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Department of Medicine E (H.M., M.M., M.T.-W., R.P., Z.F.), Institute of Endocrinology (I.V.), and Laboratory of Biochemical Pharmacology (Z.F.), Sheba Medical Center, Tel Aviv University, Tel Hashomer 52621, Israel
Address all correspondence and requests for reprints to: Zvi Farfel, M.D., Department of Medicine E, Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail: . farfel{at}ccsg.tau.ac.il
Abstract
Mutations in WNK kinases cause pseudohypoaldosteronism type II (PHA II) and may represent a novel signaling pathway regulating blood pressure and K+ and H+ homeostasis. PHA II is an autosomal dominant disorder characterized by hypertension, hyperkalemia, and metabolic acidosis, with normal glomerular filtration rate. Thiazide diuretics correct all abnormalities. Inactivating mutations in the thiazide-sensitive NaCl cotransporter cause Gitelman syndrome, featuring hypotension, hypokalemia, and metabolic alkalosis plus hypocalciuria and hypomagnesemia. We investigated whether hypercalciuria and hypermagnesemia occurred in a large family with PHA II. Eight affected and eight unaffected members of a PHA II family with the Q565E WNK 4 mutation were studied. In affected members blood and urinary chemistry were measured on and off hydrochlorothiazide (HCTZ), and bone mineral density was determined. Marked sensitivity to HCTZ was found. A mean dose of 20 mg/d reduced mean blood pressure in the six hypertensive subjects by 54.3 (systolic) and 24.5 (diastolic) mm Hg. In affected subjects, HCTZ reduced mean serum K+ by 1.12 mmol/liter, mean serum Cl- by 6.2 mmol/liter, and mean urinary calcium by 65% and elevated mean serum calcium by 0.11 mmol/liter and mean serum urate by 118 µmol/liter. Compared with the literature, this represents an increase of 6–7 in HCTZ potency. Affected members had normomagnesemia, hypercalciuria (336 ± 113 vs. 155 ± 39 mg/d in unaffected relatives, P = 0.0002), and decreased bone mineral density. In PHA II the observed marked sensitivity to thiazides and the hypercalciuria are consistent with increased NaCl cotransporter activity. PHA II may serve as a model to investigate thiazides’ beneficial effects and side effects.
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