Jerome G. Porush

Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial of Patients with Type 2 Diabetes and Overt Nephropathy

Context Previously published results of this randomized, double-blind trial showed that high-risk patients with type 2 diabetic nephropathy had better renal protection if they were treated with irbesartan rather than amlodipine in addition to conventional antihypertensive therapy. Contribution These detailed analyses showed no differences in overall cardiovascular outcomes between patients given irbesartan or amlodipine. Fewer patients given irbesartan had heart failure and fewer patients given amlodipine had heart attacks. Cautions The trial had limited power to detect important differences between groups in mortality or strokes, and most patients received several antihypertensive agents. The Editors Patients with diabetes have an increased risk for cardiovascular complications and death (1). Studies that analyzed the effects of inhibition of the reninangiotensin system on the risk for cardiovascular complications included a substantial number of patients with diabetes (2-5) or were done exclusively in patients with diabetes (6-8). The meta-analysis of these studies (9), the analysis of the diabetic cohorts in the Heart Outcomes Prevention Evaluation (HOPE) study (2), and the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial (5) demonstrated that angiotensin-converting enzyme (ACE) inhibitors (2, 9) and angiotensin-receptor blockers (5) had a statistically significant advantage over placebo or alternative agents in decreasing the risk for several cardiovascular events. These studies randomly assigned few patients with renal involvement and overt proteinuria. Overt proteinuria occurred in fewer than 20% of the 470 patients in the Appropriate Blood Pressure Control in Diabetes (ABCD) trial (6), and only 11% of the 1195 patients in the LIFE trial (5). The Captopril Prevention Project (CAPP) (3) and the Swedish Trial in Old Patients with Hypertension-2 (STOP Hypertension-2) (4) did not state the number of patients with diabetes and overt proteinuria. There were no such patients in the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET) (7), and patients with dipstick-positive albuminuria were excluded from the HOPE trial (2). Since proteinuria is an independent risk factor for cardiovascular disease (10, 11), the data obtained in the aforementioned trials cannot be extrapolated to patients with type 2 diabetes and overt nephropathy. Trials performed in such patients have reported a blood pressureindependent effect of two different angiotensin-receptor blocker agents to protect against nephropathy (12, 13) without a change in all-cause mortality. Apart from studies in heart failure, few cardiovascular data exist for receptor blockers compared with either placebo or calcium-channel blockers. We report on the analysis of the cardiovascular end points that were monitored as secondary end points in the Irbesartan Diabetic Nephropathy Trial (IDNT) (12) and assess whether an angiotensin II receptor blocker or a calcium-channel blocker alters the risk for cardiovascular events beyond those observed by blood pressure reduction alone without such agents. Methods Patients The IDNT was a randomized, double-blind study on the effect of treatment with irbesartan or amlodipine compared with placebo in patients with type 2 diabetic nephropathy. The protocol of this study has been published (12, 14). Entry criteria required that patients be between 30 and 70 years of age and have type 2 diabetes mellitus and overt nephropathy, as evidenced by current treatment for hypertension or by a protein excretion rate of 900 mg/d or greater, serum creatinine level of 89 mol/L (1.0 mg/dL) to 266 mol/L (3.0 mg/dL) in women or of 106 mol/L (1.2 mg/dL) to 266 mol/L (3.0 mg/dL) in men, and baseline seated blood pressure greater than 135/85 mm Hg. The institutional review boards of each center approved the protocol. All patients gave written informed consent. Treatment and Randomization Patients were randomly assigned centrally by computer to receive treatment with irbesartan, 300 mg/d (Avapro, Bristol-Myers Squibb, Princeton, New Jersey); amlodipine, 10 mg/d (Norvasc, Pfizer, New York); or matched placebo. To minimize any center effect, randomization was blocked by center. All patients had blood pressure controlled to the same blood pressure goal of less than 135/85 mm Hg by using antihypertensive agents other than ACE inhibitors, angiotensin II receptor blocking agents, or calcium-channel blockers. For the analysis of cardiovascular end points, patients were followed to initiation of treatment for end-stage renal failure (dialysis or renal transplantation), reaching a serum creatinine level of 530.4 mol/L (6.0 mg/dL) or higher, death, or administrative censoring in December 2000. Outcomes We prospectively established cardiovascular outcomes, defined in the Appendix Table. Appendix Table. Classification for Fatal and Nonfatal Cardiovascular Events Ascertainment