GENOTYPE-PHENOTYPE CORRELATIONS IN NORMOTENSIVE PATIENTS WITH PRIMARYRENAL TUBULAR HYPOKALEMIC METABOLIC ALKALOSIS

Among the different forms of hereditary renal tubulopathies associated with hypokalemia, metabolic alkalosis and normotension, two main type s of disorders have been identified: Gitelman disease, which appears t o be a homogeneous post-Henle's loop disorder, and Bartter syndrome, a heterogeneous Henle loop disorder. A specific gene has been found res ponsible for Gitelman disease, encoding the thiazide-sensitive Na-Cl c otransporter (TSC) of the distal convoluted tubule. From a phenotypic point of view the characteristic findings of this disease are hypocalc iuria, 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-sen sitive 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 tran sport proteins have been demonstrated in patients with the hypercalciu ric forms of Bartter syndrome associated with nephrocalcinosis (respec tively Bartter syndrome type I and II), who were often born after preg nancies complicated by polyhydramnios and premature delivery. Mutation s in the gene encoding a renal chloride channel were recently recogniz ed in patients with a Henle tubular defect not associated with nephroc alcinosis (Bartter syndrome type III). Most of the latter group of pat ients were normo-hypercalciuric and presented dehydration and life-thr eatening hypotension in the first year of life. However, these three g enes do not explain all the patients with Bartter syndrome which unlik e Gitelman disease, appears to be a very heterogeneous disorder. Clear ance studies, especially if done during furosemide and/or hydrochlorot hiazide administration, have been helpful in identifying the site of t ubular involvement. Considering both phenotypic and genotypic data, we propose a clinical-pathophysiological and molecular approach to diagn ose the different tubulopathies associated with hypokalemic metabolic alkalosis.