Edmund J. Lewis

THE EFFECT OF ANGIOTENSIN-CONVERTING-ENZYME INHIBITION ON DIABETIC NEPHROPATHY. THE COLLABORATIVE STUDY GROUP

BACKGROUND Renal function declines progressively in patients who have diabetic nephropathy, and the decline may be slowed by antihypertensive drugs. The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy. METHODS We performed a randomized, controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was > or = 500 mg per day and the serum creatinine concentration was < or = 2.5 mg per deciliter (221 mumol per liter). Blood-pressure goals were defined to achieve control during a median follow-up of three years. The primary end point was a doubling of the base-line serum creatinine concentration. RESULTS Two hundred seven patients received captopril, and 202 placebo. Serum creatinine concentrations doubled in 25 patients in the captopril group, as compared with 43 patients in the placebo group (P = 0.007). The associated reductions in risk of a doubling of the serum creatinine concentration were 48 percent in the captopril group as a whole, 76 percent in the subgroup with a baseline serum creatinine concentration of 2.0 mg per deciliter (177 mumol per liter), 55 percent in the subgroup with a concentration of 1.5 mg per deciliter (133 mumol per liter), and 17 percent in the subgroup with a concentration of 1.0 mg per deciliter (88.4 mumol per liter). The mean (+/- SD) rate of decline in creatinine clearance was 11 +/- 21 percent per year in the captopril group and 17 +/- 20 percent per year in the placebo group (P = 0.03). Among the patients whose base-line serum creatinine concentration was > or = 1.5 mg per deciliter, creatinine clearance declined at a rate of 23 +/- 25 percent per year in the captopril group and at a rate of 37 +/- 25 percent per year in the placebo group (P = 0.01). Captopril treatment was associated with a 50 percent reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small disparity in blood pressure between the groups. CONCLUSIONS Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone.

The Effect of Angiotensin-Converting-Enzyme Inhibition on Diabetic Nephropathy

Background Renal function declines progressively in patients who have diabetic nephropathy, and the decline may be slowed by antihypertensive drugs. The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy. Methods We performed a randomized, controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was ≥ 500 mg per day and the serum creatinine concentration was ≤ 2.5 mg per deciliter (221 μmol per liter). Blood-pressure goals were defined to achieve control during a median follow-up of three years. The primary end point was a doubling of the base-line serum creatinine concentration. Results Two hundred seven patients received captopril, and 202 placebo. Serum creatinine concentrations doubled in 25 patients in the captopril group, as compared with 43 patients in the placebo group (P =0.007). The associated reductions in risk...

Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy

BACKGROUND Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. METHODS We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months. RESULTS The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups. CONCLUSIONS Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].).

A Controlled Trial of Plasmapheresis Therapy in Severe Lupus Nephritis

BACKGROUND The prognosis of patients with systemic lupus erythematosus who have glomerulonephritis is poor, despite treatment with immunosuppressive therapy. Plasmapheresis therapy has been used, but there have been few controlled clinical observations of its efficacy. METHODS We carried out a randomized, controlled trial comparing a standard-therapy regimen of prednisone and cyclophosphamide (standard therapy) with a regimen of standard therapy plus plasmapheresis in 86 patients with severe lupus nephritis in 14 medical centers. The patients underwent plasmapheresis three times weekly for four weeks. Drug therapy was standardized, with strict adherence to nine detailed medical-management protocols. RESULTS Forty-six patients received standard therapy, and 40 patients received standard therapy plus plasmapheresis. The mean follow-up was 136 weeks. Six patients (13 percent) in the standard-therapy group and eight patients (20 percent) in the plasmapheresis group died. Renal failure developed in 8 patients (17 percent) in the standard-therapy group, as compared with 10 (25 percent) in the plasmapheresis group. Thirty patients (35 percent) reached stopping points--14 (30 percent) in the standard-therapy group and 16 (40 percent) in the plasmapheresis group. A similar number of patients in each group had a decrease in both the serum creatinine concentration and urinary protein excretion to approximately normal values. Patients treated with plasmapheresis had a significantly more rapid reduction of serum concentrations of antibodies against double-stranded DNA and cryoglobulins. CONCLUSIONS Treatment with plasmapheresis plus a standard regimen of prednisone and cyclophosphamide therapy does not improve the clinical outcome in patients with systemic lupus erythematosus and severe nephritis, as compared with the standard regimen alone.

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

Independent and Additive Impact of Blood Pressure Control and Angiotensin II Receptor Blockade on Renal Outcomes in the Irbesartan Diabetic Nephropathy Trial: Clinical Implications and Limitations

Elevated arterial pressure is a major risk factor for progression to ESRD in diabetic nephropathy. However, the component of arterial pressure and level of BP control for optimal renal outcomes are disputed. Data from 1590 hypertensive patients with type 2 diabetes in the Irbesartan Diabetic Nephropathy Trial (IDNT), a randomized, double-blind, placebo-controlled trial performed in 209 clinics worldwide, were examined, and the effects of baseline and mean follow-up systolic BP (SBP) and diastolic BP and the interaction of assigned study medications (irbesartan, amlodipine, and placebo) on progressive renal failure and all-cause mortality were assessed. Other antihypertensive agents were added to achieve predetermined BP goals. Entry criteria included elevated baseline serum creatinine concentration up to 266 micromol/L (3.0 mg/dl) and urine protein excretion >900 mg/d. Baseline BP averaged 159/87 +/- 20/11 mmHg. Median patient follow-up was 2.6 yr. Follow-up achieved SBP most strongly predicted renal outcomes. SBP >149 mmHg was associated with a 2.2-fold increase in the risk for doubling serum creatinine or ESRD compared with SBP <134 mmHg. Progressive lowering of SBP to 120 mmHg was associated with improved renal and patient survival, an effect independent of baseline renal function. Below this threshold, all-cause mortality increased. An additional renoprotective effect of irbesartan, independent of achieved SBP, was observed down to 120 mmHg. There was no correlation between diastolic BP and renal outcomes. We recommend a SBP target between 120 and 130 mmHg, in conjunction with blockade of the renin-angiotensin system, in patients with type 2 diabetic nephropathy.

