Ira W. Reiser

Trimethoprim-sulfamethoxazole induces reversible hyperkalemia.

Table. SI Units and Abbreviation Hyperkalemia in patients infected with the human immunodeficiency virus (HIV) [1, 2] has been attributed to various factors including adrenal insufficiency [3, 4], hyporenin-hypoaldosteronism [5], and pentamidine therapy [6]. Recently, two case reports described the development of marked hyperkalemia and hyponatremia coincident with high-dose trimethoprim-sulfamethoxazole (Tmp-Smx) therapy in HIV-infected patients [7, 8]. In patients with the acquired immunodeficiency syndrome (AIDS) who were receiving Tmp-Smx therapy for Pneumocystis carinii pneumonia, Murphy and colleagues [8] reported these electrolyte abnormalities on the ninth day. All abnormalities resolved spontaneously after discontinuation of Tmp-Smx. Both glucocorticoid and mineralocorticoid systems were assessed in this patient and were found to be normal. The authors attributed these electrolyte disturbances to the Tmp-Smx therapy. At our institution, we have also observed several HIV-infected patients in whom hyperkalemia developed approximately 9 to 10 days after initiation of high-dose Tmp-Smx therapy for the treatment of P. carinii pneumonia. The hyperkalemia was often associated with hyponatremia and mild azotemia and universally resolved after discontinuation of Tmp-Smx. These observations provided the impetus for a retrospective analysis, comparing a cohort of HIV-infected patients who received high dose Tmp-Smx with those who did not. Methods The hospital records of all HIV-infected patients who were hospitalized and treated for P. carinii pneumonia at The Brookdale Hospital Medical Center from December 1989 to February 1991 were reviewed. Those patients who received Tmp-Smx either intravenously or orally at doses of 20 mg/kg per day (trimethoprim) and 100 mg/kg per day (sulfamethoxazole) (the accepted protocol for the treatment of P. carinii infection) for more than 6 days were studied. Trimethoprim-sulfamethoxazole was dispensed in generic forms. Patients who received potassium supplements or any medication known to alter potassium homeostasis and metabolism or renal function were excluded. Patients who had renal insufficiency, as defined by a serum creatinine level of 186 mol/L or more, and those with significant diarrhea or vomiting were also excluded from the study. All patients who met our inclusion criteria formed the study group. The records of all HIV-infected patients who were hospitalized during the same period but who did not receive Tmp-Smx served as the control group. These patients met the same inclusion and exclusion criteria as the study group. All patients received a normal hospital diet, containing 4 g of sodium and 3 to 3.5 g of potassium. We recorded the age, sex, risk factors for HIV disease and other infections, and medications taken both before and during hospitalization for each patient who met the study criteria. The serum potassium concentrations during the first 2 weeks of Tmp-Smx therapy were recorded. In addition to serum potassium concentration, the blood urea nitrogen, serum creatinine, sodium, carbon dioxide content, cholesterol, creatine kinase, lactic dehydrogenase, albumin, arterial pH, hemoglobin, and weight were recorded when available. The same measurements were recorded in the control group as in the Tmp-Smx-treated group within 3 days of hospitalization and again as the averaged value observed on the ninth and tenth day of hospitalization (designated as the follow-up period). This interval was chosen because it represented the average period required for the peak serum potassium concentration to be observed in those patients treated with Tmp-Smx. All results are expressed as a mean standard error or as a mean with a 95% confidence interval (CI). The statistical significance of the difference was determined by paired or unpaired t-test. A P value of less than 0.05 was considered statistically significant. Results All patients tested positive for HIV by Western blot assay. Twenty-six patients who were not treated with Tmp-Smx met our study criteria and formed the control group. This group ranged between 22 and 61 years old (mean SE, 36.6 1.6 years). Twenty patients were men and six were women. Sixteen were black, eight were Hispanic, and two were white. Risk factors for HIV in the control group included intravenous drug abuse in 18, homosexuality in 2, multiple sexual partners in 2, and no known risk factors in 4. Twenty-five HIV-infected patients who received Tmp-Smx met our study criteria (treatment group). This group ranged between 22 and 52 years old (37.0 1.6 years). Twenty-one patients were men and four were women. Fourteen were black, 10 were Hispanic, and 1 was white. Risk factors for HIV included intravenous drug abuse in 15, homosexuality in 2, multiple sexual partners in 4, and no identifiable risk factors in 4. All 25 patients received Tmp-Smx at a dose of 20 mg/kg per day (trimethoprim) and 100 mg/kg per day (sulfamethoxazole) for more than 6 days for the treatment of P. carinii pneumonia. The diagnosis of P. carinii pneumonia was established by bronchoscopy in 18 patients and by clinical criteria in 7. The study drug was administered orally in 10 patients, intravenously in 5, and by both methods in the remaining 10 patients. Table 1 summarizes the clinical data obtained within 3 days after hospitalization in the control and treatment groups. No statistically significant differences were noted with respect to demographic or laboratory variables, except that the serum lactic dehydrogenase level was significantly higher in patients treated with Tmp-Smx. Table 1. Baseline Characteristics of Controls and Patients Treated with Trimethoprim-Sulfamethoxazole In the control group, no significant alterations were noted in any of the laboratory variables during the follow-up period. The serum potassium concentration during the follow-up period was 4.2 0.1 mmol/L, a value similar to the baseline value of 4.3 0.1 mmol/L. In the Tmp-Smx-treated group, the serum potassium level before therapy was 4.1 0.1 mmol/L and increased significantly by 1.1 mmol/L (CI, 0.8 to 1.5 mmol/L) to a peak level of 5.2 0.1 mmol/L 9.8 0.5 days after initiation of Tmp-Smx therapy (Figure 1). Of these 25 patients, 19 had an increase in their serum potassium concentration of 1.0 mmol/L or more from their baseline value. Seven patients had a serum potassium concentration greater than 5.5 mmol/L; three of these patients had a maximum potassium level greater than 6.0 mmol/L, and in one patient the serum potassium reached 7.2 mmol/L. Two of the seven hyperkalemic patients required kayexalate therapy at an average dose of 60 g to correct the hyperkalemia. Serial potassium measurements both during and after discontinuation of Tmp-Smx therapy were available in five patients in whom no potassium-lowering agents were administered. The serum potassium concentration increased progressively during the course of the Tmp-Smx therapy and returned to baseline after discontinuing therapy (Figure 2). Figure 1. Changes in serum potassium concentrations with trimethoprim-sulfamethoxazole therapy. P Figure 2. Serial changes in serum potassium concentrations. dotted lines The laboratory results obtained within 1 day of initiating Tmp-Smx therapy and at the time of the peak recorded potassium concentration are summarized in Table 2. In the Tmp-Smx group, both the blood urea nitrogen and serum creatinine levels increased significantly, whereas the serum sodium and chloride concentrations decreased significantly. No other changes were noted during Tmp-Smx therapy; in particular, none of the patients manifested a significant change in carbon dioxide content, arterial blood pH, or body weight. In one patient, the renin-aldosterone system was assessed both before and after Tmp-Smx therapy. Before therapy, the serum potassium concentration was 4.6 mmol/L. The supine plasma renin activity and serum aldosterone level were 8.8 nmol/L per hour and 363.9 pmol/L and increased to 10.0 nmol/L per hour and 625.1 pmol/L, respectively, after the patient assumed an upright position for 2 hours. After 10 days of Tmp-Smx therapy, the serum potassium level increased to 5.7 mmol/L. The supine plasma renin activity and serum aldosterone level increased to 16.0 nmol/L per hour and 914.1 pmol/L and were 15.3 nmol/L per hour and 833.4 pmol/L, respectively, after the patient remained upright for 2 hours. Table 2. Plasma Values at the Initiation of Trimethoprim-Sulfamethoxazole Therapy and at the Time of Peak Hyperkalemia Discussion Within the last several years, a spectrum of glomerular, tubulointerstitial, and electrolyte disorders associated with AIDS and with the treatment of HIV-related disorders have been reported [1, 2, 9]. We observed that serum potassium levels increased significantly in patients with AIDS who were treated with high-dose Tmp-Smx therapy; these changes were associated with a decrease in serum sodium concentration and mild elevations in blood urea nitrogen and serum creatinine levels, typically occurring 9 to 10 days after the initiation of therapy. The increase in serum potassium level was usually disproportionate to the degree of azotemia that developed, suggesting that the high-dose Tmp-Smx therapy altered potassium homeostasis. This hypothesis is supported by the temporal relation between the initiation of Tmp-Smx therapy and the progressive increase in the serum potassium concentration and a progressive decline in the serum potassium concentration after discontinuation of therapy (see Figure 2). A control group of HIV-infected patients who did not receive Tmp-Smx had no alteration in the serum potassium concentration during the same period. Finally, other factors that could cause this electrolyte abnormality in these hospitalized patients were not evident, including specific measurements of the renin-aldosterone system in one patient. To date, Tmp-Smx has been associated with two major forms of nephrotoxicity. Acute

