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Renal Mechanism of Trimethoprim-induced Hyperkalemia
- 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).
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 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.
Hyperkalemia is increasingly being recognized in patients with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS) [1-7]. In this setting, it is likely that hyperkalemia is the result of inadequate renal potassium excretion. Three mechanisms could be responsible for renal potassium retention: adrenal insufficiency with inadequate production of aldosterone; acute renal failure with reduced glomerular filtration and damage to tubule cells; and inhibition of potassium secretion. Most attention has focused on the first two mechanisms [1-8]. We are aware, however, of three reports of reversible hyperkalemia [4, 9, 10] that suggest that a therapeutic agent may have a direct action on renal tubules to suppress potassium transport. A common factor in the three reports was the administration of trimethoprim for treatment of Pneumocystis carinii pneumonia. The purpose of our study was to test the hypothesis that trimethoprim causes hyperkalemia by a direct action on the distal nephron cells responsible for secreting potassium.
Methods
Study in Humans
All patients receiving high-dose trimethoprim (20 mg/kg per day), with either sulfamethoxazole or dapsone, at the Yale-New Haven Hospital during a 4-month period, were included. As a part of the clinical management of these patients, serum measurements of sodium, potassium, and creatinine levels were recorded before, during, and after trimethoprim treatment. In some patients, increased serum potassium levels (>5.0 mmol/L) were identified while patients were receiving trimethoprim. In a group of these patients, we reviewed the clinical course and recommended further evaluation to search for causes of hyperkalemia. This evaluation included measurements of serum glucose, renin, aldosterone, and cortisol levels as well as osmolality; measurements of urinary sodium, potassium, chloride, glucose, and protein levels as well as osmolality; and examination of the urinary sediment. The tubule fluid/plasma concentration ratio for potassium in the cortical collecting duct (transtubular potassium gradient) [11, 12] was calculated from urine and serum values for potassium and osmolality as (K)urine/[K]serum)/([Osm]urine/[Osm]serum). The ability of cosyntropin to stimulate cortisol secretion was determined in patients whose cortisol level was < 552 nmol/L (<20 g/dL).
Studies in Rats
Male Sprague-Dawley rats, allowed free access to standard rat chow and tap water up to the time of the experiment, were anesthetized before surgical exposure of one kidney, as previously described [13]. The ureter was cannulated.
Intravenous Infusion of Trimethoprim
A salt solution (140 mmol/L sodium chloride, 4 mmol/L potassium chloride) was infused at 15 mL/h per kg body weight, and 45 minutes was allowed for equilibration after surgical preparation was completed. Subsequently, six 30-minute urine collections were obtained. The first 90 minutes was period I (collections 1 to 3), and the subsequent 90 minutes was period II (collections 4 to 6). The control and experimental groups of animals differed only in that at 90 minutes (after period I), 0.64 g/L of trimethoprim was added to the intravenous infusate (the trimethoprim infusion rate was 9.6 mg/h per kg body weight) in the experimental group and was maintained throughout period II. Sodium, potassium, and chloride concentrations were measured in urine [13]. The urine flow rate was measured, and the excretion rates for fluid, sodium, potassium, and chloride were calculated.
Microperfusion of Distal Tubules
Microperfusion experiments were done as described previously [13, 14]. Distal tubules were perfused with an artificial tubule fluid with or without trimethoprim (the composition of the perfusion solutions is given in Table 1. A perfusion pipette was positioned at the upstream end of the tubule, and a collection pipette was positioned at the downstream end. The perfusion pump was set to deliver 15 nL/min. A paired design was used as follows: After the first tubule fluid sample was collected, both the collection pipette and the perfusion pipette were removed: Then a second perfusion pipette containing a different solution [the order of solutions was alternated] and a second collection pipette were used to collect a second tubule fluid sample. The volume of collected samples was measured. Sodium, potassium, chloride, and inulin concentrations in perfused and collected fluids were measured, as described previously [14]. Osmolality and pH of bulk solutions were measured [14]. The perfusion rate was calculated from the collection rate and the inulin concentrations. Net fluid transport was calculated as the difference between perfusion and collection rates. Net transport rates for sodium, potassium, and chloride levels by each distal tubule were determined. Transepithelial voltage across the wall of the late distal tubule was measured, as previously described [15]. In experiments designed to test the effect of different concentrations of trimethoprim on transepithelial voltage, a higher perfusion rate (30 compared with 15 nL/min) was used to minimize changes in luminal ion composition along the length of the perfused tubule.
