Renal Mechanism of Trimethoprim-induced Hyperkalemia

15 August 1993 | Volume 119 Issue 4 | Pages 296-301

Objectives: 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.

Patients: Thirty consecutive patients who were treated with trimethoprim-containing drugs. All patients included in the study had the acquired immunodeficiency syndrome (AIDS).

Experimental animals: Thirty-nine male Sprague-Dawley rats receiving normal rat chow and tap water (allowed free access).

Intervention: 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).

Measurements: 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% CI, 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% (CI, 21% to 60%) and increased renal sodium excretion by 46% (CI, 9% to 83%). Trimethoprim (1 mmol/L) in tubule fluid inhibited distal tubule potassium secretion by 59% (CI, 26% to 92%) and depolarized the lumen-negative transepithelial voltage by 66% (CI, 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.

Author and Article Information

From the Department of Veterans Affairs Medical Center, West Haven, Connecticut; Yale University School of Medicine, New Haven, Connecticut.
Requests for Reprints: Heino Velazquez, PhD, Yale University School of Medicine, Department of Medicine/Nephrology, 333 Cedar Street, 2073 LMP, New Haven, CT 06510.
Acknowledgments: The authors thank David G. Kaiser for technical assistance.
Grant Support: Drs. Velazquez, Wright, and Ellison were recipients of Merit Review awards from the Department of Veterans Affairs Medical Center. This work was done during the tenure of an Established Investigatorship of the American Heart Association (DHE).