Clinical and genetic characteristics of dent's disease type 1 in europe

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 spectrum.

Results Two-hundred seven DD1 male patients were reported, being clinical data available for 163 with confirmed CLCN5 mutations. Proteinuria was the most common leading 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 renal dysfunction, 20.7% developed CKD ≥ 3, and 11.1% KF. At last visit, hypercalciuria was more frequent in pediatric patients than in adults (73.4% vs. 19.0%). Conversely, nephrolithiasis, nephrocalcinosis and renal dysfunction were more prominent in adults. Furthermore, CKD progressed with age. Despite no clear phenotype/genotype correlation was observed, decreased glomerular filtration rate was more frequent in subjects with CLCN5 mutations affecting the pore or CBS domains compared to 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.