Statistical Analysis
Results were analyzed using the t-statistic. A P value of less than 0.05 (95% CI) was statistically different.
Results
Human Studies
Records from 30 consecutive inpatients who were treated with high-dose trimethoprim at Yale-New Haven Hospital between 10 July and 18 November 1992 were reviewed. No patients were excluded from this study. All patients were HIV positive and were treated for presumed or confirmed P. carinii pneumonia. Twenty-three of the patients were treated with trimethoprim-sulfamethoxazole, and seven were treated with trimethoprim-dapsone. On average, the length of the trimethoprim treatment period was 5.3 2.79 days (mean SD; range, 1 to 13 days). Figure 1 shows that the serum potassium concentration increased by 0.6 mmol/L (CI, 0.29 to 0.95 mmol/L) during treatment with trimethoprim. When the drug was discontinued, the potassium concentration decreased to pretreatment values. In 15 of 30 patients (50%), the serum potassium concentration was more than 5.0 mmol/L on at least 1 day during trimethoprim treatment. Severe and potentially life-threatening hyperkalemia (potassium > 6.0 mmol/L) occurred in three patients (10%). The serum creatinine concentration was slightly higher during trimethoprim treatment than during recovery (mean difference, 15.9 mmol/L; CI, 5.3 to 26.5 mmol/L [0.18 mg/dL; CI, 0.06 to 0.30 mg/dL]). None of the patients were taking nonsteroidal anti-inflammatory drugs, converting-enzyme inhibitors, or potassium-sparing diuretics.
Renal and adrenal function were evaluated in seven patients during hyperkalemia (potassium > 5 mmol/L). The mean serum potassium concentration was 5.9 0.9 mmol/L, and the urinary potassium concentration was 11.3 5.8 mmol/L (mean SD). Oliguria was not present in any of the patients, and the serum creatinine concentration was not increased above baseline (mean difference, 17.7 mmol/L; CI, 9.72 to 43.3 mmol/L [0.2 mg/dL; CI, 0.11 to 0.49 mg/dL]). The transtubular potassium gradient calculated for the cortical collecting duct [11, 12] was 1.9 1.1 (mean SD). This value was low (expected range was 6 to 11) for a plasma potassium concentration of >5 mmol/L. In three patients, the transtubular potassium gradient was calculated both during and after treatment with trimethoprim. After discontinuation of trimethoprim, the transtubular potassium gradient increased to normal values in all three patients (mean difference, 4.5; CI, 1.4 to 7.5). The urinary sodium concentration was 103 65.7 mmol/L, and there was mild hyponatremia (132 2.8 mmol/L). The plasma cortisol (497 152 nmol/L, supine [18.0 5.5 g/dL, supine]); renin (0.667 0.25 ng/[L x s], supine [2.4 0.9 ng/mL per hour, supine]); and aldosterone (535 264 pmol/L, supine [19.3 9.5 ng/dL, supine]) levels were all high normal or increased during hyperkalemia. In two patients with borderline serum cortisol levels (221 and 469 nmol/L [8 and 17 g/dL]), cosyntropin stimulation test results were normal. Glucose levels were all within the normal range.
Rat Studies
The effect of trimethoprim on potassium and sodium excretion rates in the whole kidney is shown in Figure 2. Compared with the control group, trimethoprim decreased potassium excretion by 572 nmol/min (CI, 299 to 845 nmol/min). The reduction in potassium excretion during trimethoprim infusion was 40% (CI, 21% to 60%) of the control rate measured in period II. Although sodium excretion in the control group increased with time, trimethoprim caused a twofold larger increase in sodium excretion. The difference between these changes, 1192 nmol/min (CI, 240 to 2142), was statistically significant. The increase in sodium excretion during trimethoprim infusion was 46% (CI, 9% to 83%) of the control rate measured in period II. There was no effect of trimethoprim on urine flow or chloride excretion rate (Appendix 1).
