title: Familial hyperkalemia and hypertension: pathogenetic insights based on lithium clearance.
abstract: BACKGROUND
  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.
  
  
  METHODS
  We conducted a study of a large family with FHHt and WNK4 Q565E mutation and of control subjects at a referral medical center.
  
  
  METHODS
  Forty-six members of a family with FHHt and WNK4 Q565E mutation, 23 of them affected, and 12 control subjects participated.
  
  
  METHODS
  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 micromol/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.
authors.affiliation: Department of Medicine E, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Mayan
authors.forename: Semyon
authors.initials: S
authors.lastname: Melnikov
authors.forename: Ilya
authors.initials: I
authors.lastname: Novikov
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Holtzman
authors.forename: Zvi
authors.initials: Z
authors.lastname: Farfel
mesh_terms: D000328:Adult; D002118:Calcium / Q000097:blood / Q000652:urine; D005260:Female; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics; D006947:Hyperkalemia / Q000235:genetics*; D006973:Hypertension / Q000235:genetics*; D008094:Lithium / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011188:Potassium / Q000097:blood; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011955:Receptors, Drug / Q000502:physiology; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000502:physiology
chemical_list: D011955:Receptors, Drug; C578874:SLC12A3 protein, human; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D008094:Lithium; D017346:Protein Serine-Threonine Kinases; C433806:WNK4 protein, human; D011188:Potassium; D002118:Calcium