title: Thiazide-induced hyponatraemia is associated with increased water intake and impaired urea-mediated water excretion at low plasma antidiuretic hormone and urine aquaporin-2.
abstract: BACKGROUND
  Hyponatraemia is a common, potentially life-threatening, complication of thiazide diuretics. The mechanism of thiazide-induced hyponatraemia is incompletely understood. Previous experiments have suggested a direct effect of thiazide diuretics on the plasma membrane expression of aquaporin (AQP)2.
  
  
  METHODS
  We examined the effects of a single re-exposure to hydrochlorothiazide (HCTZ) 50 mg on water balance, renal sodium handling and osmoregulation in 15 elderly hypertensive patients with a history of thiazide-induced hyponatraemia and 15 matched hypertensive controls using thiazide diuretics without previous hyponatraemia.
  
  
  RESULTS
  Patients with thiazide-induced hyponatraemia had significantly lower body weight and lower plasma sodium and osmolality at baseline. After HCTZ administration, plasma sodium and osmolality significantly decreased and remained lower in patients compared with controls (P < 0.001). Plasma antidiuretic hormone (ADH) and urine AQP2 were low or suppressed in patients, whereas solute and electrolyte-free water clearance was significantly increased compared with controls. Ad libitum water intake was significantly higher in patients (2543 ± 925 ml) than in controls (1828 ± 624 ml, P < 0.05), whereas urinary sodium excretion did not differ. In contrast, urea excretion remained significantly lower in patients (263 ± 69 mmol per 24 h) compared with controls (333 ± 97 mmol per 24 h, P < 0.05) and predicted the decrease in plasma sodium following HCTZ administration.
  
  
  CONCLUSIONS
  Thiazide diuretics are associated with markedly impaired free water excretion at low ADH and AQP2 in elderly patients. The higher water intake and lower urea excretion in patients points to an important role for polydipsia and urea-mediated water excretion in the pathogenesis of thiazide-induced hyponatraemia.
authors.affiliation: aDivision of Internal and Vascular Medicine bDivision of Nephrology cDivision of Geriatrics, Department of Internal Medicine, Academic Medical Center, Amsterdam dDepartment of Physiology, Nijmegen Centre of Molecular Life Science, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Nanne J
authors.initials: NJ
authors.lastname: Frenkel
authors.forename: Liffert
authors.initials: L
authors.lastname: Vogt
authors.forename: Sophia E
authors.initials: SE
authors.lastname: De Rooij
authors.forename: Christiane
authors.initials: C
authors.lastname: Trimpert
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Levi
authors.forename: Peter M T
authors.initials: PM
authors.lastname: Deen
authors.forename: Bert-Jan H
authors.initials: BJ
authors.lastname: van den Born
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D051399:Aquaporin 2 / Q000652:urine*; D004326:Drinking / Q000187:drug effects / Q000502:physiology*; D004573:Electrolytes; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage* / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D007010:Hyponatremia / Q000139:chemically induced / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D012964:Sodium / Q000378:metabolism; D049993:Sodium Chloride Symporter Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D014508:Urea / Q000378:metabolism*; D014667:Vasopressins / Q000097:blood*; D014882:Water-Electrolyte Balance
chemical_list: D051399:Aquaporin 2; D004573:Electrolytes; D049993:Sodium Chloride Symporter Inhibitors; D006852:Hydrochlorothiazide; D014667:Vasopressins; D014508:Urea; D012964:Sodium