Pseudohypoaldosteronism type II: Marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density
Pseudohypoaldosteronism type II: Marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density
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DOI：
10.1210/jc.87.7.3248
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发表时间：
2002-07-01
影响因子：
5.8
通讯作者：
Farfel, Z
中科院分区：
文献类型：
--
作者：
Mayan, H;Vered, I;Farfel, Z
WNK激酶的突变导致假性醛固酮减少症II型（PHA II），可能代表一种调节血压和K（+）和H（+）稳态的新信号通路。PHA II是一种常染色体显性遗传疾病，以高血压、高钾血症和代谢性酸中毒为特征，肾小球滤过率正常。噻嗪类利尿剂纠正所有异常。噻嗪敏感性NaCl协同转运蛋白的失活突变导致Gitelman综合征，其特征为低血压、低钾血症和代谢性尿过多加上低钙尿症和低镁血症。我们调查是否高钙尿症和高镁血症发生在一个大家庭与PHA II。八个受影响的和八个未受影响的成员的PHA II的家庭与Q565 E WNK 4突变进行了研究。在受影响的成员的血液和尿液化学进行了测量和关闭氢氯噻嗪（HCTZ），并测定骨密度。HCTZ的敏感性显著，平均剂量为20 mg/d时，6名高血压患者的平均血压分别降低了54.3（收缩压）和24.5（舒张压）mm Hg。在受影响的受试者中，HCTZ使平均血清K（+）降低1.12 mmol/L，平均血清Cl（-）降低6.2 mmol/L，平均尿钙降低65%，使平均血清钙升高0.11 mmol/L，平均血清尿酸升高118 mumol/L。与文献相比，这表示HCTZ效力增加6-7。受影响的成员有正常镁血症，高钙尿症（336 +/- 113与155 - 39毫克/天，在未受影响的亲属，P = 0.0002），骨密度降低。在PHA II中，观察到的对噻嗪类药物的显著敏感性和高钙尿症与NaCl协同转运蛋白活性增加一致。PHA II可作为研究噻嗪类药物的有益作用和副作用的模型。
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 mumol/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.