Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.

BACKGROUND: It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure. METHODS: We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point. RESULTS: The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P<0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group (P=0.008) and 21 percent more slowly than in the amlodipine group (P=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point. CONCLUSIONS: The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.

Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.

BACKGROUND: A clinical trial of cyclosporine in patients with steroid-resistant membranous nephropathy (MGN) was conducted. Although MGN remains the most common cause of adult-onset nephrotic syndrome, its management is still controversial. Cyclosporine has been shown to be effective in cases of progressive MGN, but it has not been used in controlled studies at an early stage of the disease. METHODS: We conducted a randomized trial in 51 biopsy-proven idiopathic MGN patients with nephrotic-range proteinuria comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 78 weeks, and the short- and long-term effects on renal function were assessed. RESULTS: Seventy-five percent of the treatment group versus 22% of the control group (P < 0.001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 43% (N = 9) of the cyclosporine remission group and 40% (N = 2) of the placebo group by week 52. The fraction of the total population in remission then remained almost unchanged and significant different between the groups until the end of the study (cyclosporine 39%, placebo 13%, P = 0.007). Renal function was unchanged and equal in the two groups over the test medication period. In the subsequent follow-up, renal insufficiency, defined as doubling of baseline creatinine, was seen in two patients in each group, but remained equal and stable in all of the other patients. CONCLUSION: This study suggests that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of MGN. Although a high relapse does occur, 39% of the treated patients remained in remission and were subnephrotic for at least one-year post-treatment, with no adverse effect on filtration function.

A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group.

UNLABELLED: A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. BACKGROUND: A clinical trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis (FSGS) was conducted. Despite the fact that it is the most common primary glomerulonephritis to progress to renal failure, treatment trials have been very limited. METHODS: We conducted a randomized controlled trial in 49 cases of steroid-resistant FSGS comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 200 weeks, and the short- and long-term effects on renal function were assessed. RESULTS: Seventy percent of the treatment group versus 4% of the placebo group (P < 0. 001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 40% of the remitters by 52 weeks and 60% by week 78, but the remainder stayed in remission to the end of the observation period. Renal function was better preserved in the cyclosporine group. There was a decrease of 50% in baseline creatinine clearance in 25% of the treated group compared with 52% of controls (P < 0.05). This was a reduction in risk of 70% (95% CI, 9 to 93) independent of other baseline demographic and laboratory variables. CONCLUSIONS: These results suggest that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of FSGS. Although a high relapse rate does occur, a long-term decrease in proteinuria and preservation of filtration function were observed in a significant proportion of treated patients.

Aggressive blood pressure lowering is safe, but benefit is still hard to prove.

In the Hypertension Optimal Treatment (HOT) study, hypertensive patients who were randomly assigned to undergo antihypertensive treatment to achieve a goal diastolic blood pressure of 80 mm Hg or lower did not experience fewer cardiovascular events than did patients who received treatment with goal pressures of 85 or 90 mm Hg. Such aggressive antihypertensive treatment was safe and well tolerated, and did result in fewer cardiovascular events in the subset of patients with diabetes. All patients were randomly assigned to take aspirin 75 mg/day or placebo, and patients in the aspirin group had a 15% lower rate of major cardiovascular events and myocardial infarctions than did patients who received placebo. This finding establishes the efficacy of aspirin in preventing strokes and myocardial infarctions in hypertensive patients.

The urine protein to creatinine ratio as a predictor of 24-hour urine protein excretion in type 1 diabetic patients with nephropathy. The Collaborative Study Group.

The purpose of this study was to determine the usefulness of a random urine specimen protein to creatinine (P/C) ratio in predicting 24-hour urine protein excretion (24 UP) in type 1 diabetic patients with overt nephropathy. Two hundred twenty-nine outpatient diabetic subjects enrolled in the Collaborative Study Group's multicenter clinical trial of "Angiotensin-Converting Enzyme Inhibition in Type 1 Diabetic Nephropathy" provided specimens for study, which encompassed a wide range of proteinuria (0.05 to 13.3 g/d). Twenty-four hour urine collections for total protein and creatinine (g/d) were obtained in the outpatient setting. This was followed shortly thereafter by an untimed single urine specimen for protein and creatinine (mg/dL). For longitudinal analysis, 33 patients provided two 24-hour urine collections with concomitant random urine specimens, separated by at least a 3-month period. Across the range of proteinuria that we studied, the log random urine P/C ratio correlated to log 24 UP (r = 0.90). The regression line was almost identical to the line of unity, which indicates that a patient's 24 U/P (in g/d) can be predicted directly from the random urine specimen P/C ratio (P/C = 24 UP in g/d). However, the standard deviations associated with these predictions were large, especially at the higher 24 UP values. Of the 33 patients who provided two time-separated specimens, the direction of change in P/C ratio was discordant with the direction of change in 24 UP in 14 of the 33 repeat specimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Pseudo-gamma heavy chain (IgG4 lambda) deposition disease.

