A controlled trial of cyclosporine in patients with progressive membranous nephropathy. Canadian Glomerulonephritis Study Group. The Medical Research Council trial of short-term high-dose alternate day prednisolone in idiopathic membranous nephropathy with nephrotic syndrome in adults. The MRC Glomerulonephritis Working Party. A randomized controlled trial of prednisone in patients with idiopathic membranous nephropathy. Controlled trial of cyclophosphamide in idiopathic membranous nephropathy. Controlled trial of azathioprine in the nephrotic syndrome secondary to idiopathic membranous glomerulonephritis. Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial. Oral cyclophosphamide versus chlorambucil in the treatment of patients with membranous nephropathy and renal insufficiency. Treatment of progressive membranous glomerulopathy. A randomized trial comparing cyclophosphamide and corticosteroids with corticosteroids alone. The Glomerular Disease Collaborative Network. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. Prognosis and management of membraneous nephropathy. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy. The Italian Idiopathic Membranous Nephropathy Treatment Study Group. Preserving renal function in patients with membranous nephropathy: daily oral chlorambucil compared with intermittent monthly pulses of cyclophosphamide. Randomized controlled trial of cyclophosphamide, warfarin and dipyridamole in idiopathic membranous glomerulonephritis.
A controlled trial of cyclosporine in patients diagnosed with progressive membranous nephropathy (MGN) was carried out to determine whether cyclosporine (D) would be more effective than placebo (P) in reducing the rate of deterioration in renal function. Patients (N = 64) with MGN were placed on a restricted protein diet (< or = 0.9 g/kg) and followed closely for 12 months (Part 1). Patients at high risk of progression based on an absolute loss in creatinine clearance (CCr) of > or = 8 ml/min and persistent nephrotic range proteinuria (Pr) were selected and randomly assigned to either (D) (N = 9) or (P) (N = 8) for 12 months (Part 2). No differences in the two groups were noted at entry. After 12 months, the improvement in CCr slope in ml/min/month was significantly greater in the D patients (D + 2.1 vs. P + 0.5, mean difference 1.6; 95% CI 0.3 to 3.0, P < 0.02). This improvement was maintained in six of eight D (75%) over a mean follow-up period of 21 months. Daily Pr also improved with D (by month 3, D - 4.5 g/day vs. P + 0.7 g/day, P = 0.02) and was sustained in six of eight (75%) D patients. When Pr was expressed as a function of their concurrent CCr, the D versus P patients' time to halving was faster (P = 0.02) and absolute number higher (4/9 D vs 0/8 P). In the D group a trend towards worse hypertension and an increase in the number of transient rises in serum creatinine were noted.(ABSTRACT TRUNCATED AT 250 WORDS) We have assessed the medium-term effect of a short course of high-dose, alternate-day prednisolone on adult nephrotic patients with membranous nephropathy, using a randomized, prospective, double-blind, controlled trial. Patients were entered over the period 1981 to 1984 and were observed for a minimum of three years. One hundred and seven adult patients who had not previously received immunosuppressive treatment were included in the trial. One hundred and sixty further patients, excluded from the trial, but with membranous nephropathy were identified, followed and assessed retrospectively at the end of the trial. At 36 months there was no significant difference between control and treatment groups in plasma creatinine, creatinine clearance or 24-h excretion of protein. At between three and six months serum albumin concentrations were higher and protein excretions lower in the treatment group compared to controls. No significant benefit was therefore observed on renal function in the medium term. We conducted a prospective randomized study in which patients with biopsy-confirmed idiopathic membranous nephropathy were assigned to receive either a six-month course of prednisone given on alternate days (45 mg per square meter of body-surface area; n = 81) or no specific treatment (n = 77). The mean duration of follow-up was 48 months. Patients in the prednisone group (median age, 46 years) entered with a mean disease duration of 15 months, a median creatinine clearance of 1.2 ml per second per 1.73 m2 (range, 0.25 to 2.6), and a median rate of urinary protein excretion of 6.8 g per day (0.3 to 26). The annual change in the corrected creatinine clearance at six months did not differ between the prednisone group and the control group (0.10 vs. 0.06 ml per second; P = 0.8), or at the last follow-up evaluation (-0.07 vs. -0.02 ml per second; P = 0.2; 95 percent confidence interval on the difference, -0.03 to 0.13). The proportion of patients with complete remission of proteinuria was also similar in the groups at 6 and 12 months and after a mean of 48 months. Outcomes were similar in the two groups with respect to progression to renal failure (3 vs. 4 patients), death (3 vs. 1 patient), complete remission of proteinuria at 36 months (16 vs. 19 patients), and a decline of 25 percent or more in the creatinine clearance at 60 months (32 vs. 25 percent of patients). A multivariate analysis, which adjusted for differences at entry in sex distribution, urinary protein excretion, and creatinine concentration, as well as other prognostic variables, failed to provide an explanation for the lack of effect of prednisone. We conclude that a six-month course of therapy in which prednisone is given on alternate days is of no benefit to patients with idiopathic membranous nephropathy. nan In a controlled double-blind trial five patients with the nephrotic syndrome due to idiopathic membranous glomerulonephritis received azathioprine, 2.5 mg/kg-d, while four others received placebo. After 1 year of treatment there was no significant difference between the two groups with regard to the changes in leukocyte count, values for hemoglobin, serum creatinine, blood urea nitrogen or serum albumin, 24-hour excretion of protein in the urine, or creatinine clearance. In this study azathiprine appeared not to be useful in the treatment of idiopathic membranous glomerulonephritis. 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.
