Divalent cation transport by the distal nephron: insights from Bartter's and Gitelman's syndromes

Elucidation of the gene defects responsible for many disorders of renal flu id and electrolyte homeostasis has provided new insights into normal and ab normal physiology. Identifying the causes of Gitelman's and Bartter's syndr omes has greatly enhanced our understanding of ion transport by thick ascen ding limb and distal convoluted tubule cells. Despite this information, sev eral phenotypic features of these diseases remain confusing, even in the fa ce of molecular insight. Paramount among these are disorders of divalent ca tion homeostasis. Bartter's syndrome is caused by dysfunction of thick asce nding limb cells. It is associated with calcium wasting, but magnesium wast ing is usually mild. Loop diuretics, which inhibit ion transport by thick a scending limb cells, markedly increase urinary excretion of both calcium an d magnesium. In contrast, Gitelman's syndrome is caused by dysfunction of t he distal convoluted tubule. Hypocalciuria and hypomagnesemia are universal parts of this disorder. Yet although thiazide diuretics, which inhibit ion transport by distal convoluted tubule cells, reduce urinary calcium excret ion, they have minimal effects on urinary magnesium excretion, when given a cutely. This review proposes mechanisms that may account for the difference s between the effects of diuretic drugs and the phenotypic features of Gite lman's and Bartter's syndromes. These mechanisms are based on recent insigh ts from another inherited disease of ion transport, inherited magnesium was ting, and from a review of the chronic effects of diuretic drugs in animals and people.