Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density

J Clin Endocrinol Metab. 2002 Jul;87(7):3248-54. doi: 10.1210/jcem.87.7.8449.

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.

MeSH terms

  • Adult
  • Benzothiadiazines*
  • Blood Pressure / drug effects
  • Bone and Bones*
  • Calcium / urine*
  • Diuretics
  • Female
  • Humans
  • Magnesium / blood*
  • Male
  • Middle Aged
  • Potassium / antagonists & inhibitors
  • Potassium / blood
  • Pseudohypoaldosteronism / classification
  • Pseudohypoaldosteronism / drug therapy*
  • Pseudohypoaldosteronism / genetics
  • Pseudohypoaldosteronism / physiopathology*
  • Reference Values
  • Sodium Chloride Symporter Inhibitors / therapeutic use*

Substances

  • Benzothiadiazines
  • Diuretics
  • Sodium Chloride Symporter Inhibitors
  • Magnesium
  • Potassium
  • Calcium