Renal mechanism of trimethoprim-induced hyperkalemia

Heino Velázquez, Mark A. Perazella, Fred S. Wright, David Ellison

Research output: Contribution to journalArticle

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Abstract

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 immunodefi-ciency 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% 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.

Original languageEnglish (US)
Pages (from-to)296-301
Number of pages6
JournalAnnals of Internal Medicine
Volume119
Issue number4
StatePublished - Aug 15 1993
Externally publishedYes

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Hyperkalemia
Trimethoprim
Potassium
Kidney
Distal Kidney Tubule
Sodium Channels
Nephrons
Serum
Sodium Chloride
Urine
Kidney Tubules
Inulin
Amiloride
Aldosterone
Glomerular Filtration Rate
Ion Channels
Renin
Pharmaceutical Preparations
Electrolytes
Sprague Dawley Rats

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Velázquez, H., Perazella, M. A., Wright, F. S., & Ellison, D. (1993). Renal mechanism of trimethoprim-induced hyperkalemia. Annals of Internal Medicine, 119(4), 296-301.

Renal mechanism of trimethoprim-induced hyperkalemia. / Velázquez, Heino; Perazella, Mark A.; Wright, Fred S.; Ellison, David.

In: Annals of Internal Medicine, Vol. 119, No. 4, 15.08.1993, p. 296-301.

Research output: Contribution to journalArticle

Velázquez, H, Perazella, MA, Wright, FS & Ellison, D 1993, 'Renal mechanism of trimethoprim-induced hyperkalemia', Annals of Internal Medicine, vol. 119, no. 4, pp. 296-301.
Velázquez H, Perazella MA, Wright FS, Ellison D. Renal mechanism of trimethoprim-induced hyperkalemia. Annals of Internal Medicine. 1993 Aug 15;119(4):296-301.
Velázquez, Heino ; Perazella, Mark A. ; Wright, Fred S. ; Ellison, David. / Renal mechanism of trimethoprim-induced hyperkalemia. In: Annals of Internal Medicine. 1993 ; Vol. 119, No. 4. pp. 296-301.
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abstract = "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 immunodefi-ciency 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{\%} 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.",
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N2 - 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 immunodefi-ciency 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% 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.

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