Dent disease (DD) is a rare X-linked tubulopathy characterized by a proximal tubular dysfunction leading to nephrocalcinosis/nephrolithiasis and progressive renal failure. The disease is associated with a mutation either in CLCN5 or OCRL genes. We aim to define clinical and genetic disease characteristics and summarize treatments of Polish patients with DD. The study cohort consists of 10 boys (aged 5 - 16.5 years) whose data were collected through POLtube Registry. All of the patients had tubular proteinuria, hypercalciuria, and nephrocalcinosis/nephrolithiasis. Renal impairment and growth deficiency were found in 3 patients and rickets in 2 patients. In total, 9 of 10 patients carried a mutation in the CLCN5 gene. Five of 9 detected mutations were novel. In 1 patient with a clinical phenotype of DD, no mutations in either CLCN5 or OCRL were discovered. Therapy consisted of thiazides in 7 patients, and phosphate supplements and enalapril in 3 cases. Growth hormone therapy was initiated in 3 patients and resulted in improved growth rate. We report clinical and molecular characterization of Polish children with DD. Our study suggests that this tubulopathy may be generally under-diagnosed in Poland. The study revealed variable treatments, demonstrating a need for therapeutic guidelines.

Background: Hyperuricemia is recognized as an important feature of nephropathy, associated with a mutation in the hepatocyte nuclear factor-1B (HNF1B) gene, and could serve as a useful marker of the disease. However, neither a causal relationship nor its predictive value have been proven. The purpose of this study was to assess this in children with renal malformations, both with (mut+) and without HNF1B mutations (mut-). Methods: We performed a retrospective analysis of clinical characteristics of pediatric patients tested for HNF1B mutations, collected in a national registry. Results: 108 children were included in the study, comprising 43 mut+ patients and 65 mut- subjects. Mean sUA was higher and hyperuricemia more prevalent (42.5% vs. 15.4%) in HNF1B carriers. The two groups were similar with respect to respect to age, sex, anthropometric parameters, hypertension, and renal function. Renal function, fractional excretion of uric acid and parathyroid hormone level were independent predictors of sUA. The potential of hyperuricemia to predict mutation was low, and addition of hyperuricemia to a multivariate logistic regression model did not increase its accuracy. Conclusions: Hyperuricemia is an early and common feature of HNF1B nephropathy. A strong association of sUA with renal function and parathyroid hormone limits its utility as a reliable marker to predict HNF1B mutation among patients with kidney anomalies.

Background: We aimed to develop a tool for predicting HNF1B mutations in children with congenital abnormalities of the kidneys and urinary tract (CAKUT). Methods: The clinical and laboratory data from 234 children and young adults with known HNF1B mutation status were collected and analyzed retrospectively. All subjects were randomly divided into a training (70%) and a validation set (30%). A random forest model was constructed to predict HNF1B mutations. The recursive feature elimination algorithm was used for feature selection for the model, and receiver operating characteristic curve statistics was used to verify its predictive effect. Results: A total of 213 patients were analyzed, including HNF1B-positive (mut + , n = 109) and HNF1B-negative (mut − , n = 104) subjects. The majority of patients had mild chronic kidney disease. Kidney phenotype was similar between groups, but bilateral kidney anomalies were more frequent in the mut + group. Hypomagnesemia and hypermagnesuria were the most common abnormalities in mut + patients and were highly selective of HNF1B. Hypomagnesemia based on age-appropriate norms had a better discriminatory value than the age-independent cutoff of 0.7 mmol/l. Pancreatic anomalies were almost exclusively found in mut + patients. No subjects had hypokalemia; the mean serum potassium level was lower in the HNF1B cohort. The abovementioned, discriminative parameters were selected for the model, which showed a good performance (area under the curve: 0.85; sensitivity of 93.67%, specificity of 73.57%). A corresponding calculator was developed for use and validation. Conclusions: This study developed a simple tool for predicting HNF1B mutations in children and young adults with CAKUT. Graphical

Background The diagnosis of HNF1B disease is a challenge. We aimed to developa tool for predicting HNF1B mutations in children with congenital abnormalities of the kidneys and urinary tract (CAKUT). Methods The clinical and laboratory data from 234 children and young adults with known HNF1B mutation status were collected and analyzed retrospectively. All subjects were randomly divided into a training (70%) and a validation set (30%). A random forest model was constructed to predict HNF1B mutations. The recursive feature elimination algorithm was used for feature selection into the model, and receiver operating characteristiccurve statistics were used to verify its predictive effect. Results 213 patients were analyzed, including HNF1B‑positive (mut+, n=109) and HNF1B‑negative (mut−, n=104) subjects. The majority of patients had mild chronic kidney disease. Kidney phenotype was similar between groups, but bilateral kidney anomalies were more frequent in the mut+ group. Hypomagnesemia and hypermagnesuria were the most common abnormalities in mut+ patients, and were highly selective of HNF1B. Hypomagnesemia based on age‑appropriate norms had a better discriminatory value than the age‑independent cutoff of 0.7 mmol/l. Pancreatic anomalies were almost exclusively found in mut+ patients. No subjects had hypokalemia; the mean serum potassium level was lower in the HNF1Bcohort. The above‑mentioned, discriminative parameters were selected for the model, which showed a good performance (area under the curve: 0.85; sensitivity of 93.67%, specificity of 73.57%). A corresponding calculator was developed for use and validation. ConclusionThis study developed a simple tool for predicting HNF1B mutations in children with CAKUT.

Background This study aimed to investigate the genetic landscape and to identify predictors of a molecular diagnosis in pediatric nephrocalcinosis. Methods This prospective, nationwide cohort study enrolled 79 unrelated pediatric patients with ultrasound-based medullary nephrocalcinosis of unknown etiology. Genetic evaluation was conducted using whole-exome sequencing ( n = 75) or targeted (Sanger) sequencing ( n = 4). Only (likely)pathogenic variants were considered diagnostic. Results A molecular diagnosis of Mendelian disease (MD) was established in 16% of patients, which included infantile hypercalcemia type 1 ( CYP24A1 , n = 3) and type 2 ( SLC34A1 , n = 2), familial hypomagnesemia, hypercalciuria and nephrocalcinosis ( CLDN16 , n = 2; CLDN19 , n = 1), distal renal tubular acidosis ( ATP6V0A4 , n = 1; ATP6V1B1 , n = 1), Bartter syndrome type 2 ( KCNJ1 , n = 1) and type 3 ( CLCNKB , n = 1), and Dent disease type 1 ( CLCN5 , n = 1). Monoallelic (MA) variants, possibly predisposing to nephrocalcinosis, were found in 16% of patients, encompassing four genes, predominantly within the SLC34A1 and SLC34A3 (61%). In patients with MD, except for two patients with Bartter syndrome, typical phenotypes were observed, in contrast to carriers of MA variants, in whom the majority had subtle abnormalities. Clinical parameters, prematurity and family history for nephrocalcinosis/lithiasis were not associated with MD diagnoses. Conclusions This study clarifies the distinct genetic architecture of pediatric nephrocalcinosis. The data may possibly explain the etiology in approximately 30% of cases, when considering both MD and MA variants. Disease-specific phenotypes are associated with MD; however, the absence of typical features should not preclude a genetic diagnosis.