Two patients with Ig deposition disease presented with acute renal failure, moderate proteinuria, and hematuria. A plasmacytoid lymphocytic infiltrate was identified in bone marrow that produced IgG4 lambda and free lambda light chains. One patient developed an anaplastic plasmacytoma (secreting only lambda light chains) 1 yr after renal biopsy. Renal biopsy in both patients demonstrated a nodular intercapillary glomerulopathy and electron dense granular deposits, associated with a linear pattern of IgG4 heavy chain deposition in vascular, tubular, and glomerular basement membranes (VBM, TBM, and GBM). In one patient this entrapped IgG4 was unassociated with detectable kappa or lambda light chains. In the second patient, lambda light chains (1+) were detected only in the GBM, but IgG4 (4+) was identified in GBM/TBM. Neither circulating (peripheral blood and bone marrow serum) nor cellular free gamma chains were present. We propose the term "pseudo-gamma heavy chain deposition disease" for the process.

Plasmapheresis does not increase the risk for infection in immunosuppressed patients with severe lupus nephritis. The Lupus Nephritis Collaborative Study Group.

OBJECTIVE: To determine whether plasmapheresis increases the risk for infection in immunosuppressed patients. DESIGN: Randomized, controlled trial. SETTING: Multicenter. PATIENTS: Eighty-six patients enrolled in a trial of plasmapheresis for severe diffuse proliferative lupus nephritis. INTERVENTIONS: Forty-six of the patients received high-dose steroid therapy plus cyclophosphamide therapy for 8 weeks. Thereafter, cyclophosphamide therapy was discontinued, and steroid therapy was tapered (standard treatment group). Forty patients received identical treatment and had 12 plasmapheresis procedures during the first 4 weeks of the treatment. MEASUREMENTS: Patients were examined for the development of infection. MAIN RESULTS: No statistical difference in age, sex, race, serum creatinine level, proteinuria, or complement levels was found between the two groups. Over a follow-up period of 5376 patient-weeks, 74% of patients in the standard treatment group had 62 infections, yielding an aggregate infection rate of 1.15 infections per 100 weeks (median individual infection rate, 1.08; 25th and 75th percentiles, 0.0 and 2.44). This rate was comparable to that seen in the plasmapheresis-treated patients who were followed for 4187 patient-weeks: 68% had 51 infections, for an aggregate infection rate of 1.22 infections per 100 weeks (median individual infection rate, 0.94; 25th and 75th percentiles, 0.0 and 2.32). The infection rate was also comparable in the initial acute phase of the study, despite the fact that patients who received plasmapheresis then had significantly lower immunoglobulin (IgG) levels (P less than 0.001). Neither the site (superficial compared with systemic) nor the nature (conventional compared with unconventional) of infection differed statistically between the two groups. Of 14 patient deaths, 7 were from infection (4 in control group and 3 in the plasmapheresis group). CONCLUSION: Plasmapheresis did not increase the risk for infection in immunosuppressed patients with severe lupus nephritis.

Preserving renal function by revascularization.

Renal revascularization may improve or stabilize kidney function in properly selected patients with atherosclerotic renal artery stenosis. Determining kidney salvability, choosing the optimal form of intervention, and assessing preoperative risk are essential in approaching the treatment of this complex patient group.

Trends in surgical revascularization for renal artery disease. Ten years' experience.

We reviewed our experience with surgical revascularization (SR) for renal artery disease (RAD) in 361 patients from 1975 through 1984 to illustrate the evolving role of SR in the management of these patients. The time intervals selected for comparison were 1975 through 1980 (n = 174) and 1981 through 1984 (n = 187). Since 1981, in patients with atherosclerosis, SR has been done more often in elderly patients (30% vs 10.4%), in patients with generalized atherosclerosis (87% vs 73%), and for the sole purpose of preserving renal function (36% vs 14%). Since 1981, fewer patients with atherosclerosis have undergone SR solely to treat renovascular hypertension (26% vs 41%). Since 1981, in patients with fibrous dysplasia, SR has been done in more patients with branch renal artery disease (70% vs 28%). These trends in the performance of SR have been due to the advent of percutaneous transluminal angioplasty as effective therapy for certain patients, improved results of SR in elderly patients with atherosclerosis, an enhanced appreciation of advanced atherosclerotic RAD as a correctable cause of renal failure, and the development of more effective techniques for SR in patients with severe aortic atherosclerosis and branch RAD. The overall clinical results of SR remain excellent in properly selected patients with RAD.

