title: Nephrolithiasis, kidney failure and bone disorders in Dent disease patients with and without CLCN5 mutations.
abstract: Dent disease (DD) is a rare X-linked recessive renal tubulopathy characterised by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis and/or nephrolithiasis. DD is caused by mutations in both the CLCN5 and OCRL genes. CLCN5 encodes the electrogenic chloride/proton exchanger ClC-5 which is involved in the tubular reabsorption of albumin and LMW proteins, OCRL encodes the inositol polyphosphate 5-phosphatase, and was initially associated with Lowe syndrome. In approximately 25 % of patients, no CLCN5 and OCRL mutations were detected. The aim of our study was to evaluate whether calcium phosphate metabolism disorders and their clinical complications are differently distributed among DD patients with and without CLCN5 mutations. Sixty-four male subjects were studied and classified into three groups: Group I (with CLCN5 mutations), Group II (without CLCN5 mutations) and Group III (family members with the same CLCN5 mutation). LMWP, hypercalciuria and phosphaturic tubulopathy and the consequent clinical complications nephrocalcinosis, nephrolithiasis, bone disorders, and chronic kidney disease (CKD) were considered present or absent in each patient. We found that the distribution of nephrolithiasis, bone disorders and CKD differs among patients with and without CLCN5 mutations. Only in patients harbouring CLCN5 mutations was age-independent nephrolithiasis associated with hypercalciuria, suggesting that nephrolithiasis is linked to altered proximal tubular function caused by a loss of ClC-5 function, in agreement with ClC-5 KO animal models. Similarly, only in patients harbouring CLCN5 mutations was age-independent kidney failure associated with nephrocalcinosis, suggesting that kidney failure is the consequence of a ClC-5 dysfunction, as in ClC-5 KO animal models. Bone disorders are a relevant feature of DD phenotype, as patients were mainly young males and this complication occurred independently of age. The triad of symptoms, LMWP, hypercalciuria, and nephrocalcinosis, was present in almost all patients with CLCN5 mutations but not in those without CLCN5 mutations. This lack of homogeneity of clinical manifestations suggests that the difference in phenotypes between the two groups might reflect different pathophysiological mechanisms, probably depending on the diverse genes involved. Overall, our results might suggest that in patients without CLCN5 mutations several genes instead of the prospected third DD underpin patients' phenotypes.
authors.affiliation: Division of Nephrology, Department of Medicine DIMED, Laboratory of Histomorphology and Molecular Biology of the Kidney, University of Padua, Via Giustiniani n° 2, 35128 Padua, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Anglani
authors.affiliation: Division of Nephrology, Department of Medicine DIMED, Laboratory of Histomorphology and Molecular Biology of the Kidney, University of Padua, Via Giustiniani n° 2, 35128 Padua, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: D'Angelo
authors.affiliation: Division of Nephrology, Department of Medicine DIMED, Laboratory of Histomorphology and Molecular Biology of the Kidney, University of Padua, Via Giustiniani n° 2, 35128 Padua, Italy.
authors.forename: Luisa Maria
authors.initials: LM
authors.lastname: Bertizzolo
authors.affiliation: Division of Nephrology, Department of Medicine DIMED, Laboratory of Histomorphology and Molecular Biology of the Kidney, University of Padua, Via Giustiniani n° 2, 35128 Padua, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Tosetto
authors.affiliation: Division of Nephrology, Department of Medicine DIMED, Laboratory of Histomorphology and Molecular Biology of the Kidney, University of Padua, Via Giustiniani n° 2, 35128 Padua, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Ceol
authors.affiliation: Division of Nephrology, Department of Medicine DIMED, Laboratory of Histomorphology and Molecular Biology of the Kidney, University of Padua, Via Giustiniani n° 2, 35128 Padua, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cremasco
authors.affiliation: Division of Nephrology, Department of Medicine DIMED, Laboratory of Histomorphology and Molecular Biology of the Kidney, University of Padua, Via Giustiniani n° 2, 35128 Padua, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Bonfante
authors.affiliation: Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Addis
authors.affiliation: Division of Nephrology, Department of Medicine DIMED, Laboratory of Histomorphology and Molecular Biology of the Kidney, University of Padua, Via Giustiniani n° 2, 35128 Padua, Italy.
authors.forename: Dorella
authors.initials: D
authors.lastname: Del Prete
keywords: CLCN5 gene; Calcium phosphate metabolism; Chronic kidney disease; Dent disease; Nephrolithiasis; OCRL gene