Familial hyperkalemia and hypertension: Pathogenetic insights based on lithium clearance

Haim Mayan, Semyon Melnikov, Ilya Novikov, Eliezer J. Holtzman, Zvi Farfel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Context: Familial hyperkalemia and hypertension (FHHt) is caused by mutations in WNK kinases. Its pathogenesis is not completely understood. Objective: Our objective was to investigate the mechanism of hypercalciuria in FHHt. Design and Setting: We conducted a study of a large family with FHHt and WNK4 Q565E mutation and of control subjects at 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 participated. Main Outcome Measures: Urinary calcium and sodium concentrations, endogenous lithium clearance, age of hypertension appearance were assessed. 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-fold higher in affected compared with 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 yr earlier than in females (26.0 ± 7.5 vs. 37.9 ± 11.3 yr; 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-hormone activity.

Original languageEnglish
Pages (from-to)3010-3016
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Issue number8
StatePublished - Aug 2009


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