Table 1 gives flow rates, lumen ion concentrations, and ion transport rates from in vivo microperfusion of distal tubules of rats. Figure 3 shows that 1 mmol/L of trimethoprim inhibited net potassium secretion by 59% (CI, 26% to 92%). The rate of net sodium absorption did not decrease. Rates of net chloride and water absorption were also not affected.
Figure 4 shows the effect of trimethoprim concentration on the transepithelial voltage in the distal tubule when perfused at a constant high flow rate of 30 nL/min. Maximum inhibition of transepithelial voltage occurred at approximately 1 mmol/L of trimethoprim. In paired experiments at this dose, trimethoprim inhibited the voltage by 66% (CI, 44% to 85%). The concentration of trimethoprim needed to inhibit the transepithelial voltage by 50% is approximately 0.1 mmol/L.
Discussion
Hyperkalemia has been reported in 16% of hospitalized patients with AIDS [16] and has been attributed to adrenal insufficiency, hyporeninemic hypoaldosteronism, or advanced renal failure [1-4]. An increased plasma potassium level may also result from pharmacologic agents used to treat these patients. Although hyperkalemia is not generally recognized as a complication of trimethoprim therapy, disorders of potassium metabolism have been described in patients receiving high-dose trimethoprim (20 mg/kg per day). Four patients with AIDS described by Kalin and coworkers [4] developed mild-to-moderate hyperkalemia that was ascribed to the hyporeninemic hypoaldosterone state. However, these patients were also receiving trimethoprim at the time they developed an increased plasma potassium level. It is possible that trimethoprim could have caused or at least contributed to the hyperkalemia. In a prospective trial of therapeutic efficacy, 20% of patients treated with trimethoprim-sulfamethoxazole and 53% of patients treated with trimethoprim-dapsone developed mild hyperkalemia [10].
Our results show that patients with AIDS frequently have an increase in plasma potassium concentration when treated with trimethoprim (combined with either dapsone or sulfamethoxazole), at the dose recommended for P. carinii pneumonia (20 mg/kg per day). In some patients (10% of 30 consecutive patients treated with trimethoprim), hyperkalemia was severe (potassium > 6 mmol/L). A similar incidence was reported by Greenberg and colleagues [17], who found that serum potassium concentration was more than 6 mmol/L in 3 of 25 (12%) consecutive patients treated with trimethoprim-sulfamethoxazole, despite normal adrenal function and normal glomerular filtration rate. Patients with AIDS may be at a greater risk for developing hyperkalemia during trimethoprim treatment because they have a coexisting but clinically asymptomatic defect in renal or adrenal function. Merenich and colleagues [18] recently studied 40 HIV-positive asymptomatic patients who had decreased baseline cortisol and aldosterone levels as well as impaired cortisol response to adrenocorticotropic hormone infusion when compared with normal controls. The authors suggested there might be a subtle defect in adrenal function underlying the abnormal response. It is conceivable that the superimposition of trimethoprim therapy on these patients with AIDS could precipitate hyperkalemia that would not have occurred otherwise.
Although many factors may contribute to hyperkalemia in patients with AIDS, our results indicate that trimethoprim (a dihydrofolate reductase inhibitor), by itself, inhibits renal potassium excretion and may participate importantly in this disturbance. Trimethoprim and amiloride are both organic cations, and the similarity of their actions may relate to their common structure [19]. Fonseca and coworkers [20] reported that trimethoprim inhibits sodium transport across frog skin and competes with amiloride for blockade of conductive sodium channels. More recently, trimethoprim has also been shown to inhibit amiloride-sensitive short circuit current in the epithelial cell line A6 [19]. Our results indicate that trimethoprim blocks sodium channels in the distal nephron of the mammalian kidney. When trimethoprim was perfused directly into the lumen of distal tubules of rats, potassium secretion decreased by 59% (see Table 1, Figure 3, and the lumen negative transepithelial voltage decreased by 66% (Figure 4). These results are similar to results obtained when the diuretic amiloride is perfused into the distal tubule [21, 22]. In the distal tubule, amiloride inhibits potassium secretion indirectly by blocking luminal sodium channels. Because the lumen negative voltage depends on electrogenic sodium transport in this nephron segment, blockade of this pathway depolarizes the transepithelial voltage. In contrast, when potassium channels in the luminal membrane are blocked directly, as with barium (a divalent cation), potassium secretion decreases, but the magnitude of the transepithelial voltage increases [23]. Thus, the presence of both inhibited potassium secretion and depolarization of the transepithelial voltage during luminal application of trimethoprim indicates that the drug blocks sodium channels in the luminal membrane of the mammalian distal tubule.