of Cardiovascular Events Information about hospitalizations and adverse events were screened at Bristol-Myers Squibb, Princeton, New Jersey, by trained, blinded clinical research associates to identify potential cardiovascular events. Investigators used study forms to report and characterize all cardiovascular outcomes. For all potential events, records, including laboratory values, electrocardiograms, and radiographic reports were obtained for clarification. Since myocardial infarctions may go unrecognized, a central electrocardiogram reading center was established at Brigham and Womens Hospital, Boston, Massachusetts, where two cardiologists reviewed every electrocardiogram. Electrocardiography was performed at baseline, 6 months, 12 months, and annually thereafter. A total of 5698 electrocardiograms were reviewed at the center. When a new Q-wave infarction was found, the cardiologists asked whether a clinical myocardial infarction was reported. Even when myocardial infarctions were not clinically reported, these Q-wave infarctions were adjudicated as myocardial infarctions. Adjudication of Cardiovascular Events Investigators at each center reported cardiovascular events, defined in the Appendix Table. The information on all potential events was referred to one member of the Outcomes Confirmation and Classification Committee (Appendix). If the committee member agreed with the judgment of the center investigator, their combined judgment was accepted. If the center investigator and the committee member differed, the case material was reviewed by the membership of the committee, whose decision was accepted. Deaths were adjudicated by a Mortality Committee (Appendix). Each death was reviewed by two members of the committee and presented to the membership, whose decision was accepted as final. Statistical Analysis For graphical presentation (Figure) and overall testing for statistically significant differences among the three treatment groups, time to the first occurrence of either a specific cardiovascular outcome or one of the composite outcomes was analyzed by product-limit survival curves and the log-rank test (15). We used proportional hazards modeling to determine hazard ratios. For the cardiovascular death outcome, which could occur only once, we used the standard proportional hazards model (16), with treatment assignment as the only independent covariate. For other cardiovascular outcomes, which could occur more than once, we used the AndersonGill formulation of the proportional hazards model (17), in which patients are considered at risk for the first event from randomization to the first event, at risk for the second event from the day following the first event to the second event, and so forth, permitting use of all the data. In accordance with the method of Lee and colleagues (18), we used a robust variance estimate that accounts for the possibility of correlation of risk for several events within a patient. We believed that occurrence of a first event of a given type increases the likelihood of a subsequent similar event. Therefore, both treatment assignment and a time-dependent covariate indicating whether the event was the first of its type or a subsequent event were included in these analyses. The time-dependent covariate was statistically significant in each case, confirming the above assumption. There was no statistically significant interaction between treatment and the time-dependent covariatethe effects of treatment assignment were similar for first and subsequent eventsand inclusion of the time-dependent covariate did not change either the estimates of the treatment effect or their statistical significances. Figure. Time to first cardiovascular composite event as a function of treatment assignment. P Data management and computations were done by using SAS software for Windows, version 8 (SAS Institute, Inc., Cary, North Carolina), or S-Plus for Windows, version 6.0 (Insightful Corp., Seattle, Washington). Statistical tests were two sided. A P value of 0.05 or less, unadjusted for the multiple comparisons, was considered statistically significant. Role of the Funding Sources The funding sources were involved in the data collection but not in the analysis or interpretation or the decision to submit the manuscript for publication. Results The baseline characteristics of the three groups are shown in Table 1. A flow diagram of the study is shown in the Appendix Figure. Table 1. Baseline Characteristics Appendix Figure. Flow diagram for the Irbesartan Diabetic Nephropathy Trial. Clinical Management During the study, the blood pressure decreased from the baseline values to 140/77 mm Hg in the irbesartan group, 141/77 mm Hg in the amlodipine group, and 144/80 mm Hg in the placebo group. Blood pressure in the two active treatment groups did not differ; values in both groups were statistically significantly lower than in the placebo group (P = 0.001). The distribution of nonstudy drugs used to achieve the target blood pressure was similar i

Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial.

Elevated arterial pressure enhances the risk for cardiovascular (CV) events in patients with diabetic nephropathy. The optimal BP and the component of the elevated BP that affect the risk have not been defined. A post hoc analysis was performed to assess the impact of achieved systolic, diastolic, and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial (IDNT) and had a baseline serum creatinine above the normal range, up to 266 micromol/L (3.0 mg/dL), 24-h urine protein >900 mg/d, and at least 6 mo of follow-up. Patients were randomized to irbesartan, amlodipine, or placebo, with other antihypertensive agents to a BP goal of < or =135/85 mmHg. Progressively lower achieved systolic BP (SBP) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure (CHF) but not myocardial infarctions (MI). A SBP below this threshold was associated with increased risk for CV deaths and CHF events. Achieved diastolic BP <85 mmHg was associated with a trend to increase in all-cause mortality, significant increase in MI, but decreased risk for strokes. Increased pulse pressure predicted increased all-cause mortality, CV mortality, MI, and CHF. It is concluded that achieved SBP approaching 120 mmHg and diastolic BP of 85 mmHg are associated with the best protection against CV events in these patients. BP < or =120/85 may be associated with an increase in CV events.

Achievement and Safety of a Low Blood Pressure Goal in Chronic Renal Disease: The Modification of Diet in Renal Disease Study Group*

The Modification of Diet in Renal Disease Study showed a beneficial effect of a lower-than-usual blood pressure (BP) goal on the progression of renal disease in patients with proteinuria. The purpose of the present analyses was to examine the achieved BP, baseline characteristics that helped or hindered achievement of the BP goals, and safety of the BP interventions. Five hundred eighty-five patients with baseline glomerular filtration rate between 13 and 55 mL/min per 1.73 m2 (0.22 to 0.92 mL/s per 1.73 m2) were randomly assigned to either a usual or low BP goal (mean arterial pressure < or = 107 or < or = 92 mm Hg, respectively). Few patients had a history of cardiovascular disease. All antihypertensive agents were permitted, but angiotensin-converting enzyme inhibitors (with or without diuretics) followed by calcium channel blockers were preferred. The mean (+/- SD) of the mean arterial pressures during follow-up in the low and usual BP groups was 93.0 +/- 7.3 and 97.7 +/- 7.7 mm Hg, respectively. Follow-up BP was significantly higher in subgroups of patients with preexisting hypertension, baseline mean arterial pressure > 92 mm Hg, a diagnosis of polycystic kidney disease or glomerular diseases, baseline urinary protein excretion > 1 g/d, age > or = 61 years, and black race. The frequency of medication changes and incidence of symptoms of low BP were greater in the low BP group, but there were no significant differences between BP groups in stop points, hospitalizations, or death. When data from both groups were combined, each 1-mm Hg increase in follow-up systolic BP was associated with a 1.35-times greater risk of hospitalization for cardiovascular or cerebrovascular disease. Lower BP than usually recommended for the prevention of cardiovascular disease is achievable by several medication regimens without serious adverse effects in patients with chronic renal disease without cardiovascular disease. For patients with urinary protein excretion > 1 g/d, target BP should be a mean arterial pressure of < or = 92 mm Hg, equivalent to 125/75 mm Hg.

Prevalence of hypertension in 1,795 subjects with chronic renal disease: The modification of diet in renal disease study baseline cohort