The Incidence and Epidemiology of Human Immunodeficiency Virus Infection in 320 Patients Treated in an Inner-City Hemodialysis Center

From January 1, 1986 through June 30, 1989, 320 maintenance hemodialysis patients treated at The Brookdale Hospital Medical Center were tested for the presence of antibody to the human immunodeficiency virus (HIV) using the enzyme-linked immunosorbent assay (ELISA) and Western blot assays. Thirty-nine patients (12%) tested positive for HIV antibody (HIV+) with both the ELISA and Western blot, 24 (62%) of whom were known intravenous drug abusers (IVDA). Of the remaining non-IVDA patients, unanticipated HIV+ results were found in 10 (25%). Thirty-four (87%) of the 39 HIV+ patients were asymptomatic at the start of the study, while two had acquired immunodeficiency syndrome (AIDS) and three others, AIDS-related complex (ARC). Four patients subsequently developed AIDS 20 +/- 4.9 weeks (range, 12 to 32) after testing, three of whom initially had ARC. One patient developed ARC 7 months after testing. Sixteen HIV+ patients died, including five of the six with AIDS, one with ARC, and two others from Mycobacterium tuberculosis. The eight other deaths were from causes unrelated to HIV disease and occurred 12 +/- 2.3 months (range, 1 to 24) after testing. Two HIV+ patients were lost to follow-up. Twenty-one HIV+ patients (54%) are alive and 20 (51%) asymptomatic 15 +/- 2.4 months (range, 1 to 42) after HIV testing. Thus, despite HIV positivity, 28 patients (72%) had an asymptomatic period lasting 14 +/- 1.9 months (range, 1 to 42). Seventy-two of the 281 HIV-negative (HIV-) patients died during the study. None of the HIV- patients manifested ARC or AIDS, confirming that there was no false-negative HIV test.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypercalcemia-Induced Hypokalemic Metabolic Alkalosis in a Multiple Myeloma Patient: The Risk of Furosemide Use.

Hypercalcemia is often seen in patients with malignancies, and in the past treatment for this has traditionally included loop diuretics. Clinically, patients with hypercalcemia frequently present with polyuria and volume contraction which may be further exacerbated by diuretic therapy. In the lab, hypercalcemia has been shown to activate the calcium-sensing receptor in the thick ascending limb of Henle and inactivate the 2 chloride sodium potassium co-transporter and induce a hypokalemic metabolic alkalosis, an effect similar to that of the loop diuretic furosemide. We now report what may well be the first clinical correlate of this laboratory finding in a patient who developed a hypokalemic metabolic alkalosis as a consequence of severe hypercalcemia due to multiple myeloma and whose metabolic derangement was corrected without the use of a loop diuretic which may have exacerbated the electrolyte abnormalities.

Evaluation of Renal Function and Proteinuria

When evaluating renal function, the clinician is oftentimes asked to estimate the glomerular filtration rate (GFR) and to determine whether the ability of the kidney to dilute and concentrate, acidify the urine, or function as a barrier to the excretion of protein is impaired. This chapter reviews each of these integral functions of the kidney and provides the clinician with a useful and practical approach to their assessment.