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Renal Mechanism of Trimethoprim-induced Hyperkalemia

Heino Velazquez; Mark A. Perazella; Fred S. Wright; and David H. Ellison
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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).


Copyright 2004 by the American College of Physicians


Ann Intern Med. 1993;119(4):296-301. doi:10.7326/0003-4819-119-4-199308150-00008
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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.

Figures

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Figure 1.
Effect of trimethoprim on serum potassium concentration in patients with AIDS.

Values are for individual patients, averaged for available potassium measurements in the 4 weeks before the initiation of therapy (Before), throughout the period (1 to 13 days) of therapy (During), and during the 2 weeks after trimethoprim was discontinued (After). Lines connect values in individual patients. Missing lines indicate that the data were not collected during that period. Mean values for all patients SE for each period are 4.2 0.09 mmol/L, 4.8 0.14 mmol/L, and 4.3 0.09 mmol/L.

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Figure 2.
The scales depict the change () in ion excretion rate with time (period II minus period I) in control and experimental (Trimethoprim) animals.Panel APanel B

Bars and vertical lines indicate means and 95% CIs. Trimethoprim statistically inhibited renal potassium excretion when compared with control animals. The absolute potassium excretion rates that were used to calculate these values were: for the control animals in periods I and II, 1369 nmol/min (CI, 1173 to 1565 nmol/min) and 1415 nmol/min (CI, 1222 to 1608 nmol/min); for the trimethoprim animals: 1334 nmol/min (CI, 1093 to 1575 nmol/min) and 807 nmol/min (CI, 565 to 1049 nmol/min). Trimethoprim statistically increased renal sodium excretion when compared with control animals. The absolute sodium excretion rates that were used to calculate these values were: for the control animals in periods I and II, 1450 nmol/min (CI, 800 to 2100 nmol/min) and 2592 nmol/min (CI, 1703 to 3481 nmol/min); for the trimethoprim animals, 1491 nmol/min (CI, 956 to 2026 nmol/min) and 3824 nmol/min (CI, 2627 to 5021 nmol/min).

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Figure 3.
Net potassium transport during perfusion of 14 distal tubules with control and trimethoprim (TMP) solutions.

Lines connect measurements in the same tubule. Black circles and vertical lines indicate means and CIs. Positive values indicate absorption; negative values indicate secretion.

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Figure 4.
Dose-response curve for trimethoprim effect on transepithelial voltage in the rat distal tubule.

Values are means and CIs. Paired tests of the effect of four concentrations of trimethoprim versus the control solution (no trimethoprim) were done. The mean voltage measured with the control solution (lumen versus blood) ranged from 31.6 to 37.2 mV. The effect of each dose of trimethoprim on the distal tubule voltage is plotted as percentage change compared with its own control voltage. The maximum effect of luminal trimethoprim was reached at approximately 1 mM.

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