Dent Disease (DD) is a rare X-linked recessive proximal renal tubulopathy. Progression to chronic kidney disease (CKD) and renal failure may occur between the 3rd and 5th decades of life. The presentation of DD appears variable: a universal feature is low-molecular-weight proteinuria (LMWP), but other presenting features in children and adolescents include nephrocalcinosis and hypercalciuria, with or without nephrolithiasis. Hypophosphataemia and bone disorders (BDs) have also been observed. The disorder is caused by mutations mainly affecting the CLCN5 gene (Dent Disease 1, DD1). Defects in OCRL gene account for the 10-15% of the Dent disease patients (Dent disease 2, DD2). About 25% of Dent disease cases lack mutations in both of these genes. The aim of our study was to evaluate whether the main clinical/metabolic signs of DD and their clinical complications are differently distributed among DD patients with different genotypes.
Seventy-one unrelated patients with clinical suspicion of DD were classified according to their genotypes into three groups: 41 as having DD1, 13 as having DD2 and 17 without CLCN5 and OCRL mutations (DD3). Three clinical/metabolic signs (LMWP, hypercalciuria, phosphaturic tubulopathy) and four consequent clinical complications (nephrocalcinosis, nephrolithiasis, CKD, and BDs) were considered as present or absent in each patient.
Nephrocalcinosis was more frequent in DD1 than in DD2 (p=0.006) and DD3 (p=0.000) whereas hypercalciuria in DD1 than in DD3 (p=0.009). Phosphaturic tubulopathy was higher in DD3, CKD more frequent in DD2 than in DD1 (p=0.006). The associations between nephrocalcinosis and nephrolithiasis, hypercalciuria and nephrolithiasis, and nephrocalcinosis and CKD were significant only in Group I, thus suggesting a causal relationship as in CLCN5 KO mouse models.
Although we found a low number of significant differences, the distribution of the clinical signs among the three groups of patients reveals different renal phenotypes which reflect different pathophysiological mechanisms.
On behalf of the Dent Disease Italian Network: Gian Marco Ghiggeri and Giancarlo Barbano (Division of Nephrology, Dialysis and Kidney Transplantation, Pediatric Institute G. Gaslini, Genova), Francesco Emma and Gianluca Vergine (Division of Nephrology and Dialysis, Pediatric Hospital Bambin Gesù, Rome), Giuseppe Vezzoli (Division of Nephrology, Dialysis and Hypertension, IRCCS San Raffaele Hospital, Milan), Marilena Cara (Division of Nephrology, Camposampiero General Hospital, Camposampiero) Gabriele Ripanti (Division of Pediatrics and Neonatology, San Salvatore Hospital, Pesaro), Anita Ammenti (Pediatric Institute, University of Parma), Licia Peruzzi (Division of Nephrology, Dialysis and Transplantation, Regina Margherita Hospital,Turin), Giacomo Colussi (Unit of Nephrology, Varese Hospital, Varese), Mario Giordano (Nephrology and Pediatric Dialysis, Pediatric Hospital, Bari) Maria Rosa Caruso (Unit of Nephrology, Bergamo Hospital, Bergamo), Ilse Maria Ratsch (Pediatric Institute, University of Ancona), Giuseppina Marra and Fabio Paglialonga (Nephrology Unit, IRCCS foundation, Ca’ Granda Ospedale Maggiore Policlinico, University of Milano), Angela La Manna (Department of Pediatrics, 2° University of Napoli).