The Modification of Diet in Renal Disease Study was a multicenter trial of the effect of protein restriction and strict blood pressure control on the progression rate of chronic renal failure of multiple causes. At the first baseline visit, 1,795 screened patients with renal disease had blood pressure measured, antihypertensive medications recorded, glomerular filtration rate (GFR) determined by 125I-iothalamate clearance, a nutritional assessment, and a 24-hour urine collection to determine sodium and potassium levels. A total of 1,494 patients in this cohort were classified as hypertensive (83%) and the remainder (301 patients) as nonhypertensive. Ninety-one percent of the hypertensive subjects were on treatment, 54% being controlled to a blood pressure of < or = 140/90 mm Hg. To better understand the factors that contribute to the development of hypertension in chronic renal disease, some determinants of the prevalence of hypertension in this cohort were investigated. Compared with normotensive subjects, hypertensive patients were older (51.2 +/- 12.7 years v 46.6 +/- 13.1 years [mean +/- SD]), had a higher body mass index (BMI; 27.5 +/- 4.7 kg/m2 v 25.4 +/- 4.2 kg/m2), and had a lower GFR (37.8 +/- 19.6 mL/min/1.73 m2 v 50.1 +/- 25 mL/min/1.73 m2). All these differences were significant (P < 0.01). The prevalence of hypertension was significantly higher for men than for women (86% v 80%; P = 0.001), and for blacks than for whites (93% v 81%; P < 0.001). The prevalence of hypertension was higher in subjects with glomerular disease than in those with tubulointerstitial disease (85% v 62.6%; P < 0.001). The prevalence of hypertension varied inversely with GFR (from 66% at a GFR of 83 mL/min/1.73 m2 to 95% at a GFR of 12 mL/min/1.73 m2). The prevalence of hypertension varied directly with BMI (from 70% with a BMI at the 10th percentile to 94% with a BMI at the 97th percentile). This relationship was independent of GFR. Multiple logistic regression analysis showed five predictors in decreasing order of significance as determined by chi-square values: GFR, 83.2; BMI, 36.7; black race, 19.9; increasing age, 14.5 (all P < 0.001); and male gender, 5.1 (P = 0.024). Salt intake was not a determinant of blood pressure status. These results confirm previous reports indicating that hypertension in renal disease is determined by the level of renal function. For the first time, three factors known to predict blood pressure levels in populations with normal renal function were also shown to be determinants of blood pressure in renal disease: BMI, black race, and age. In addition, the data suggest that hypertension is inadequately treated in more than half of patients with chronic renal disease in the United States.

Treatment of Idiopathic Membranous Nephropathy

In a retrospective study of the effect of treatment in biopsy-proved idiopathic membranous nephropathy, 91 adults and 12 children were followed for periods up to 29 years after clinical onset (mean, 6.5 years). Forty-four were treated with corticosteroids, 15 with corticosteroids and immunosuppressants; 44 had no treatment and served as a control group. Clinical cure and improvement were significantly greater in the treated than in the nontreated group (P less than 0.01). The recurrence rate, occurrence of renal failure and probability of death were significantly greater in the nontreated group, although some of these patients eventually showed improvement. Prognosis was better in patients who responded to therapy. These data strongly suggest that steroid therapy is beneficial in patients with membranous nephropathy.

Nephrolithiasis as a Complication of Ulcerative Colitis and Regional Enteritis

Excerpt The coexistence of gastrointestinal disease and renal calculi has been noted in few clinical entities. Calcium urolithiasis and upper gastrointestinal symptoms with occasional frank peptic ...

Comparison of nifedipine and propranolol used in combination with diuretics for the treatment of hypertension.

One hundred patients participated in a double-blind, randomized study to compare the antihypertensive efficacy of sustained-release nifedipine and propranolol in hypertensive patients whose diastolic blood pressure exceeded 95 mm Hg while receiving diuretic therapy. Nifedipine (mean dose, 79.6 mg per day) decreased blood pressure by 11.4/10.5 mm Hg; propranolol (mean dose, 198.4 mg per day) decreased blood pressure by 13.5/10.3 mm Hg. Reduction of diastolic blood pressure to below 90 mm Hg was achieved in 63 percent of nifedipine-treated patients and in 57 percent of propranolol-treated patients. Nifedipine therapy was associated with an increase in high-density lipoprotein cholesterol levels and a decrease in serum triglyceride levels. In contrast, propranolol therapy was associated with a decrease in high-density lipoprotein cholesterol levels and an increase in serum triglyceride levels. Nifedipine is as effective as propranolol in the treatment of patients with mild to moderate hypertension whose blood pressure is inadequately controlled by diuretic therapy.

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 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.

Paraproteinemia and cryoglobulinemia associated with atypical glomerulonephritis and the nephrotic syndrome

Abstract A patient with an atypical from of glomerulonephritis and the nephrotic syndrome, whose serum contained a paraprotein and mixed cryoglobulin and had rheumatoid factor activity, is described. The nephritis was characterized by the presence of numerous intracellular crystals, wire loops and hyaline thrombi in the glomeruli. It appears reasonable to assume that the crystals and other deposits represent precipitated protein, probably related to the paraprotein and cryoglobulin in the serum. It is suggested that the crystals are derived from the paraprotein and that the mixed cryoglobulins (possibly antigen-antibody complexes) give rise to the deposits seen along the basement membrane.