                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.
                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.
                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. We treated patients with idiopathic membranous nephropathy (iMGN) and renal insufficiency, using: (i) (n = 15) monthly cycles of steroids (1 g methyl-prednisolone i.v. on three consecutive days, followed by oral prednisone 0.5 mg/kg/day months 1, 3 and 5) and chlorambucil (0.15 mg/kg/day months 2, 4 and 6); or (ii) (n = 17) oral cyclophosphamide (1.5-2.0 mg/kg/day for 1 year) and steroids in a comparable dose. The groups were comparable in age, renal function and levels of proteinuria. During the 6 months preceding treatment, serum creatinine levels increased from 148 +/- 50 to 219 +/- 73 mumol/l in the chlorambucil group and from 164 +/- 86 to 274 +/- 126 mumol/l in the cyclophosphamide group. Median (range) follow-ups were: chlorambucil 38 months (8-71); cyclophosphamide 26 months (5-68) (NS). Renal function improved in both groups, but the improvement was short-lived in the chlorambucil group; 12 months after starting treatment, mean serum creatinine was 6.3 mumol/l lower in the chlorambucil group and 121 mumol/l lower in the cyclophosphamide group (p < 0.01). Four chlorambucil-treated patients developed ESRD, and five needed a second course of therapy, whereas only one cyclophosphamide-treated patient developed ESRD (p < 0.05). Remissions of proteinuria occurred more frequently after cyclophosphamide treatment (15/17 vs. 5/15; p < 0.01). Side-effects necessitated interruption of treatment in six patients on cyclophosphamide and in 11 on chlorambucil (p < 0.05). In our patients, oral cyclophosphamide was better tolerated than oral chlorambucil. The suggested greater efficacy of the oral cyclophosphamide regimen needs to be ascertained by longer follow-up. To determine if deterioration in renal function could be ameliorated by adding cyclophosphamide to corticosteroid therapy in patients with progressive membranous glomerulopathy.
                Randomized, controlled treatment trial. Patients were followed for a mean of 29.2 +/- 17.1 months.
                Collaborative network of 120 university and private-practice nephrologists.
                Patients with membranous glomerulopathy whose renal function deteriorated (as evidenced by doubling of the serum creatinine level, a 50% fall in the glomerular filtration rate, or a sustained serum creatinine level of greater than 2.0 mg/dL [reciprocal creatinine value, 0.5], or whose nephrotic range proteinuria persisted in association with morbid complications. Of 156 patients with biopsy-proven membranous glomerulopathy, 36 became eligible for randomization. Twenty-six of these 36 patients were randomly assigned to receive one of the two treatments.
                Pulse methylprednisolone, oral corticosteroids, and 6 months of intravenous cyclophosphamide or alternate-day corticosteroid therapy alone.
                At entry, no statistical differences were found between the treatment groups in duration of renal disease, age, gender, serum creatinine level, 24-hour urine protein excretion, or biopsy stage. The groups showed no difference in mean arterial blood pressure during follow-up. Four of the 13 patients receiving corticosteroids alone and 4 of the 13 patients receiving corticosteroids plus intravenous cyclophosphamide progressed to end-stage renal disease during follow-up. Reciprocal creatinine values tested at 6-month intervals showed no statistical differences between treatment groups at any time point. The log of the 24-hour protein excretion values showed no statistical differences between treatment groups after treatment. The power to detect a substantial improvement in renal function, defined as a doubling of the reciprocal of the serum creatinine, at the 0.05 significance level was 0.92.
