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Item does not contain fulltext, Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.

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Contains fulltext : 232177.pdf (Publisher’s version ) (Open Access), Context A congenital solitary functioning kidney (cSFK) is a common developmental defect that predisposes to hypertension and chronic kidney disease (CKD) as a consequence of hyperfiltration. Every urologist takes care of patients with a cSFK, since some will need lifelong urological care or will come with clinical problems or questions to an adult urologist later in life. Objective We aim to provide clear recommendations for the initial clinical management and follow-up of children with a cSFK. Evidence acquisition PubMed and EMBASE were searched to identify relevant publications, which were combined with guidelines on related topics and expert opinion. Evidence synthesis Initially, cSFK diagnosis should be confirmed and risk factors for kidney injury should be identified using ultrasound. Although more research into early predictors of kidney injury is needed, additional congenital anomalies of the kidney or urinary tract and absence of compensatory kidney hypertrophy have repeatedly been associated with a worse prognosis. The role of voiding cystourethrography and antibiotic prophylaxis remains controversial, and is complicated by the exclusion of children with a cSFK from studies. A yearly follow-up for signs of kidney injury is recommended for children with a cSFK. As masked hypertension is prevalent, annual ambulatory blood pressure measurement should be considered. During puberty, an increasing incidence of kidney injury is seen, indicating that long-term follow-up is necessary. If signs of kidney injury are present, angiotensin converting enzyme inhibitors are the first-line drugs of choice. Conclusions This overview points to the urological and medical clinical aspects and long-term care guidance for children with a cSFK, who are at risk of hypertension and CKD. Monitoring for signs of kidney injury is therefore recommended throughout life. Large, prospective studies with long-term follow-up of clearly defined cohorts are still needed to facilitate more ris

Contains fulltext : 170897.pdf (Publisher’s version ) (Open Access), BACKGROUND: Children with unilateral Wilms tumor (WT) treated with chemotherapy and/or radiotherapy and nephrectomy have excellent survival rates. A solitary functioning kidney (SFK) is associated with progressive renal injury. This study aims to investigate the additional effect of Wilms tumor treatment on renal function compared with children with an SFK for non-oncological reasons. METHODS: A single-center retrospective cohort study on the renal injury markers of 79 survivors of unilateral WT was performed and compared with a matched group of children with an SFK for non-oncological reasons. Mean age at follow-up was 12.4 (SD 5.9) years. RESULTS: During follow-up, mean estimated glomerular filtration rate (eGFR) and blood pressure z-scores remained stable at an acceptable level. However, in the group of 31 WT patients with a follow-up of 15 years, 23 % showed signs of renal injury. This proportion was smaller than the 54 % in a group of SFK patients based on non-oncological causes (p = 0.004). CONCLUSIONS: A significant proportion of WT survivors develop renal injury during follow-up. Our data may be an underestimation of the true frequency of progressive renal injury, due to a lack of information on proteinuria. As with patients with a non-oncological SFK, long-term follow-up is essential to monitor WT survivors.

Item does not contain fulltext, Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO study cohort for which pathogenic mutations in three genes commonly implicated in CAKUT were excluded. In total, 13 known or novel genomic imbalances in 11 of 80 patients were absent or extremely rare in 23,362 population controls. To identify the most likely genetic drivers for the CAKUT phenotype underlying these rare copy number variations, we used a systematic in silico approach based on frequency in a large data set of controls, annotation with publicly available databases for developmental diseases, tolerance and haploinsufficiency scores, and gene expression profile in the developing kidney and urinary tract. Five novel candidate genes for CAKUT were identified that showed specific expression in the human and mouse developing urinary tract. Among these genes, DLG1 and KIF12 are likely novel susceptibility genes for CAKUT in humans. Thus, there is a significant role of genomic imbalance in the determination of kidney developmental phenotypes. Additionally, we defined a systematic strategy to identify genetic drivers underlying rare copy number variations.

