title: Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density.
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 micromol/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.
authors.affiliation: Department of Medicine E, Institute of Endocrinology, Sheba Medical Center, Tel Aviv University, Tel Hashomer 52621, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Mayan
authors.forename: Iris
authors.initials: I
authors.lastname: Vered
authors.forename: Meir
authors.initials: M
authors.lastname: Mouallem
authors.forename: Michal
authors.initials: M
authors.lastname: Tzadok-Witkon
authors.forename: Rachel
authors.initials: R
authors.lastname: Pauzner
authors.forename: Zvi
authors.initials: Z
authors.lastname: Farfel
mesh_terms: D000328:Adult; D001581:Benzothiadiazines; D001794:Blood Pressure / Q000187:drug effects; D001842:Bone and Bones; D002118:Calcium / Q000652:urine*; D004232:Diuretics; D005260:Female; D006801:Humans; D008274:Magnesium / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000037:antagonists & inhibitors / Q000097:blood; D011546:Pseudohypoaldosteronism / Q000145:classification / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D012016:Reference Values; D049993:Sodium Chloride Symporter Inhibitors / Q000627:therapeutic use*
chemical_list: D001581:Benzothiadiazines; D004232:Diuretics; D049993:Sodium Chloride Symporter Inhibitors; D008274:Magnesium; D011188:Potassium; D002118:Calcium