Isolated hypercalciuria with mutation in CLCN5: Relevance to idiopathic hypercalciuria

Background. Idiopathic hypercalciuria (IH) is the most common risk factor f or kidney stones and often has a genetic component. Dent's disease (X-linke d nephrolithiasis) is associated with mutations in the CLCN5 chloride chann el gene, and low molecular weight (LMW) proteinuria was universally observe d in affected males. We sought to identify mutations in CLCN5 or abnormalit ies in LMW protein excretion in a large group of patients with IH and in a rat model of genetic hypercalciuria. Methods. One hundred and seven patients with IH (82 adults and 25 children) and one asymptomatic hypercalciuric man with a known inactivating mutation in CLCN5 were studied. Secondary causes of hypercalciuria were excluded in all. The excretion of retinol-binding protein and beta 2-microglobulin was measured by immunoassay in 101 patients with IH. Mutation analysis of the CLCN5 gene was performed in 32 patients with IH and in the genetic hypercal ciuric stone-forming (GHS) rat strain. Results. LMW protein excretion was normal in 92 patients with IH, and only slight abnormalities were found in the other nine, none of whom had a mutat ion in CLCN5. One 27-year-old man who had a CLCN5 mutation was found to hav e isolated hypercalciuria without LMW proteinuria, renal failure, or other evidence of renal disease. Mutation analysis was normal in 32 patients with IH. The CLCN5 sequence was normal in the GHS rat. Conclusions. Inactivation of CLCN5 can be found in the setting of hypercalc iuria without other features of X-linked nephrolithiasis. However, mutation s in CLCN5 do not represent a common cause of IH.