Context: Familial hyperkalemia and hypertension (FHHt) is caused by mutations in WNK kinases. Its pathogenesis is not completely understood.

Objective: To investigate the mechanism of hypercalciuria in FHHt.

Design: Study of a large family with FHHt and WNK4 Q565E mutation, and of control subjects.

Setting: A referral medical center.

Subjects: Forty-six members of a family with FHHt and WNK4 Q565E mutation, 23 of them affected, and 12 control subjects.

Intervention: None.

Main outcome measures: Urinary calcium and sodium concentrations, endogenous lithium clearance, age of hypertension appearance.

Results: In 40 urine samples of 20 affected subjects, urinary calcium was correlated to urinary sodium (r=0.567, p=0.0001). In 28 urinary samples of 22 unaffected members no correlation was found (r=0.285, p=0.14). Mean ratio of urinary calcium to urinary sodium was 2.7-higher in affected compared to unaffected members (58.7±25.9 vs 22.1±14.0 µmol/mmol, p<0.0001). Endogenous lithium clearance in eight affected members was about 50% lower than in 12 controls (16.2±7.7 vs 28.8±9.8 ml/min, p=0.0073). Hypertension was detected in males 12 years earlier than in females (26.0±7.5 vs 37.9±11.3 years, p=0.031).

Conclusions: Hypercalciuria in FHHt seems to be dependent on urinary sodium. According to molecular studies, FHHt patients are presumed to have increased distal nephron sodium reabsorption, and therefore decreased proximal reabsorption of sodium, lithium and calcium. The observed decreased lithium clearance reflects probable abnormal renal handling of lithium, i.e. distal nephron lithium reabsorption. Therefore, hypercalciuria may result from proximal nephron aberration. Finally, earlier appearance of hypertension in males may be the result of sex-hormones activity.