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Background: Tolvaptan preserves kidney function in adults with autosomal dominant polycystic kidney disease (ADPKD) at elevated risk of rapid progression. A trial (NCT02964273) evaluated tolvaptan safety and pharmacodynamics in children (5–17 years). However, progression risk was not part of study eligibility criteria due to lack of validated criteria for risk assessment in children. As risk estimation is important to guide clinical management, baseline characteristics of the study participants were retrospectively evaluated to determine whether risk of rapid disease progression in pediatric ADPKD can be assessed and to identify parameters relevant for risk estimation. Methods: Four academic pediatric nephrologists reviewed baseline data and rated participant risk from 1 (lowest) to 5 (highest) based on clinical judgement and the literature. Three primary reviewers independently scored all cases, with each case reviewed by two primary reviewers. For cases with discordant ratings (≥ 2-point difference), the fourth reviewer provided a secondary rating blinded to the primary evaluations. Study participants with discordant ratings and/or for whom data were lacking were later discussed to clarify parameters relevant to risk estimation. Results: Of 90 evaluable subjects, primary reviews of 69 (77%) were concordant. The proportion considered at risk of rapid progression (final mean rating ≥ 3.5) by age group was: 15–17 years, 27/34 (79%); 12– < 15, 9/32 (28%); 4– < 12, 8/24 (33%). The panelists agreed on characteristics important for risk determination: age, kidney imaging, kidney function, blood pressure, urine protein, and genetics. Conclusions: High ratings concordance and agreement among reviewers on relevant clinical characteristics support the feasibility of pediatric risk assessment. A higher resolution version of the Graphical abstract is available as Supplementary information [ABSTRACT FROM AUTHOR]

Background Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) occurs in 1:20,000 live births. Disease expression is widely variable, with approximately 30% of affected neonates dying perinatally, while others survive to adulthood. Mutations at the PKHD1 locus are responsible for all typical presentations. The objectives of this study were to define the clinical and genetic characteristics in a cohort of South African patients of Afrikaner origin, a population with a high prevalence of ARPKD. Methods DNA from the cohort was analyzed for background haplotypes and the p.M627K mutation previously identified in two unrelated Afrikaner patients. The clinical phenotype of the homozygous group was characterized. Results Analysis of 36 Afrikaner families revealed that 27 patients, from 24 (67%) families, were homozygous for the p.M627K substitution, occurring on a common haplotype. The clinical phenotype of the homozygous individuals was variable. Conclusions Our data provide strong evidence that the p.M627K substitution is a founder mutation in the Afrikaner population and can be used for streamlined diagnostic testing for at-risk pregnancies. The observed clinical variability suggests that disease expression is modulated by other genetic loci or by gene-environment interactions. Keywords Autosomal recessive polycystic kidney disease * ARPKD * PKHD1 * Afrikaner population * Founder mutation, Introduction Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) is an important childhood nephropathy [1]. The clinical phenotype is dominated by dilatation of the renal collecting ducts, biliary dysgenesis, and [...]

Background Dent disease is an X-linked recessive renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure (MIM 300009). A recent case series identified four patients with CLCN5 mutations who presented with nephrotic-range proteinuria, histologic evidence of focal segmental and/or global sclerosis, and low molecular weight proteinuria. Case-Diagnosis/Treatment We characterize the clinical, genetic, and histopathological features of seven unrelated adolescent males with nephrotic-range proteinuria and CLCN5 mutations. Six patients underwent renal biopsy prior to assessing tubular proteinuria. All biopsied patients had either segmental sclerosis (3/6) or segmental increase in mesangial matrix (3/6). Five patients revealed some degree of foot process effacement, but only one patient biopsy revealed >50 % foot process effacement. The attenuated foot process effacement suggests the glomerulosclerosis is not due to a primary podocytopathy. Conclusions These data suggest that clinicians should consider a diagnostic evaluation for Dent disease in young males presenting with high-grade proteinuria. Keywords Dent disease * Nephrotic-range proteinuria * Glomerulosclerosis, Introduction Dent disease (MIM 300009) is an X-linked renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis or nephrolithiasis, and progressive renal failure. Individuals with Dent disease classically [...]

