Correction of Hypokalemia with Antialdosterone Therapy in Gitelman’s Syndrome

Abstract

Six adult patients (4 females and 2 males, age range 26-57 years) with Gitelman’s syndrome (GS) were treated with spironolactone 200-300 mg/day (n = 5) and/or amiloride 10-30 mg/day (n = 3) for 1-18 months. The patients had hypokalemia, hyperreninemia, chloride-resistant metabolic alkalosis, renal hypomagnesemia (n = 5), and hypocalciuria (n = 5). Free water clearance studies during maximal water diuresis and furosemide administration were suggestive of a solute reabsorptive defect beyond the loop of Henle. Antialdosterone therapy induced a significant increase of Pk (from 2.6 ± 0.4 to 3.4 ± 0.4 τaM\ p < 0.0001) and a decrease of C_ĸ (from 21.4 ± 13.2 to 10.6 ± 4.8 ml/ min, p < 0.02) and FE_K (from 21.0 ± 13.6 to 13.4 ± 5.7%; p < 0.03); P_Mgincreased from 1.38 ± 0.38 to 1.64 ± 0.21 mg/dl (p < 0.03) with a parallel fall of C_Mg (from 5.5 ± 2.3 to 2.9 ± 1.5 ml/min; p < 0.02) and FE_Mg (from 5.7 ± 2.6 to 2.9 ± 0.6%; p < 0.05); arterial blood pH and HCO^-₃ did not change (P = plasma, C = clearance, FE = fractional excretion). The creatinine clearance fell (from 90.5 ± 16.8 to 65.8 ± 20.9 ml/min; p < 0.05), and P_renin rose (from 16.6 ± 8.9 to 35.3 ± 25.3 ng/ml/h;p < 0.02, as did P_aldo (from 26.1 ± 12.3 to 109 ± 82.6ng/dl; p < 0.01), indicating extracellular fluid volume contraction; however no significant clinical symptoms of hypovolemia ensued. Despite increased P_aldo levels, estimated transtubular K gradient in K secretory sites fell (from 8.0 ± 4.0 to 6.7 ± 3.4; p < 0.01), confirming blunted aldosterone tubular effect. At the dosages employed, spironolactone induced a greater increase of P_ĸ (0.81 ± 0.52 mM) than amiloride (0.07 ± 0.41; p < 0.001). In conclusion, antialdosterone therapy is effective in ameliorating hypokalemia and hypomagnesemia in GS. Its effects appear to result mainly from a direct tubular effect on K secretion and Mg reabsorption; extracellular fluid volume contraction appears also to occur during therapy, but has no relevant clinical effects. These results confirm that hypokalemia in GS is more a consequence of increased tubular secretion in the cortical collecting tubule than of impaired tubular K reabsorption; moreover, impaired tubular Mg conservation in GS might also occur in more distal segments of the nephron than previously supposed.

Phenotype–genotype correlation and follow-up in adult patients with hypokalaemia of renal origin suggesting Gitelman syndrome

“…Our results provided here were found in a recruitment that was regional and mainly endocrinological with phenotype and follow-up assessment. Indeed, few studies have focused on the treatment of GS (10,11), and none have been done on the clinical and biological progression of GS. Therefore, the first aim of this study was to determine the prevalence of genetically proven GS in a population of patients referred for chronic low blood potassium levels with renal potassium wasting.…”

Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia

“…In this respect, it is interesting to note that aldosterone excess has been shown to be associated with renal Mg 2+ wasting, whereas hypermagnesemia may accompany aldosterone deficiency (4,41). In addition, it has been shown that the mineralocorticoid receptor antagonist spironolactone reduces urinary Mg 2+ excretion in patients with Gitelman syndrome (42,43). During thiazideinduced ECV contraction as well as in NCC -/-mice, aldosterone levels are increased (25).…”

Indomethacin, Amiloride, or Eplerenone for Treating Hypokalemia in Gitelman Syndrome

“…Hypokalemia is associated with the intensity of musculoskeletal symptoms and the occurrence of more severe complications, and it has previously been shown to respond to each of three study drugs in preliminary reports. 11,15,16 Hypokalemia in patients with GS is caused by secondary consequences of the inherited inactivation of NCC in the proximal DCT, including increased sodium delivery to late DCTand cortical connecting duct and secondary renin-dependent hyperaldosteronism triggered by sodium depletion. This biologic and hormonal phenotype mimics the electrolytic consequences of chronic administration of thiazide diuretics, which specifically block NCC in the kidney.…”