuclear localization of FGFR1, elevated expression score of FGFR1 mRNA, the increased area percentage of FGFR1-positive cells in the kidney cortex, and the overall decrease in the expression after the peak at the 27th developmental week in dysplastic kidneys (DYS), suggest an altered expression pattern and protein function in response to CAKUT pathophysiology. The RT-qPCR analysis revealed a significantly higher FGFR2 mRNA expression score in the CAKUT kidneys compared to the CTRL. This increase could be due to the repair mechanism involving the downstream mediator, Extracellular Signal-Regulated Kinase 1/2 (ERK1/2). The expression of RIP5 during normal human kidney development was reduced temporarily, due to urine production and increased later since it undertakes additional functions in the maturation of the postnatal kidney and homeostasis, while the expression dynamics in CAKUT-affected kidneys exhibited a decrease in the percentage of RIP5-positive cells during the investigated developmental period. Our findings highlight the importance of FGFR1, FGFR2, and RIP5 as markers in normal and pathological kidney development.

Hnf1b renal expression directed by a distal enhancer responsive to Pax8

Xenopus provides a simple and efficient model system to study nephrogenesis and explore the mechanisms causing renal developmental defects in human. Hnf1b (hepatocyte nuclear factor 1 homeobox b), a gene whose mutations are the most commonly identified genetic cause of developmental kidney disease, is required for the acquisition of a proximo-intermediate nephron segment in Xenopus as well as in mouse. Genetic networks involved in Hnf1b expression during kidney development remain poorly understood. We decided to explore the transcriptional regulation of Hnf1b in the developing Xenopus pronephros and mammalian renal cells. Using phylogenetic footprinting, we identified an evolutionary conserved sequence (CNS1) located several kilobases (kb) upstream the Hnf1b transcription start and harboring epigenomic marks characteristics of a distal enhancer in embryonic and adult renal cells in mammals. By means of functional expression assays in Xenopus and mammalian renal cell lines we showed that CNS1 displays enhancer activity in renal tissue. Using CRISPR/cas9 editing in Xenopus tropicalis, we demonstrated the in vivo functional relevance of CNS1 in driving hnf1b expression in the pronephros. We further showed the importance of Pax8-CNS1 interaction for CNS1 enhancer activity allowing us to conclude that Hnf1b is a direct target of Pax8. Our work identified for the first time a Hnf1b renal specific enhancer and may open important perspectives into the diagnosis for congenital kidney anomalies in human, as well as modeling HNF1B-related diseases.

Tekrarlayan İdrar Yolu Enfeksiyonu Olan Çocuklarda Tuvalet Alışkanlıklarının Değerlendirilmesi ve Böbrek Hasarı Gelişmesinde Rol Oynayan Risk Faktörlerinin Araştırılması

Objective: Urinary tract infection is one of the common infections in children. The patients with recurrent infection are at risk for permanent renal damage in later life. In this study, it was aimed to investigate the toilet habits and risk factors for renal scarring in children with recurrent urinary tract infection without congenital anomalies of the kidney and urinary tract.Materials and Methods: Patients between the ages of 6 and 18 with a diagnosis of recurrent urinary tract infection who were toilet trained were included in this study. Data of patients with congenital anomalies of kidney and urinary tract were excluded from the study. The detailed information on the voiding postponement, infrequent voiding, holding maneuvers and renal scarring were obtained from file records.Results: The 208 patients (146 girls, 62 boys) were included in this study. The more than half of the patients (n=132, 63.5%) had a habit voiding postponement, and one third (n=65, 31.3%) had holding maneuver. There was infrequent voiding in 47 (22.6%) patients. Renal scarring was determined in 38 (18.3%) patients. The frequencies of voiding postponement, holding maneuver and infrequent voiding were higher in patients with renal scarring than those of without [30 (78.9%)/102 (60%), p=0.048; 12 (31.6%)/53 (21.2%), p=0.039; 15 (39.5%)/32 (18.8%), p=0.009, respectively]. It was determined a significant positive association between renal scarring and voiding postponement with infrequent voiding [Odds ratio=3.21, p=0.011; Odds ratio=1.46, p=0.021; Odds ratio=3.43, p=0.001, respectively]. Conclusion: Toilets habits should be questioned in routine follow-up program in children with recurrent urinary tract infection. The development of true toilet habits may be useful to prevent the development of renal scarring in children.

Risk factors for childhood chronic kidney disease: a population-based study.

The population-based prevalence and risk factors of childhood chronic kidney disease (CKD) are not well-defined. We ascertained childhood CKD epidemiology and perinatal risk factors, based on a large computerized medical record database that covers most of southern Israel's population. Pre- and post-natal records of 79,374 eligible children (with at least one serum creatinine test) born during 2001-2015 were analyzed. "Ever-CKD" was defined as ≥ 2 estimated glomerular filtration rate (eGFR) values < 60ml/min/1.73 m2 beyond age 2years, more than 3months apart. The last CKD status was determined on March 2019. Of 82 (0.1%) patients with ever-CKD, 35 (42.7%) had their first abnormal eGFR identified already at age 2years. In multiple logistic regression analysis, congenital anomalies of kidney and urinary tract (CAKUT)-related diagnoses, glomerulopathy, maternal oligohydramnios, small for gestational age, prematurity (under 34weeks), post-term delivery, and small for gestational age at birth were significant risk factors for ever-CKD (odds ratio (95% confidence interval): 44.34(26.43-74.39), 64.60(32.42-128.70), 5.54(3.01-10.19), 2.02(1.25-3.28), 4.45(2.13-9.28), 2.96(1.28-6.86 and 2.02(1.25-3.28), respectively). Seventy children with ever-CKD (85.4%) had a depressed eGFR (< 90ml/min/1.73 m2) on the last assessment (current-CKD), yielding a prevalence of 882/million. CKD is more prevalent among children in southern Israel than previously reported, even after excluding those with aborted-CKD. Prenatal conditions increase the risk to develop CKD in childhood. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.