Background Autosomal recessive polycystic kidney disease (ARPKD) is an inherited disorder characterized by enlarged, cystic kidneys with progressive chronic kidney disease (CKD), systemic hypertension, and congenital hepatic fibrosis. Children with ARPKD can have early onset CKD and severe hypertension, both of which are known to have adverse neurocognitive effects. The objectives of this study were (1) to determine whether ARPKD patients have greater neurocognitive deficits compared to that of children with other causes of CKD, and (2) to examine the relative prevalence of hypertension in ARPKD, a known risk factor for neurocognitive dysfunction. Methods We performed a cross-sectional, control-matched analysis of 22 ARPKD patients with mild-to-moderate CKD in the Chronic Kidney Disease in Children (CKiD) cohort study, compared with a control group of 44 children with other causes of CKD, matched based on glomerular filtration rate, age at study entry, and age at diagnosis. Results Children with ARPKD in this cohort had neurocognitive functioning comparable to children with other causes of CKD in domains of intellectual functioning, academic achievement, attention regulation, executive functioning, and behavior. Blood pressure parameters were similar between the two groups; however, ARPKD patients required a significantly greater number of antihypertensive medications to achieve similar BP levels. Conclusions ARPKD patients are potentially at risk for neurocognitive dysfunction due to early onset CKD and more severe hypertension. However, this study of children with mild-to-moderate CKD in the CKiD cohort did not demonstrate increased risk in children with ARPKD compared to children with other causes of CKD. Further studies are needed to determine if these findings are applicable to children with more severe manifestations of ARPKD. Keywords Autosomal recessive polycystic kidney disease * Behavior * Chronic kidney disease * Hypertension * Neurocognition * Neuropsychological, Introduction Autosomal recessive polycystic kidney disease (ARPKD, OMIM 263200) is an important genetic cause of progressive chronic kidney disease (CKD), and occurs in an estimated 1 in 20,000 live births [...]

Abstract Inherited renal cystic diseases constitute an important set of single-gene disorders that frequently progress to end stage renal disease (ESRD). Transmitted as autosomal dominant, autosomal recessive, or X-linked traits, [...]

Byline: Lisa M. Guay-Woodford (1), Carlos A. Galliani (3), Elizabeth Musulman-Mroczek (3), Gerald S. Spear (4), Ann P. Guillot (5), Jay Bernstein (6) Keywords: Key words: Renal cystic disease; Autosomal recessive polycystic kidney disease; Autosomal dominant polycystic kidney disease; Glomerulocystic kidney disease; Meckel syndrome; Molecular analysis Abstract: During a 5-year period, we evaluated seven infants and two fetuses who presented with enlarged, hyperechoic kidneys. In each, the initial clinical diagnosis was autosomal recessive polycystic kidney disease (ARPKD). Among the seven unrelated infants were three Caucasian and four African-American infants. No syndromic stigmata were evident in any of these infants. At the time of the initial evaluation, the family data were incomplete for four infants. The two fetuses were presumed to be at-risk for ARPKD based on the diagnosis in previous siblings. Renal histopathology was evaluated in all nine cases and revealed a spectrum of cystic disease ranging from ARPKD to glomerulocystic kidney disease to autosomal dominant polycystic kidney disease to diffuse cystic dysplasia. In the eight cases for whom liver histopathology was available, varying degrees of biliary dysgenesis were evident. We present a detailed analysis of the key histopathological features in each case and discuss the histopathological findings in an embryological context. In addition, we address the current role of molecular genetics in the diagnostic evaluation. Author Affiliation: (1) Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA, US (2) Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA, US (3) Department of Pediatric Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA, US (4) Department of Pathology, University of California Irvine, Medical Center, Orange, California, USA, US (5) Department of Pediatrics, University of Vermont, Burlington, Vermont, USA, US (6) William Beaumont Hospital Research Institute, Royal Oak, Michigan, USA, US Article note: Received May 14, 1997 received and accepted in revised form September 22, 1997