Item does not contain fulltext, BACKGROUND: Children with a solitary functioning kidney are at increased risk of developing chronic kidney disease. Hypertension may be an early indicator of renal dysfunction in these patients. We determined blood pressure (BP) profiles of children with a solitary functioning kidney by using ambulatory BP monitoring (ABPM). METHODS: To assess the occurrence with (pre)hypertension, we compared ABPM to office BP measurement in 47 children with a solitary functioning kidney. None of the subjects used antihypertensive agents or had been hypertensive during previous clinical visits. RESULTS: Mean age of study subjects was 12.7 (+/-3.3) years. Hypertension was identified in ten (21 %) subjects with ABPM, whereas only two (4 %) children were hypertensive during office BP measurement (p < 0.01). Fifteen (32 %) children had an ABPM standard deviation (SD) value >/=90th percentile versus six (13 %) subjects based on office BP measurement (p = 0.051). Although 24-h ABPM SD scores were higher in the congenital type than in the acquired type of solitary functioning kidney (p

Item does not contain fulltext, Congenital anomalies of the kidney and urinary tract are the major cause of ESRD in childhood. Children with a solitary functioning kidney form an important subgroup of congenital anomalies of the kidney and urinary tract patients, and a significant fraction of these children is at risk for progression to CKD. However, challenges remain in distinguishing patients with a high risk for disease progression from those patients without a high risk of disease progression. Although it is hypothesized that glomerular hyperfiltration in the lowered number of nephrons underlies the impaired renal prognosis in the solitary functioning kidney, the high proportion of ipsilateral congenital anomalies of the kidney and urinary tract in these patients may further influence clinical outcome. Pathogenic genetic and environmental factors in renal development have increasingly been identified and may play a crucial role in establishing a correct diagnosis and prognosis for these patients. With fetal ultrasound now enabling prenatal identification of individuals with a solitary functioning kidney, an early evaluation of risk factors for renal injury would allow for differentiation between patients with and without an increased risk for CKD. This review describes the underlying causes and consequences of the solitary functioning kidney from childhood together with its clinical implications. Finally, guidelines for follow-up of solitary functioning kidney patients are recommended.

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1 mei 2013, Item does not contain fulltext, 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.

1 juli 2013, Item does not contain fulltext, 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 approximately 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.

01 februari 2013, Item does not contain fulltext, 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.

1 juni 2012, Item does not contain fulltext

Item does not contain fulltext, 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.

Item does not contain fulltext, BACKGROUND: Children with a solitary functioning kidney (SFK) have an increased risk of developing hypertension, albuminuria and chronic kidney disease in later life. This renal injury is hypothesized to be caused by glomerular hyperfiltration that follows renal mass reduction in animal studies. Furthermore, children with an SFK show a high incidence of congenital anomalies of the kidney and urinary tract (CAKUT), which could further compromise renal function. METHODS: A retrospective study of renal injury markers was performed in 206 children, divided into groups based on the origin of SFK [primary (congenital) SFK (n = 116) and secondary SFK (n = 90)]. Data on ipsilateral CAKUT were stratified separately. For blood pressure, albuminuria and glomerular filtration rate, longitudinal models were additionally developed using generalized estimated equation analysis. RESULTS: Renal injury, defined as the presence of hypertension and/or albuminuria and/or the use of renoprotective medication, was present in 32% of all children with an SFK at a mean age of 9.5 (SD 5.6) years. Children with ipsilateral CAKUT had higher proportions of renal injury (48.3 versus 24.6%, P < 0.05). Furthermore, longitudinal models showed a decrease in glomerular filtration rate in both groups from the beginning of puberty onwards. CONCLUSIONS: This large cohort study demonstrates that renal injury is present in children with an SFK at a young age, whereas our longitudinal models show an increased risk for chronic kidney disease in adulthood. Renal injury is even more pronounced in the presence of ipsilateral CAKUT. Therefore, we underline that clinical follow-up of all children with an SFK is needed.

Contains fulltext : 81011.pdf (publisher's version ) (Closed access), 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.

The report is a procedural guide for the application of a Technique for Establishing Personnel Performance Standards (TEPPS). It specified the types of input data required, provides instructions and examples on how to proceed through the various steps in TEPPS's application and includes guidelines for interpretation of results. The TEPPS computer program procedures also are discussed along with instructions for use.