If trimethoprim acts as a sodium channel blocker to reduce potassium secretion by decreasing the electrical driving force favoring potassium secretion, a decrease in net sodium transport would be predicted. Trimethoprim statistically increased renal sodium excretion compared with control Figure 2, a result consistent with this mechanism of action. In perfused distal tubules, however, net sodium absorption was not statistically decreased by trimethoprim. It may be difficult to show inhibition of sodium transport by trimethoprim in perfused distal tubules because most of the sodium absorption by this nephron segment traverses pathways that are insensitive to amiloride [22]. A change in net sodium flux through an amiloride-sensitive pathway can be masked by variations in salt absorption through other transport pathways. In contrast, sodium absorption downstream along the cortical collecting duct is mediated predominantly by an amiloride-sensitive pathway. Effects of trimethoprim on renal sodium transport along the collecting duct may lead to natriuresis and salt wasting. Treatment with trimethoprim-sulfamethoxazole has been associated with hyponatremia in previous reports [5], but this effect was attributed to the free water infused during drug administration rather than to a direct effect of the drug. Hyponatremia may occur in more than 50% of patients with AIDS and may be associated with salt wasting [3]. Although many factors including inappropriate release of antidiuretic hormone, adrenocortical insufficiency, and renal tubular dysfunction contribute to hyponatremia and salt wasting, our results suggest that trimethoprim may also cause salt wasting and hyponatremia. Even when trimethoprim itself does not lead to disorders of sodium or fluid balance, the administration of this dihydrofolate reductase inhibitor may exacerbate or unmask preexisting abnormalities.
Previous results indicating a higher incidence of hyperkalemia in patients treated with trimethoprim-dapsone were interpreted [5] as indicating that dapsone alters potassium metabolism. Other results, however, suggest an alternative explanation. Plasma trimethoprim concentrations are 48% higher in patients receiving trimethoprim-dapsone compared with those receiving trimethoprim-sulfamethoxazole and are thought to be related to dapsone-induced decreases of trimethoprim metabolism by the liver [10, 24]. The higher plasma trimethoprim levels would increase trimethoprim concentration in tubule fluid and could lead to a more complete inhibition of renal potassium excretion.
Our data indicate that high-dose trimethoprim (20 mg/kg per day) impairs renal potassium excretion and leads to an increase in serum potassium concentration. The effect of lower doses on potassium metabolism was not studied. However, even when the serum potassium concentration is not more than 5 mmol/L, it appears from Figure 1 that in nearly all patients the serum potassium concentration was greater during trimethoprim treatment compared with the pretreatment value. After a single oral dose of 200 mg trimethoprim, the urinary concentration of trimethoprim may reach 320 g/mL (1.1 mmol/L) [25]. Figure 4 shows, however, that a 10-fold lower dose of trimethoprim (0.1 mmol/L) in the lumen of the distal tubule is sufficient to inhibit the transepithelial voltage by about one half of the maximal level. Although trimethoprim concentrations in tubule fluid during treatment with standard doses (160 mg trimethoprim twice daily) may not cause frank hyperkalemia in otherwise normal adults, such treatment may predispose to hyperkalemia when trimethoprim is administered to patients with underlying disorders of potassium metabolism, such as hyporeninemic hypoaldosteronism.
Portions of this work were presented at the 25th meeting of the American Society of Nephrology and were published in abstract form (J Am Soc Nephrology. 1992; 3:322).
- Copyright 2004 by the American College of Physicians
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