Abnormal Reabsorption of Na⁺/CI^- by the Thiazide-lnhibitable Transporter of the Distal Convoluted Tubule in Gitelman’s Syndrome

Abstract

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-reabsorp-tive 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.

Gitelman syndrome DD thiazide diuretics abuse

“…Gitelman syndrome (GS) was first described by Gitelman et al [1] in 1966 [1][2][3][4][5][6]. It is a rare inherited autosomal recessive renal disorder with decreased tubulary resorption of Na + , Cl -, Mg 2+ and K + [3][4][5][7][8][9][10][11][12][13][14][15][16][17][18].…”

“…Renal dysfunction causes blood and urine abnormalities typically characterized by hypokalemic metabolic alkalosis, salt loss, hypomagnesaemia and hypocalciuria [2][3][4][5][6][7]9,11,[13][14][15][16][17][18]20]. These abnormalities are caused by dysfunction of thiazide-sensitive NCCT in distal convoluted tubuli [2][3][4][5][6][7]9,12,13,15,16,[18][19][20][21].…”

“…These abnormalities are caused by dysfunction of thiazide-sensitive NCCT in distal convoluted tubuli [2][3][4][5][6][7]9,12,13,15,16,[18][19][20][21]. However, dysfunction in NCCT is not directly responsible for all electrolyte abnormalities.…”

“…GS is frequently overlooked at its beginning [4,12]. The symptoms include adynamia, loss of muscle strength, fatigue, vertigo, hypotension, muscle spasm, tetania and paraesthesia [2,4,[6][7][8]10,12,13,16,19,20]. Other rare symptoms are abdominal pain, nausea, vomiting and fever [4,12,13].…”

“…This fact could be used for diagnostic purposes [4,8]. If patients with GS (with sufficient hydration) take a test dose of TD, the normal effect of increased Na + , Cl -and K + diuresis fails to appear [2,4,8,9,12,24,26]. Conversely, loop diuretics increase Na + and Cl -diuresis [2,8,12,26].…”