Genotype-phenotype correlations in normotensive patients with primary renal tubular hypokalemic metabolic alkalosis

Among the different forms of hereditary renal tubulopathies associated with hypokalemia, metabolic alkalosis and normotension, two main types of disorders have been identified: Gitelman disease, which appears to be a homogeneous post-Henle's loop disorder, and Bartter syndrome, a heterogeneous Henle loop disorder. A specific gene has been found responsible for Gitelman disease, encoding the thiazide-sensitive Na-Cl cotransporter (TSC) of the distal convoluted tubule. From a phenotypic point of view the characteristic findings of thin disease are hypocalciuria, hypomagnesemia and tetanic crises appearing during childhood or later. Many subjects are asymptomatic. At least three different genes have been shown to be responsible for Bartter syndrome, characterized by mutations in the proteins encoding respectively the bumetanide-sensitive Na-K-2Cl cotransporter, the inwardly-rectifying renal potassium channel and a renal chloride channel, all protein transports located in the ascending limb of Henle's loop. Mutations in the first two transport proteins have been demonstrated in patients with the hypercalciuric forms of Bartter syndrome associated with nephrocalcinosis (respectively Bartter syndrome type I and H), who were often born after pregnancies complicated by polyhydramnios and premature delivery. Mutations in the gene encoding a renal chloride channel were recently recognized in patients with a Henle tubular defect not associated with nephrocalcinosis (Bartter syndrome type III). Most of the latter group of patients were normo-hypercalciuric and presented dehydration and life-threatening hypotension in the first year of life. However, these three genes do not explain all the patients with Bartter syndrome which unlike Gitelman disease, appears to be a very heterogeneous disorder. Clearance studies, especially if done during furosemide and/or hydrochlorothiazide administration, have been helpful in identifying the site of tubular involvement. Considering both phenotypic and genotypic data, we propose a clinical-pathophysiological and molecular approach to diagnose the different tubulopathies associated with hypokalemic metabolic alkalosis.