Shyan-Yih Chou

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

Renal Hemodynamics in Acute Unilateral Ureteral Obstruction: Contribution of Endothelium-Derived Relaxing Factor

The increase in ureteral pressure after acute unilateral ureteral obstruction (UUO) is associated with an initial increase in renal blood flow (RBF). The present study examines the role of nitric oxide, a major endothelium-derived relaxing factor (EDRF), in UUO-induced renal hyperemia in anesthetized dogs. In Group 1, vehicle solution was infused into the left renal artery. In Group 2, nitric oxide formation from L-arginine was competitively inhibited by intrarenal infusion of N omega-monomethyl-L-arginine (L-NMMA) (50 micrograms/kg./min.) before UUO. In Group 3, L-arginine (2 mg./kg./min.) was infused together with L-NMMA (50 micrograms/kg./min.) into the renal artery. After UUO, ureteral pressure increased in all groups, averaging 69 mm.Hg. In Group 1, RBF at 10 and 20 minutes after UUO increased 7.9 +/- 1.6% and 16.5 +/- 5.2%, respectively, significantly greater than in Group 2 (1.2 +/- 1.6% and 2.4 +/- 1.5%). After L-NMMA was discontinued in Group 2, RBF increased 17%, reaching a level similar to that in Group 1. In Group 3, L-arginine infusion abolished the effects of L-NMMA, and RBF was similar to that in Group 1 at all postobstructive intervals. Our data indicate that release of nitric oxide in the kidney is augmented by UUO and mediates the early renal hyperemia induced by UUO.

Renal actions of endothelin-1 and endothelin-3: Interactions with the prostaglandin system and nitric oxide

Endothelins (ET) possess both vasodilatory and vasoconstrictive properties. The renal actions of ET-1 and ET-3, as well as in vivo interactions of these two isopeptides with the prostaglandin and endothelium-derived relaxation factor/nitric oxide systems were studied in anesthetized dogs. The ETs were infused intrarenally at doses not affecting systemic hemodynamics. Both ET-1 and ET-3 induced an early transient renal vasodilation, followed by a prolonged vasoconstriction. Inhibition of nitric oxide synthase with NG-monomethyl-L-arginine completely abolished the renal vasodilation induced by either ET-1 or ET-3 and enhanced the vasoconstriction. Endothelin-1 was associated with an increase in the renal release of prostacyclin, while urinary thromboxane A2 was increased after ET-3 administration. Inhibition of cyclooxygenase (with indomethacin) augmented the renal vasoconstriction induced by ET-1, but inhibition of cyclooxygenase (with meclofenamate) abolished the ET-3-evoked vasoconstriction. Endothelin-1 showed little effects on urinary water and sodium excretion; however, ET-3 displayed significant diuretic and natriuretic effects, which were inhibited by nitric oxide synthase inhibition. These findings suggest that these two isopeptides activate the endothelial endothelium-derived relaxation factor/nitric oxide system, which elicits early renal vasodilation, whereas direct effects on the vascular smooth muscle leads to vasoconstriction. Endothelin-3 causes diuresis and natriuresis, possibly by inducing release of nitric oxide in medullary collecting duct cells.

Atrial Natriuretic Peptide in Patients with Obstructive Uropathy

Renal response to release of bilateral ureteral obstruction resembles that to intravenous administration of atrial natriuretic peptide. In a prospective study we measured plasma atrial natriuretic peptide levels before and serially after relief of obstruction in 9 patients (mean age 65 +/- 2 years old) with bilateral ureteral obstruction and azotemia. Obstruction was documented by renal ultrasonography. Before relief of obstruction blood urea nitrogen and serum creatinine levels were 85 +/- 18 (mean +/- standard error) and 8.2 +/- 1.3 mg. per dl., respectively, accompanied by metabolic acidosis but not hyperkalemia. Mean plasma atrial natriuretic peptide (measured by radioimmunoassay) was 129 +/- 28, which was markedly elevated compared to 46 +/- 7 pg. per ml. in 7 age-matched control subjects (p less than 0.01). After relief of obstruction, prominent post-obstructive diuresis and natriuresis ensued; the plasma atrial natriuretic peptide level progressively decreased to that noted in the control group, accompanied by improvement in renal function, and diminishing diuresis and natriuresis. These findings were associated with a significant weight loss and an increase in plasma renin activity (from a mean of 1.57 +/- 0.68 to 5.27 +/- 1.82 ng. per ml. per hour, p less than 0.01). These results suggest that atrial natriuretic peptide release is augmented in patients with bilateral ureteral obstruction and azotemia, probably due to hypervolemia, and may contribute to post-obstructive diuresis and natriuresis.

