Clinical and genetic characteristics of Dent's disease type 1 in Europe
Authors: Burballa Carla , Cantero-Recasens Gerard , Prikhodina Larisa , Lugani Francesca , Schlingmann Karlpeter , Ananin Petr V , Besouw Martine , Bockenhauer Detlef , Madariaga Leire , Bertholet-Thomas Aurelia , Taroni Francesca , Parolin Mattia , Conlon Peter , Emma Francesco , Del Prete Dorella , Chauveau Dominique , Koster-Kamphuis Linda , Fila Marc , Pasini Andrea , Castro Isabel , Colussi Giacomo , Gil Marta , Mohidin Barian , Wlodkowski Tanja , Schaefer Franz , Ariceta Gema ,   for the DENT study group, Enfant Hopital Femme Mère , Bacchetta Justine , Paglialonga Fabio , Murer Luisa , Andersone Ilze , Sayer John A , Boyer Olivia , Levart Tanja Kersnik , Rus Rina , Paripović Dušan , Gonzalez Esther Rubio , Nieto Francisco , Zieg Jakub , Caballero José Ángel , Vara Julia , Keijzer-Veen Mandy , Ferraro Pietro Manuel , Gonzalez Ramon , Rotaeche Ramon Maria Saracho , Fenoglio Roberta , Ballesteros Sandra Sanz , Lobo Serafin Tallon , Ghuysen Marie Sophie , Ordóñez Álvarez Flor A , Vandyck Maria , Rosenberg Mai , Thorsteinsdottir Hjørdis , Tasic Velibor , Bayram Meral Torun , Mir Sevgi , Costea George Claudiu , Yildiz Nurdan , Lumbreras Javier , Yel Sibel , Cerkauskiene Rimante , La Manna Angela , Elhassan Elhussein , Ciurli Francesca , Meseguer Anna , Duran Monica 
Published: November 2022

ABSTRACT

Background
Dent's disease type 1 (DD1) is a rare X-linked nephropathy caused by CLCN5 mutations, characterized by proximal tubule dysfunction, including low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis–nephrocalcinosis, progressive chronic kidney disease (CKD) and kidney failure (KF). Current management is symptomatic and does not prevent disease progression. Here we describe the contemporary DD1 picture across Europe to highlight its unmet needs.

Methods
A physician-based anonymous international e-survey supported by several European nephrology networks/societies was conducted. Questions focused on DD1 clinical features, diagnostic procedure and mutation spectra.

Results
A total of 207 DD1 male patients were reported; clinical data were available for 163 with confirmed CLCN5 mutations. Proteinuria was the most common manifestation (49.1%). During follow-up, all patients showed LMWP, 66.4% nephrocalcinosis, 44.4% hypercalciuria and 26.4% nephrolithiasis. After 5.5 years, ≈50% of patients presented with renal dysfunction, 20.7% developed CKD stage ≥3 and 11.1% developed KF. At the last visit, hypercalciuria was more frequent in paediatric patients than in adults (73.4% versus 19.0%). Conversely, nephrolithiasis, nephrocalcinosis and renal dysfunction were more prominent in adults. Furthermore, CKD progressed with age. Despite no clear phenotype/genotype correlation, decreased glomerular filtration rate was more frequent in subjects with CLCN5 mutations affecting the pore or CBS domains compared with those with early-stop mutations.

Conclusions
Results from this large DD1 cohort confirm previous findings and provide new insights regarding age and genotype impact on CKD progression. Our data strongly support that DD1 should be considered in male patients with CKD, nephrocalcinosis/hypercalciuria and non-nephrotic proteinuria and provide additional support for new research opportunities.