Rik Westland

Unilateral multicystic dysplastic kidney: a meta-analysis of observational studies on the incidence, associated urinary tract malformations and the contralateral kidney

BACKGROUND Many papers are published on cohorts with unilateral multicystic dysplastic kidney (MCDK) patients, but show variable results as to the incidence of associated urinary tract abnormalities. The objective of this study was to describe the status of the urinary tract, including contralateral hypertrophy and malformations, in patients with unilateral MCDK based on a meta-analysis of the literature, taking into account the timing of diagnosis (pre- versus postnatal) as a possible source of bias. METHODS A systematic review of the scientific literature in English was conducted using PubMed and Embase. A meta-analysis was performed with the studies that were identified using our reproducible search. RESULTS Based on analysis of the data in 19 populations, the overall incidence of unilateral MCDK is 1 in 4300 with an increasing trend over the years. A total of 67 cohorts with over 3500 patients with unilateral MCDK were included in the meta-analysis. Fifty-nine percent of patients were male and the MCDKs were significantly more often found on the left side (53.1%). Associated anomalies in the solitary functioning kidney were found in 1 in 3 patients, mainly vesicoureteric reflux (VUR, in 19.7%). In patients with VUR, 40% have severe contralateral VUR, defined as grade III-V. Contralateral hypertrophy, present in 77% of patients after a follow-up of at least 10 years, showed a trend to be less pronounced in patients with VUR. Timing of the diagnosis of MCDK did not essentially influence the results. CONCLUSIONS These aggregate results provide insight into the incidence, demographic data and associated anomalies in patients with unilateral MCDK. One in three patients with unilateral MCDK show anomalies in the contralateral, solitary functioning kidney. However, studies into the long-term consequences of these anomalies are scarce.

Unilateral renal agenesis: a systematic review on associated anomalies and renal injury

BACKGROUND Unilateral renal agenesis (URA) is associated with other congenital anomalies of the kidney and urinary tract (CAKUT) and extra-renal anomalies. However, the reported prevalences of these anomalies are highly variable. We estimated the prevalence of associated CAKUT and extra-renal anomalies in patients with URA. Furthermore, we determined the prevalence of renal injury in URA patients. METHODS We conducted a systematic review of English and non-English articles using PubMed and Embase.com. Included studies reported at least one of the following items: incidence of URA, gender, side of URA, prenatal diagnosis, performance of micturating cystourethrogram, associated CAKUT, urinary tract infection or extra-renal anomalies. Studies that described a mean/median glomerular filtration rate (GFR) and proportions of patients with hypertension, micro-albuminuria or a decreased GFR were also included. RESULTS Analyses were based on 43 included studies (total number of patients: 2684, 63% male). The general incidence of URA was 1 in ∼2000. Associated CAKUT were identified in 32% of patients, of which vesicoureteral reflux was most frequently identified (24% of patients). Extra-renal anomalies were found in 31% of patients. Hypertension could be identified in 16% of patients, whereas 21% of patients had micro-albuminuria. Ten per cent of patients had a GFR<60 mL/min/1.73 m2;. CONCLUSIONS These aggregate results provide insight in the prevalence of associated anomalies and renal injury in patients with URA. Our systematic review implicates that URA is not a harmless malformation by definition. Therefore, we emphasize the need for clinical follow-up in URA patients starting at birth.

Risk Factors for Renal Injury in Children With a Solitary Functioning Kidney

OBJECTIVE: The hyperfiltration hypothesis implies that children with a solitary functioning kidney are at risk to develop hypertension, proteinuria, and chronic kidney disease. We sought to determine the presenting age of renal injury and identify risk factors for children with a solitary functioning kidney. METHODS: We evaluated 407 patients for signs of renal injury, defined as hypertension, proteinuria, an impaired glomerular filtration rate, and/or the use of renoprotective medication. Patients were subdivided on the basis of type of solitary functioning kidney and the presence of ipsilateral congenital anomalies of the kidney and urinary tract (CAKUT). The development of renal injury was analyzed with Kaplan-Meier analysis. Risk factors were identified by using logistic regression models. RESULTS: Renal injury was found in 37% of all children. Development of renal injury increased by presence of ipsilateral CAKUT (odds ratio [OR] 1.66; P = .04) and age (OR 1.09; P < .001). Renal length was inversely associated with the risk to develop renal injury (OR 0.91; P = .04). In all patients, the median time to renal injury was 14.8 years (95% confidence interval 13.7–16.0 years). This was significantly shortened for patients with ipsilateral CAKUT (12.8 years, 95% confidence interval 10.6–15.1 years). CONCLUSIONS: Our study determines independent risk factors for renal injury in children with a solitary functioning kidney. Because many children develop renal injury, we emphasize the need for clinical follow-up in these patients starting at birth.