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.

Factors predictive of outcome in severe lupus nephritis

In 1992, we published the results of a prospective, controlled trial of aggressive therapy (high-dose prednisone plus oral cyclophosphamide alone or with plasmapheresis) in 86 patients with severe lupus nephritis. During this study, remission (serum creatinine < or =1.4 mg/dL [< or =123 micromol/L] and proteinuria < or =330 mg/d of protein) in renal disease occurred in 37 patients (43%). To assess the long-term effect of remission on patient and renal survival, we now report the results of our extended follow-up of these patients. After an average of 10 years of follow-up in the 86 patients, patient survival rates at both 5 and 10 years were 95% in the group that had a remission and 69% at 5 years and 60% at 10 years in the no-remission group (P < 0.001). Renal survival rates were 94% at both 5 and 10 years in the remission group compared with 46% at 5 years and 31% at 10 years in the no-remission group (P < 0. 0001). Features predictive of remission included stable renal function after 4 weeks on therapy, category IV lesion, lower chronicity index, white race, lower urine protein excretion level at baseline, and lower baseline serum creatinine level. The features predictive of end-stage renal disease were higher baseline serum creatinine level, presence of anti-Ro antibodies, and failure to attain a remission. Thus, in patients with the most severe forms of lupus nephritis, a remission of clinical renal abnormalities is associated with dramatic improvement in long-term patient and renal survival.

Focal Segmental Glomerulosclerosis in Nephrotic Adults: Presentation, Prognosis, and Response to Therapy of the Histologic Variants

The histopathologic diagnosis of primary focal segmental glomerulosclerosis (FSGS) has come to include a number of histologic lesions (variants), but the prognostic significance of these discrete lesions is controversial because published information regarding the presentation, course, and response to treatment is limited. A retrospective analysis was conducted of 87 nephrotic adult patients with biopsy-proven primary FSGS. Patients were categorized on the basis of histologic criteria into those with a classic scar (36 patients), the cellular or collapsing lesion (40 patients), or the tip lesion (11 patients) of FSGS to evaluate differences in presentation, response to therapy, and clinical outcomes. The clinical features at biopsy were similar among the three groups with the exception that patients with the tip lesion were older and patients with the collapsing lesion had more severe proteinuria. Over the course of follow-up, 63% of patients treated attained remission and the response to steroid therapy was similar among the groups (classic scar 53% versus collapsing lesion 64% versus tip lesion 78%; P = 0.45). The overall renal survival was significantly better for patients who entered remission compared with patients who did not enter remission (92% versus 33% at 10 yr; P < 0.0001). The renal survival at 10 yr for patients who entered remission was similar among the three groups (classic scar 100% versus tip lesion 100% versus collapsing lesion 80%; P = 0.61). In patients who did not enter remission, the renal survival at 10 yr was significantly worse for patients with collapsing lesion and tip lesion (classic scar 49% versus tip lesion 25% versus collapsing lesion 21%; P = 0.002). In conclusion, the prognosis for nephrotic FSGS patients who enter remission is excellent regardless of the histologic lesion. Because the remission rate after treatment is similar among patients with the histologic variants, response to therapy cannot be predicted on the basis of histology alone. Thus, nephrotic patients with primary FSGS should receive a trial of therapy irrespective of the histologic lesion when not contraindicated.

Severe Lupus Nephritis: Racial Differences in Presentation and Outcome

This study assessed whether certain clinicopathologic variables could explain the impact of race on outcome in 86 patients who had severe lupus nephritis and were available for long-term follow-up after participating in a prospective, controlled, clinical trial. Fifty-four (63%) patients were white, 21 (24%) were black, and 11 (13%) were categorized as other. The proportion of patients with anti-Ro, anti-nRNP, and anti-Sm was significantly greater among black patients. Biopsies with segmental active proliferative and necrotizing lesions that involved >or=50% of glomeruli +/- membranous glomerulonephritis (class III >or=50%+/-V) were significantly more common (white 44%, black 76%, other 36%; P < 0.05) and diffuse proliferative glomerulonephritis +/- membranous glomerulonephritis (class IV+/-V) was less common (white 54%, black 24%, other 64%) among black patients. Attainment of a remission was greatest among white patients (white 52%, black 29%, other 27%; P = 0.09). Features that were predictive of a remission were white race, baseline serum creatinine, and class IV+/-V lesions. Patient survival at 10 yr (white 81%, black 59%, other 73%; P = 0.029) and renal survival at 10 yr (white 68%, black 38%, other 61%; P = 0.015) were significantly poorer in black patients. Predictors of ESRD were serum creatinine, the presence of anti-Ro antibodies, class III >or=50%+/-V lesions, and failure to achieve a remission. In conclusion, racial differences were observed in the serologic and histologic features at presentation, response to treatment, and outcome of patients with severe lupus nephritis. In a population of patients with severe lupus nephritis, black patients were significantly more likely to have a serologic profile and renal lesions that were associated with more aggressive renal disease and resulted in worse outcomes than white patients.