                Combination therapy with intravenous cyclophosphamide and corticosteroids, when compared with corticosteroid therapy alone, does not improve renal function in patients with progressive membranous glomerulopathy. We conducted a controlled trial to investigate the long-term effects of treatment with methylprednisolone and chlorambucil in patients with idiopathic membranous nephropathy. We have previously reported that after a mean of 31 months, treated patients did better. We now report the results of a longer follow-up. Eighty-one patients with proteinuria (greater than or equal to 3.5 g per day) and biopsy-proved membranous nephropathy were randomly assigned to receive either supportive therapy alone or a six-month course of corticosteroids alternated with chlorambucil (0.2 mg per kilogram of body weight per day) every other month. Methylprednisolone was first given intravenously in three pulses (1 g per day) and was then given orally (0.4 mg per kilogram per day) for 27 days. The patients were followed for 2 to 11 years (median, 5). Two patients in the control group and one in the treatment group died. At the last follow-up visit, 9 of 39 patients assigned to the control group (23 percent) and 28 of 42 patients assigned to the treatment group (67 percent) did not have the nephrotic syndrome. At five years there were more remissions of the nephrotic syndrome in treated patients than in controls (22 of 30 vs. 10 of 25; P = 0.026). Compared with base-line values, the mean reciprocal of the plasma creatinine level declined significantly in the control group (33 percent; P = 0.0002) but not in the treatment group (6 percent; P not significant). Plasma creatinine increased by 50 percent or more in 19 controls (49 percent) and in 4 treated patients (10 percent). We conclude that a six-month course of methylprednisolone and chlorambucil can bring about sustained remission of the nephrotic syndrome and help to preserve renal function in patients with idiopathic membranous nephropathy. Patients of idiopathic membranous nephropathy (MGN) were randomly assigned to received steroid and cyclophosphamide every other month (Gr-I) and steroid alone (Gr-II). Of 36 patients in Gr.I, 33 patients achieved complete remissions, 2 had relapsing course with remission on further courses of therapy and only one has reached end stage renal failure. In contrast, of the 35 patients in Gr. II, 15 (P < 0.001) achieved complete remission, 7 are in partial remission, 5 have no response, another 5 have deterioration of renal function of which two required dialysis, and 3 have relapsing course after the initial remission. Mean follow up period was 46 +/- 10.2 months. We conclude that steroid and cyclophosphamide every other month is highly effective in achieving remission in patients with membranous nephropathy. To assess whether chlorambucil or cyclophosphamide may have a better therapeutic index in patients with idiopathic membranous nephropathy, we compared two regimens based on a 6-mo treatment, alternating every other month methylprednisolone with chlorambucil or methylprednisolone with cyclophosphamide. Patients with biopsy-proven membranous nephropathy and with a nephrotic syndrome were randomized to be given methylprednisolone (1 g intravenously for 3 consecutive days followed by oral methylprednisolone, 0.4 mg/kg per d for 27 d) alternated every other month either with chlorambucil (0.2 mg/kg per d for 30 d) or cyclophosphamide (2.5 mg/kg per d for 30 d). The whole treatment lasted 6 mo; 3 mo with corticosteroids and 3 mo with one cytotoxic drug. Among 87 patients followed for at least 1 yr, 36 of 44 (82%; 95% confidence interval [CI], 67.3 to 91.8%) assigned to methylprednisolone and chlorambucil entered complete or partial remission of the nephrotic syndrome, versus 40 of 43 (93%; 95% CI, 80.9 to 98.5%) assigned to methylprednisolone and cyclophosphamide (P = 0.116). Of patients who attained remission of the nephrotic syndrome, 11 of 36 in the chlorambucil group (30.5%) and 10 of 40 in the cyclophosphamide group (25%) had a relapse of the nephrotic syndrome between 6 and 30 mo. The reciprocal of plasma creatinine improved in the cohort groups followed for 1 yr for both treatment groups (P < 0.01) and remained unchanged when compared with basal values in the cohort groups followed for 2 and 3 yr. Six patients in the chlorambucil group and two in the cyclophosphamide group did not complete the treatment because of side effects. Four patients in the chlorambucil group but none in the cyclophosphamide group suffered from herpes zoster. One patient per group developed cancer. It is concluded that in nephrotic patients with idiopathic membranous nephropathy both treatments may be effective in favoring remission and in preserving renal function for at least 3 yr. Treatment with methylprednisolone and chlorambucil may protect renal function and increase the chance of remission of the nephrotic syndrome in patients with idiopathic membranous nephropathy. To determine whether similar results might be obtained with methylprednisolone alone, we compared the effects of methylprednisolone and chlorambucil with those of methylprednisolone alone in 92 patients with the nephrotic syndrome caused by idiopathic membranous nephropathy. The patients were randomly assigned to receive either alternating one-month courses of methylprednisolone and then chlorambucil for a total of six months (group 1) or methylprednisolone alone for six months at the same cumulative dosage (group 2).
