Eleven patients with
Gitelman's syndrome and 23 controls underwent acute administration of the
thiazide diuretic hydrochlorothiazide and/or the
loop diuretic furosemide (FUR) in order to indirectly evaluate the activity of the two electroneutral Na+/Cl(-)-reabsorptive systems of the distal nephron, namely the
thiazide-sensitive
Na+-Cl- symporter of the distal convoluted tubule and the FUR-sensitive Na+-K+-2Cl-
symporter of the loop of Henle. The patients were characterized by
hypokalemia, mild metabolic
alkalosis, hypomagnesemia, hypocalciuria, and reduced free water generation during maximally diluted diuresis which indicated reduced distal nephron NaCl reabsorption. The plasma Na and Cl levels were similar in patients and controls.
Hydrochlorothiazide induced a significantly lower increase of urinary Na and Cl excretions in 6 patients with
Gitelman's syndrome than in 6 controls, indicating reduced NaCl reabsorption by the
thiazide-sensitive
Na+/Cl- symporter of the distal convoluted tubule in
Gitelman's syndrome. FUR induced a slightly higher increase of urinary Na and Cl excretions in 11 patients with
Gitelman's syndrome than in 17 controls, in keeping with reduced NaCl reabsorption in tubular sites past the loop of Henle during FUR effect or increased NaCl reabsorption in the loop itself (as a compensatory mechanism for NaCl-reabsorptive defect in the distal convoluted tubule) or both. Our results confirm that the functional activity of the renal
thiazide-sensitive Na+-Cl- cotransporter (but not of the FUR-sensitive carrier) is deficient in patients with
Gitelman's syndrome, in keeping with the recently described genetic link between the syndrome and a wide variety of nonconservative mutations of the gene encoding the
protein; it is suggested that dynamic studies with
diuretic administration may be of diagnostic help in this condition.