Atorvastatin Ameliorates Tubulointerstitial Fibrosis and Protects Renal Function in Chronic Partial Ureteral Obstruction Cases

PURPOSE Tubulointerstitial fibrosis, the histological feature of chronic obstructive nephropathy, is delineated in complete unilateral ureteral obstruction models. Histological changes during chronic partial ureteral obstruction are not well studied. We describe changes in a rat model of partial ureteral obstruction. We examined the effects of atorvastatin on histological alterations, fibrosis and function in this model. MATERIALS AND METHODS All rats underwent right nephrectomy. To create partial ureteral obstruction the left ureter was incorporated into the psoas muscle, which was split and reapproximated. Excretory urogram, histology, Western blot of alpha-smooth muscle actin and renal clearance were examined in rats with sham, 14-day or 30-day partial ureteral obstruction. Obstructed rats received a regular or a diet supplemented with 50 mg/kg body weight atorvastatin per day. RESULTS At 14 days of partial ureteral obstruction pyelogram showed hydronephrosis, which was more pronounced on obstruction day 30. Histological studies on obstruction days 14 and 30 revealed tubulointerstitial fibrosis in the medulla and cortex. Atorvastatin significantly decreased tubulointerstitial fibrosis seen in alpha-smooth muscle actin expression. On obstruction day 14 or 30 the glomerular filtration rate in rats on a regular diet was significantly lower than in sham PUO rats or rats on atorvastatin. CONCLUSIONS This model of partial ureteral obstruction enables chronic studies of morphological and histological changes of the obstructed kidney. It showed progressive fibrosis and decreased filtration function. Atorvastatin ameliorated fibrosis and helped preserve kidney filtration function.

Effects of Acetazolamide on Proximal Tubule Cl, Na, and HCO3 Transport in Normal and Acidotic Dogs during Distal Blockade

It has been suggested that the establishment of a tubular fluid to plasma chloride gradient in the late proximal tubule by the reabsorption of bicarbonate (and other anions) in the early proximal tubule is responsible for a significant part of sodium chloride and water reabsorption in the proximal tubule. In the present study the effects of acetazolamide on proximal tubule water and electrolyte excretion were examined in 6 normal dogs and 10 chronic ammonium chloride-loaded dogs during distal blockade produced by ethacrynic acid and chlorothiazide administration. During distal blockade control urine/plasma osmolality and urine/plasma sodium were close to unity in all experiments. Urine/plasma chloride and urine/plasma bicarbonate were 1.21+/-0.02 and 0.75+/-0.07 in normal and 1.24+/-0.01 and 0.04+/-0.01 in acidotic dogs, respectively. After the administration of acetazolamide (20 mg/kg i.v.), there was a significant increase in urine flow, absolute and fractional excretion of sodium, bicarbonate, and chloride in all animals. Associated with these effects, urine/plasma osmolality and urine/plasma sodium remained unchanged but urine/plasma chloride decreased significantly to 1.15+/-0.01 in normal and to 1.19+/-0.01 in acidotic dogs. In acidotic dogs there was a significant correlation between the increase in bicarbonate, sodium, or chloride excretion after acetazolamide and the plasma bicarbonate level (range 6.8-12.5 meq/liter). These data demonstrate a significant effect of acetazolamide on bicarbonate, sodium, and chloride reabsorption in the proximal tubule even in the face of severe acidosis. Moreover, the data suggest that the decrease in chloride reabsorption (and accompanying sodium) after acetazolamide is related to the decrease in bicarbonate reabsorption and the associated decrease in the transtubular chloride gradient.

Atorvastatin protects renal function in the rat with acute unilateral ureteral obstruction.

OBJECTIVES To examine the effects of atorvastatin on renal hemodynamics and urinary microalbumin levels in rats with acute unilateral ureteral obstruction (UUO). Previous studies have demonstrated that treatment with statins attenuated renal structural damages in rodents with chronic UUO. However, it is not known whether statins afford protection of renal function. METHODS UUO was created by ligation of the left ureter in rats maintained on a regular diet or the same diet but supplemented with atorvastatin (50 mg/kg/d) for 2 weeks. Renal clearance experiments were performed after release of UUO at 1 hour, 6 hours, or 12 hours. RESULTS Atorvastatin treatment lowered plasma triglyceride but not cholesterol levels. Both glomerular filtration rate and effective renal plasma flow were significantly greater in atorvastatintreated rats after release of UUO at 1 hour, 6 hours, and 12 hours. Significant reduction of urinary microalbumin to creatinine ratios occurred in the atorvastatin-treated group at 12 hours but not earlier. CONCLUSIONS Atorvastatin treatment affords protection of renal function in acute UUO and reduces urinary microalbumin levels without lowering cholesterol levels. This pleiotropic action of atorvastatin on preservation of renal hemodynamics may be important in attenuating subsequent renal structural injury in chronic UUO.

