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      Studies on the Pathogenesis of Hypokalemia in Gitelman’s Syndrome: Role of Bicarbonaturia and Hypomagnesemia

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          Objective: Hypokalemia and renal potassium (K) wasting are hallmarks of the group of disorders called Bartter’s syndrome. The presence of hypomagnesemia and a low rate of excretion of calcium are currently used to characterize a subgroup of these patients as having Gitelman’s syndrome (GS) in which the molecular lesion is a defect in the thiazide-sensitive NaCl cotransporter in the distal convoluted tubule. This study was undertaken to examine whether bicarbonaturia or hypomagnesemia exacerbates the kaliuresis in patients with GS. Methods: Six patients with most of the diagnostic features of GS were examined. To examine the role of bicarbonaturia, the transtubular K concentration gradient (TTKG) was assessed before and after an oral load of NH<sub>4</sub>Cl which caused the urine pH to be <6. To evaluate the role of hypomagnesemia, the TTKG was examined after an infusion of enough magnesium (Mg) to achieve normal levels of Mg in plasma for close to 24 h. Results: The TTKG remained very high even when the pH of the urine was <6.0. An infusion of Mg caused the TTKG to approach expected values for hypokalemia in 4 of 6 patients. The infusion of Mg was extended in 1 patient who had a sustained high TTKG for 24 h; the TTKG remained elevated for 96 h despite normal plasma Mg levels. Conclusions: Bicarbonaturia does not play a critical role in maintaining the very high TTKG in these patients. The K wasting in 4 of 6 of these patients could largely be attributed to hypomagnesemia and/or Mg depletion. The plasma aldosterone level tended to be higher in patients who did not respond to the infusion of Mg. Therefore, these patients may not represent a homogeneous group with regard to the pathophysiology of their renal K wasting.

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          Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.

          Inherited hypokalaemic alkalosis with low blood pressure can be divided into two groups-Gitelman's syndrome, featuring hypocalciuria, hypomagnesaemia and milder clinical manifestations, and Bartter's syndrome, featuring hypercalciuria and early presentation with severe volume depletion. Mutations in the renal Na-Cl cotransporter have been shown to cause Gitelman's syndrome. We demonstrate linkage of Bartter's syndrome to the renal Na-K-2Cl cotransporter gene NKCC2, and identify frameshift or non-conservative missense mutations for this gene that co-segregate with the disease. These findings demonstrate the molecular basis of Bartter's syndrome, provide the basis for molecular classification of patients with inherited hypokalaemic alkalosis, and suggest potential phenotypes in heterozygous carriers of NKCC2 mutations.
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            Diuretics, serum and intracellular electrolyte levels, and ventricular arrhythmias in hypertensive men.

            To investigate the patterns of electrolyte abnormalities resulting from thiazide administration and whether they cause ventricular arrhythmias, and to help resolve the controversy over whether clinicians should routinely prescribe potassium-conserving therapy to all patients treated with thiazides. Double-blind, randomized controlled trial. A total of 233 hypertensive men aged 35 to 70 years. Participants were withdrawn from prior diuretic treatment and were replenished with oral potassium chloride and magnesium oxide. They were then randomized to 2 months of treatment with (1) hydrochlorothiazide; (2) hydrochlorothiazide with oral potassium; (3) hydrochlorothiazide with oral potassium and magnesium; (4) hydrochlorothiazide and triamterene; (5) chlorthalidone; or (6) placebo. Ventricular arrhythmias on 24-hour Holter monitoring and serum and intracellular potassium and magnesium levels. Of the 233 participants, 212 (91%) completed the study. Serum potassium levels were 0.4 mmol/L lower in the hydrochlorothiazide group than in the placebo group (P less than 0.01), and this mean difference was not affected by supplementation with potassium, with potassium and magnesium, or with triamterene. However, the supplements did prevent the occasional occurrence of marked hypokalemia; all 12 of the men who developed serum potassium levels of 3.0 mmol/L or less were among the 90 who received diuretics without supplementation (P less than 0.01). Similarly, the overall proportion of men with ventricular arrhythmias was not affected by randomized treatment, but there was a twofold increase in the proportion with arrhythmias among the 12 men with serum potassium levels of 3.0 mmol/L or less (P = .02). Serum magnesium and intracellular potassium and magnesium levels were not reduced by hydrochlorothiazide, nor were they related to ventricular arrhythmias. In the majority of hypertensive patients, treatment with 50 mg/d of hydrochlorothiazide does not cause marked hypokalemia or ventricular arrhythmias. However, because some individuals will develop hypokalemia after starting diuretic therapy, serum potassium levels should be monitored and potassium-sparing strategies should be used when indicated.

              Author and article information

              Am J Nephrol
              American Journal of Nephrology
              S. Karger AG
              February 1998
              16 January 1998
              : 18
              : 1
              : 42-49
              a Renal Division, Department of Medicine, St. Michael’s Hospital, b Hospital for Sick Children, Toronto, Ont., Canada; c North West Renal Clinic, Portland, Oreg., USA; d Timmins and District Hospital, Timmins, Ont., Canada
              13303 Am J Nephrol 1998;18:42–49
              © 1998 S. Karger AG, Basel

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              Figures: 1, Tables: 3, References: 40, Pages: 8
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