                Four of the 45 patients in group 1 (9 percent) and 1 of the 47 in group 2 (2 percent) stopped treatment because of side effects. At one, two, and three years, the percentage of patients who did not have the nephrotic syndrome was significantly higher in group 1 than in group 2. It was 58, 54, and 66 percent, respectively, in group 1, as compared with 26, 32, and 40 percent in group 2 (P = 0.002, 0.029, and 0.011). By year 4, the difference was no longer statistically significant: 62 percent of the patients in group 1 and 42 percent of those in group 2 did not have the nephrotic syndrome (P = 0.102). The patients in group 1 were in remission longer than those in group 2 (P = 0.008).
                In patients with the nephrotic syndrome caused by idiopathic membranous nephropathy, treatment with methylprednisolone and chlorambucil for six months induces an earlier remission of the nephrotic syndrome than methylprednisolone alone, but the difference may diminish with time. To compare oral chlorambucil and intravenous cyclophosphamide-based drug regimens in the treatment of patients with membranous nephropathy and deteriorating renal function.
                Randomized study.
                University hospital and teaching hospitals.
                18 patients with membranous nephropathy, a nephrotic syndrome, and deteriorating renal function.
                Chlorambucil (0.15 mg/kg body weight per day orally in months 2, 4, and 6) and prednisone (three intravenous pulses of 1 g of methylprednisolone followed by oral prednisone at 0.5 mg/kg per day in months 1, 3, and 5) or intravenous cyclophosphamide (750 mg/m2 body surface area once every month for 6 months) and methylprednisolone (three intravenous 1-g pulses in months 1, 3, and 5).
                Serum creatinine, serum cholesterol, serum albumin, and urinary protein levels.
                Before treatment, no statistical differences were found between the treatment groups. Six months after treatment was started, serum creatinine levels had decreased in the group treated with chlorambucil, methylprednisolone, and prednisone from a mean of 260 +/- 112 mumol/L to 186 +/- 74 mumol/L (P = 0.003) and had increased in the group treated with intravenous cyclophosphamide and methylprednisolone from 218 +/- 85 mumol/L to 297 +/- 143 mumol/L (P = 0.02; difference between both groups, P < 0.001). Serum albumin levels increased in both groups by 9 and 6 g/L, respectively, and the urinary protein/creatinine ratio decreased by 2.6 and 3.1 g/10 mmol, respectively. At the end of follow-up (median, 15 months; range, 6 to 36 months), one patient in the chlorambucil group and four patients in the cyclophosphamide group had reached end-stage renal failure after 36, 12, 12, 18, and 18 months of therapy, respectively. One patient in the intravenous cyclophosphamide group died after 6 months of therapy.
                Thus far, both oral chlorambucil and oral cyclophosphamide have been shown to be effective in the treatment of patients with membranous nephropathy and deteriorating renal function. Our study shows that intermittent monthly pulses of low-dose cyclophosphamide are ineffective in preserving renal function in such patients. 40 patients with idiopathic membranous glomerulonephritis were randomized to receive either no treatment or a regime of cyclophosphamide for 6 months, and warfarin and dipyridamole for two years. During the two years of the trial there was no significant deterioration in renal function in either group. A significantly greater improvement in urinary protein excretion was, however, observed at all time points in the treatment group. Plasma albumin was also significantly higher in the treatment group at 18 and 24 months. As progressive deterioration in renal function in membranous glomerulonephritis is associated with persistent heavy proteinuria these results suggest a beneficial effect of treatment.
This review failed to show any long-term effect of immunosuppressive treatment on patient and/or renal survival. There was an increased number of discontinuations due to adverse events in immunosuppressive treatment groups. Within the class of alkylating agents there is weak evidence supporting the efficacy of cyclophosphamide as compared to chlorambucil. On the other hand, cyclophosphamide had fewer side effects leading to patient withdrawal than chlorambucil.