Natural history of atherosclerotic and fibrous renal artery disease: clinical implications.

Atherosclerotic renal artery disease and the fibrous renal artery diseases are described with respect to their radiographic and clinical characteristics. In a retrospective review, serial renal arteriograms of 85 patients with atherosclerotic renal artery disease and 66 patients with the medial fibroplasia type of fibrous renal artery disease were analyzed to characterize their natural history. Atherosclerotic renovascular disease progressed in 37 patients (44%) with total arterial occlusion occurring in 14 patients (16%). Medial fibroplasia of the renal artery progressed in 22 patients (33%) with no patient progressing to complete occlusion. Reduction in kidney size and increase in serum creatinine were good clinical markers for progressive atherosclerotic renal artery disease, but failed to discriminate between progressive and nonprogressive medial fibroplasia. The adequacy of BP control did not correlate with progressive occlusive disease in patients with either renal artery atherosclerosis or medial fibroplasia. The clinical implications of these observations are discussed with a view toward renal revascularization or transluminal angioplasty for preservation of renal function.

The natural history of atherosclerotic and fibrous renal artery disease.

From 1969 to 1979, 169 patients with two or more renal angiograms for renovascular disease (85 atherosclerotic, 75 fibrous, 9 atherosclerotic and fibrous) were reviewed in an attempt to characterize progression of disease and to determine clinical markers of progression. Progression of renal artery atherosclerosis was observed in 37 patients (44 per cent); progression to complete occlusion was observed in 14 patients (16 per cent). In the 66 patients with medial fibroplasia, progression was observed in 22 patients (33 per cent). Serial serum creatinine measurements in conjunction with measurements of kidney size may be used as markers of progressive atherosclerotic renovascular disease. These clinical markers did not represent progressive disease for individuals with medial fibroplasia.

Revascularization for preservation of renal function in patients with atherosclerotic renovascular disease.

Fifty-one patients with atherosclerotic renovascular disease have undergone elective revascularization primarily to preserve renal function. In all patients the blood pressure was well controlled preoperatively with medical therapy and was not an indication for revascularization. The preoperative serum creatinine value was 2.0 mg./dl. or more in 35 patients and less than 2.0 mg./dl. in 16. Vascular reconstruction was technically successful in all patients, with postoperative followup ranging from 4 to 76 months. The current level of over-all renal function is improved in 34 patients (67 per cent), unchanged in 14 (27 per cent) and deteriorated in 3 (6 per cent). In selected patients with atherosclerotic renal artery disease revascularization can achieve preservation or improvement of renal function.

Atherosclerotic renal artery occlusion extending into branches: successful revascularization in situ with a branched saphenous vein graft.

In some patients successful renal revascularization can be done after complete renal artery occlusion. We report on a patient with atherosclerotic occlusion of the renal artery and its branches in whom an aortorenal bypass with a branched saphenous vein graft was performed in situ, with cure of hypertension and reversal of azotemia. This is a useful and versatile technique for replacing the renal artery and its major branches.

Membranous nephropathy: a radioimmunologic search for anti-renal tubular epithelial antibodies and circulating immune complexes.

In an effort to elucidate immunopathogenic of membranous nephropathy (MN), freshly collected sera from patients with biopsy proven MN were assayed of circulating immune complexes (ICs) by the Raji cell method and for anti-renal tubular epithelial (RTE) antibodies by a newly established radioimmunoassay (RIA) and by indirect immunofluorescence. 6 of 26 MN patients tested by the Raji cell assay had detectable circulating ICs. However, 5 of these 6 patients had other medical conditions which might also explain the IC reactivity. 29 MN patients and 11 patients with other glomerular diseases had no demonstrable circulating anti-RTE antibodies. This study suggests that if RTE antigens possess a nephritogenic potential for man it is probably only rarely expressed. The inconstant detection of circulating immune complexes in idiopathic MN raises an speculation as to their immunopathogenic significance.