title: Renal mechanism of trimethoprim-induced hyperkalemia.
abstract: OBJECTIVE
  1) To determine the incidence and severity of hyperkalemia during trimethoprim therapy. 2) To test the hypothesis that trimethoprim inhibits renal potassium excretion by blocking sodium channels in the mammalian distal nephron.
  
  
  METHODS
  Thirty consecutive patients who were treated with trimethoprim-containing drugs. All patients included in the study had the acquired immunodeficiency syndrome (AIDS).
  
  
  METHODS
  Thirty-nine male Sprague-Dawley rats receiving normal rat chow and tap water (allowed free access).
  
  
  METHODS
  Humans: high dose (20 mg/kg per day) of trimethoprim therapy. Rats: trimethoprim (9.6 mg/h per kg body weight) was infused intravenously or into the renal distal tubules (1 mmol/L).
  
  
  METHODS
  Humans: Serum and urine electrolyte levels, serum creatinine, renin, aldosterone, and cortisol levels were measured, and the transtubular potassium gradient was calculated. Rats: The effects of trimethoprim infusion on urinary sodium, chloride, and potassium concentration and urine volume were measured. Sodium, chloride, potassium, and inulin concentrations were measured in fluid samples obtained from kidney distal tubules. The voltage across the wall of the distal tubule was measured.
  
  
  RESULTS
  Humans: Trimethoprim increased the serum potassium concentration by 0.6 mmol/L (95% Cl, 0.29 to 0.95 mmol/L) despite normal adrenocortical function and glomerular filtration rate. Serum potassium levels greater than 5 mmol/L were observed during trimethoprim treatment in 15 of 30 patients. Rats: Intravenous trimethoprim inhibited renal potassium excretion by 40% (Cl, 21% to 60%) and increased renal sodium excretion by 46% (Cl, 9% to 83%). Trimethoprim (1 mmol/L) in tubule fluid inhibited distal tubule potassium secretion by 59% (Cl, 26% to 92%) and depolarized the lumen-negative transepithelial voltage by 66% (Cl, 46% to 85%).
  
  
  CONCLUSIONS
  Trimethoprim (an organic cation) acts like amiloride and blocks apical membrane sodium channels in the mammalian distal nephron. As a consequence, the transepithelial voltage is reduced and potassium secretion is inhibited. Decreased renal potassium excretion secondary to these direct effects on kidney tubules leads to hyperkalemia in a substantial number of patients being treated with trimethoprim-containing drugs.
authors.affiliation: Department of Veterans Affairs Medical Center, West Haven, Connecticut.
authors.forename: H
authors.initials: H
authors.lastname: Velázquez
authors.forename: M A
authors.initials: MA
authors.lastname: Perazella
authors.forename: F S
authors.initials: FS
authors.lastname: Wright
authors.forename: D H
authors.initials: DH
authors.lastname: Ellison
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy*; D000818:Animals; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D007686:Kidney Tubules, Distal / Q000187:drug effects; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy*; D011188:Potassium / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012189:Retrospective Studies; D014295:Trimethoprim / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D014295:Trimethoprim; D011188:Potassium