Precision of Estimating Equations for GFR in Children with a Solitary Functioning Kidney: The KIMONO Study

BACKGROUND AND OBJECTIVE Children with a solitary functioning kidney may develop CKD. Although widely used, equations to estimate GFR are not validated in these patients. This study sought to determine the precision of common estimating equations in the KIMONO (KIdney of MONofunctional Origin) cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Two creatinine-based (estimated GFR [eGFR]-Schwartz, urinary creatinine clearance), two cystatin C-based (eGFR-Zappitelli1, eGFR-CKiD [Chronic Kidney Disease in Children] 1), and two cystatin C/creatinine-based (eGFR-Zappitelli2, eGFR-CKiD2) estimates were compared with the gold standard GFR measured by inulin single injection (GFR-inulin) in 77 children with a solitary functioning kidney (time span of assembly, 2005-2012). Included patients were 1.5-19.8 years of age. Kidney Disease Outcomes Quality Initiative (K/DOQI) classification was compared between GFR-inulin and eGFR methods to analyze misclassification by estimating equations. RESULTS The eGFR-CKiD2 equation performed best in children with a solitary functioning kidney (mean bias, -0.9 ml/min per 1.73 m(2); 95% and 54% of values within ±30% and ±10% of GFR-inulin, respectively). Mean bias for eGFR-Schwartz was 0.4 ml/min per 1.73 m(2), with 90% and 33% of values within ±30% and ±10% of GFR-inulin, respectively. For all estimates, misclassification in K/DOQI stage ranged from 22% (eGFR-Zappitelli1) to 44% (urinary creatinine clearance) of children. CONCLUSIONS Use of a combined serum cystatin C/creatinine-based equation (eGFR-CKiD2) is recommended to monitor renal function in children with a solitary functioning kidney. When cystatin C is not routinely available, eGFR-Schwartz should be used. Misclassification in K/DOQI-stage remains a caveat for all equations.

Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study

Chronic kidney disease (CKD) affects an estimated 14% of Americans (1, 2). These persons have 10- to 15-fold higher morbidity and mortality rates than the general population (1, 3). In most patients with CKD, the diagnosis is based on standard office work-up and sometimes kidney biopsy findings. However, early-stage CKD is often clinically silent, and subtypes can be difficult to distinguish on the basis of clinical data alone. Thus, in many persons, the precise cause of kidney failure remains unknown. Approximately 10% to 25% of patients with CKD note a family history of nephropathy (46), suggesting that in many cases the disease has a hereditary component. Recent advances in genomic technologies, such as chromosomal microarray and massively parallel (next-generation) sequencing, enable genome-wide analysis at a modest cost and precise definition of the molecular cause of many complex diseases (713). Application of these methods has suggested opportunities for individualized diagnosis and risk stratification, including targeted work-up and surveillance for associated disease complications (1113) and sometimes precision therapy (1215). However, studies to date have focused mainly on a limited range of disorders in pediatric cohorts or on cancer in adults (717); thus, the clinical utility of these approaches for a broader spectrum of diseases, particularly among adults, remains unclear. Applying chromosomal microarray analysis, we recently showed that 7.4% of 419 children with various forms of CKD had a major known pathogenic genomic imbalance that was not suspected after clinical assessment (18). These disorders were evenly distributed among patients clinically diagnosed with congenital and noncongenital forms of CKD, indicating that genetic analysis has utility across broad clinical categories. In most of these cases, the genetic findings either reclassified the disease or provided information that could guide subsequent clinical care, such as evaluation for metabolic or neuropsychiatric disease. Similarly, next-generation sequencing has been shown to have great utility for diagnosing genetic forms of nephrotic syndrome or congenital kidney defects in pediatric populations, albeit mainly in the context of targeted panels (1921). Whole-exome sequencing (WES) is a genome-wide testing approach that allows selective sequencing of the protein-coding regions of the genome, which are enriched for disease-associated variants (1215). Because of its genome-wide coverage, WES enables screening of most genes associated with kidney disease and can therefore be applied across diverse categories of renal disorders. Moreover, it can potentially identify novel etiologic genes for nephropathy or detect actionable incidental mutations unrelated to the primary indications for testing. For these reasons, WES is emerging as a preferred diagnostic tool for hereditary disorders (1215, 22, 23). In pediatric cohorts, WES recently identified diagnostic mutations in up to 11.5% of patients with congenital kidney anomalies and 26% of patients with steroid-resistant nephrotic syndrome, supporting its diagnostic utility for early-onset CKD (24, 25). However, the value of this sequencing method for the diagnosis and management of CKD in adults has not been adequately studied. We did a pilot study to test the utility of WES in adults referred for evaluation of CKD or hypertension. Methods Study Design The results of WES in a convenience sample of patients referred for evaluation of CKD were reviewed for their potential to inform clinical practice. To facilitate diagnostic interpretation of WES data, we compiled a list of genes encompassing most common Mendelian forms of kidney and hypertensive disorders. We next annotated the exomes for diagnostic variants in nephropathy genes and then analyzed other genes, including those recommended by the American College of Medical Genetics (ACMG), for return of medically actionable incidental findings (26). Patient Population and Setting The study sample was selected from a group of 344 patients seen at outpatient nephrology clinics between October 2013 and May 2014 at Columbia University Medical Center, a tertiary care medical center with a nephrology division offering highly specialized care for glomerular disorders. These 344 patients were referred for evaluation and management of kidney disease and consented to a general genetic research and biobanking protocol. Supplement Table 1 presents the characteristics of these 344 patients. From this group, we selected 81 adult patients (aged >18 years) (Supplement Table 2) for WES who fulfilled 1 of the following inclusion criteria: a family history of kidney disease (defined as any family member with urinary abnormalities or impaired kidney function, as reported by the patient), undiagnosed kidney disease, or clinical suspicion of a genetic kidney disease (for example, in a proband with young age of onset and no family history of nephropathy). The PKD1 gene is not well-captured by WES because of gene duplication (27), so patients fulfilling clinical diagnostic criteria for autosomal dominant polycystic kidney disease were not included in the WES study. Supplement. Supplementary Tables In addition to these 81 patients from Columbia University Medical Center, we also included 11 patients referred for suspected inherited kidney disease or hypertension from outside institutions. Three patients with familial tubulointerstitial nephropathy and 1 with early-onset hypertension were referred from 3 local practices in the United States (New York University and nephrology practices in suburban New York and Delaware). Four were referred for evaluation of Mendelian hypertension from the Polish Kidney Genetics Network (POLYGENES, www.polygenes.org), centered in the Department of Genetics at Pozna University of Medical Sciences and The Center of Medical Genetics GENESIS (Pozna, Poland). Three other patients were referred from Gaslini Institute (Genova, Italy) for evaluation of glomerulonephritis with nondiagnostic kidney biopsies. All participants gave informed consent, and the study was approved by the Columbia University Institutional Review Board and local ethics committees. WES and Sequence Interpretation Staff extracted DNA from whole blood. Telomere length was measured using genomic DNA from whole blood, as previously described (28, 29). For WES, fragment libraries using 200 ng of genomic DNA were constructed from each sample, following the Agilent standard library preparation protocol for TruSeq (Illumina). Exome capture was done with the SureSelectXT Human All Exon V4 (51 Mb) kit (Agilent), and sequencing was done using the HiSeq 2000 or 2500 (Illumina) at the Columbia Genome Center. On average, 92.83 million independent paired-end reads (18.56-Gb bases) were generated per sample to provide an average coverage of 110-fold, with 99.17% of target regions being covered at least 10-fold. The paired-end reads (read size, 101 bp) were mapped to the human reference genome National Center for Biotechnology Information build 37 using BurrowsWheeler Aligner, version 0.5.9. The Genome Analysis Toolkit, version 1.6-13, was used to call germline single nucleotide variants and insertions or deletions (indels). Variants were annotated for predicted effect on protein function (using ANNOVAR and SnpEff); allele frequency in public databases (ExAC, dbSNP, and the 1000 Genomes Project); and predicted pathogenicity with in silico algorithms, including PolyPhen and Combined Annotation Dependent Depletion scores (3036). Evidence for disease causality was assessed using ClinVar and the Human Genome Mutation Database (Qiagen), followed by manual review of the cited primary literature (33, 36). In addition, we developed a curated priority list of 287 Online Mendelian Inheritance in Man (OMIM; http://omim.org) genes implicated in Mendelian forms of kidney disorders and hypertension to facilitate clinical annotation (hereon, we refer to this gene list as nephropathy genes; see Supplement Table 3. A known limitation of exome sequencing is that some segments of the genome are not amenable to capture (23). Among the 287 nephropathy genes, 29 were identified with at least 1 exon that is not captured by the Agilent kit, representing potential blind spots in the analysis (Supplement Table 3). Variant interpretation was done by a panel of nephrologists or molecular geneticists with domain expertise in inherited kidney diseases (K.K., S.S.C., C.A., L.R., E.G., and A.G.G.), bioinformaticians (S.L. and D.A.F.), and a clinical molecular geneticist (V.J.), using the ACMG guidelines for clinical sequence interpretation (37). Detailed classification criteria for pathogenic and likely pathogenic variants are in Supplement Table 4. We also reviewed potentially pathogenic mutations in OMIM genes associated with other heritable disorders and in the ACMGs 59 actionable genes (26). All diagnostic variants were confirmed by Sanger sequencing. Finally, we verified the distribution of potentially functional variants in nephropathy genes in each exome. These potentially functional variants were defined as missense, nonsense, splice site, or indel variants with a minor allele frequency less than 1% in ExAC (a database of genetic variation in >60000 persons) and a Combined Annotation Dependent Depletion score greater than 10 (indicating a variant score in the top 10% of deleteriousness in a large reference data set of variants). We also verified allele frequencies using an anonymized in-house control data set derived from 9012 persons who had undergone WES for indications other than nephropathy; these control data included healthy parents of children with a developmental disorder and participants from genetic studies of amyotrophic lateral sclerosis or seizure disorders. Role of the Funding Source The study was funded by the New York State Empire Clinical Research Investigator Program, the Renal Research Institut

