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 this 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 II), 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.