Evidence for enhanced distal tubule sodium reabsorption in chronic salt-depleted dogs.

In order to assess the renal tubular site(s) at which sodium reabsorption is enhanced in chronic sodium-depletion, seven normal dogs, six salt-depleted dogs, and three normal dogs receiving aldosterone were studied during a steady-state water diuresis under Pentothal anesthesia and during progressive hypotonic saline diuresis. For both maintenance of the water diuresis and progressive hypotonic saline diuresis 0.45% NaCl was used. During the steady state water diuresis delivery of sodium to the diluting segment of the nephron as approximated by solute-free water clearance + sodium clearance/glomerular filtration rate (CH2O + CNa/GFR) was significantly lower in salt-depleted dogs compared to normal dogs with or without aldosterone. During progressive hypotonic saline infusion fractional free water excretion (CH2O/GFR) was similar in all three groups as CH2O + CNa/GFR increased up to 12-14 ml/min-100 ml GFR. Thereafter, CH2O/GFR continued to rise in virtually a straight line in salt-depleted dogs but leveled off in normal dogs with or without aldosterone. These data demonstrate that enhanced sodium reabsorption in the diluting segment of the nephron is an important determinant of the renal sodium retention in chronic extracellular volume contraction in dogs in addition to confirming the presence of increased proximal tubule sodium reabsorption in these animals.

REGIONAL EXPRESSION OF INDUCIBLE NITRIC OXIDE SYNTHASE IN THE KIDNEY IN DOGS WITH UNILATERAL URETERAL OBSTRUCTION

PURPOSE In the early stage of unilateral ureteral obstruction total renal blood flow increases but medullary blood flow decreases, exacerbating medullary tissue hypoxia. We examined the expression of inducible nitric oxide synthase, a product of a hypoxia sensitive gene, in the cortex and medulla in dogs with unilateral ureteral obstruction for 21 hours. MATERIALS AND METHODS Hemodynamic and clearance experiments were performed after release of ureteral obstruction in 6 dogs with unilateral ureteral obstruction, followed by Western blot analysis of nitric oxide synthase and immunohistochemistry. RESULTS Ureteral obstruction raised mean ureteral pressure plus or minus standard error to 35.0 +/- 7.2 mm. Hg. In dogs with unilateral ureteral obstruction mean renal blood flow was 116 +/- 10 ml. per minute, lower than the 213 +/- 22 ml. per minute in sham operated dogs (p <0.01). After unilateral ureteral obstruction release the mean glomerular filtration rate was 9.5 +/- 2.1 ml. per minute, lower than the 27.3 +/- 1.8 ml. per minute in the contralateral unobstructed kidney (p <0.01). Western blot analysis showed that mean nitric oxide synthase/beta-actin in the cortex of the obstructed kidney was 0.04 +/- 0.01 densitometry units, lower than 0.11 +/- 0.02 densitometry units in the unobstructed contralateral kidney (p <0.05). In contrast, mean nitric oxide synthase/beta-actin in the medulla of the obstructed kidney was 1.29 +/- 0.33 densitometry units, greater than the 0.34 +/- 0.03 densitometry units in the unobstructed kidney (p <0.05). Immunohistochemistry revealed that the increased expression of nitric oxide synthase protein was localized to the endothelium of the vasa recta. CONCLUSIONS Unilateral ureteral obstruction enhances nitric oxide synthase expression in the medulla but not in the cortex. This increased expression in the medulla may be the result of increased medullary hypoxia in unilateral ureteral obstruction, possibly contributing to medullary hyperemia after unilateral ureteral obstruction release.

Retroperitoneal fibrosis presenting as spontaneously reversible renal failure.

Three patients are reported who presented with severe oliguric renal failure due to retroperitoneal fibrosis and obstructive uropathy in whom spontaneous diuresis and recovery of renal function took place, a course resembling acute tubular necrosis. There were, however, several clinical and laboratory findings that provided clues to the presence of obstructive uropathy. Two of the three patients had low back or abdominal pain. All three patients presented with anemia and significant hyperkalemic, hyperchloremic metabolic acidosis with only a small increase in anion gap and two of the patients had an inappropriately high urine pH. Neither tubular cell casts nor pigmented granular casts were identified in the urine in any of the patients. In all three patients the urine output increased from oliguric levels to 1400 - 2000 ml/day within 1 day associated with rapidly improving renal function. This report demonstrates and reinforces the need to rule out obstruction in all patients with renal failure of unknown etiology and adds retroperitoneal fibrosis to the list of diseases associated with renal failure and spontaneous recovery.