Gender differences in solitary functioning kidney: do they affect renal outcome?

Dear Sir,Kummer et al. recently reviewed the influence of gender andsex hormones on the incidence and outcome of chronickidney disease (CKD) [1]. The authors described themarked differences between males and females in the prev-alence and timing of CKD. Renal failure in infancy andchildhood is more frequently identified in boys due to thehigher prevalence of congenital anomalies of the kidney andurinarytract(CAKUT),whereasfemalesshowarapidincreaseinCKDatthebeginningofthemenopausewhensexhormonelevels are declining. Since genetic factors and not hormonalinfluences are presumed to play a major role in CAKUT, theauthors chose not to review the gender differences in CAKUTpatients.We have recently published results from our KIMONOstudy onthe development of renal injury in over 400 childrenwith different types of solitary functioning kidney (i.e., afrequent CAKUT-phenotype) [2]. In line with Kummer et al.[1], our KIMONO cohort consisted mainly of boys (65 vs.35 % girls). Overall, no differences were noted in the preva-lence of renal injury, defined as hypertension, proteinuria,antihypertensive/antiproteinuric medication, or impaired glo-merular filtration rate (GFR), between both groups (boys 39vs. girls 35 %; p=0.43). Sub-analysis of renal injury in post-pubertal patients only (defined as ≥15 years of age) identifiedsimilarproportions(boys65vs.girls56%;p=0.43).Multipleregression analysis could not identify female gender as aprotectivefactorinthedevelopmentofrenalinjury(oddsratio0.73, 95 % confidence interval (CI) 0.44–1.22; p=0.23).Furthermore, Kaplan-Meier analysis showed no differencesin the median age at presenting renal injury between boys(14.7years,95%CI13.4–15.9)andgirls(15.4years,95%CI12.3–18.6; p=0.49). In contrast, 80 % of the children with animpaired GFR (i.e., <60 ml/min/1.73 m

Bartter syndrome type III and congenital anomalies of the kidney and urinary tract: an antenatal presentation.

Bartter syndrome encompasses a variety of inheritable renal tubular transport disorders characterized by hypokalemia and hypochloremic metabolic alkalosis. Bartter syndrome Type III is caused by genetic alterations in the chloride channel kidney B (CLCNKB) gene and often presents in the first 2 years of life, known as classic Bartter syndrome. However, in rare cases Bartter syndrome Type III has an antenatal presentation with polyhydramnios, premature delivery and severe dehydration in the first weeks of life. Associations between congenital anomalies of the kidney and urinary tract and Bartter syndrome are extremely rare. This case report presents a girl with Bartter syndrome Type III due to a homozygous CLCNKB mutation and bilateral congenital anomalies of the kidney and urinary tract. In addition, we describe the antenatal presentation as well as its perinatal management.

155 Glomerular Hyperfiltration Injury in Children with a Solitary Functioning Kidney: A Prediction Model - the Kimono-Study

155 Glomerular Hyperfiltration Injury in Children with a Solitary Functioning Kidney: A Prediction Model - the Kimono-Study