Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, Sasdelli M, et al.
A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy

Kidney Int (Nov) 48:1600-1604 1995

Ponticelli and his colleagues in Italy present ten year follow up data on patients who were initially entered into their previously described randomized idiopathic membranous nephropathy trial. Between 1976 and 1983, 81 patients were randomly assigned to receive either symptomatic therapy (39 patients) or treatment (41 (patients) consisting of 1 gram intravenous methylprednisolone every 24 hours for three consecutive days followed by oral prednisone at a dose of 0.5 mg/kg/day for 27 days. The prednisone was then stopped and the patient was given chlorambucil, 0.2 mg/kg/day for one month. The prednisone and chlorampucil were continued alternately for a total of six months therapy. A new course of treatment could only be given only after at least two years from the first treatment. Outcome studies included complete remission defined as a reduction of urinary protein excretion to less than 0.2 grams/day, partial remission with proteinuria between 0.21 and 2 grams/day with normal plasma creatinine and renal dysfunction defined as an increase in plasmic creatinine of at least 50% over the baseline value. Development of end stage renal disease and death were also end points. Patients who did not complete the treatment were included in the statistical analysis according to the intention-to-treat principle. Data at last observation was included in patients who died or were lost to follow up.

Nine control and two treated patients developed end stage disease. The ten year survival with renal function was 0.92 in the treated patients versus 0.60 in the control group (95% confidence interval, P=0.0038). The slopes of the mean reciprocal of plasma creatinine were also followed with a significant drop in the control group beginning at the 12th month whereas the slope remained stable in treated patients until the 90th month and then reduced significantly. At the 95% CI, only 15 of 39 controls versus 35 of 42 treated patients had either a complete or partial remission. The probability of remission was significantly higher in treated patients than in controls. Univariate analysis for multiple other factors including sex, age, duration of disease, stage, vascular lesions, tubulo- interstitial lesions, hypertension, creatinine, and proteinuria showed that only treatment was significantly associated with the probability of obtaining remission. This study also showed that therapy significantly reduced time without nephrotic syndrome when compared with untreated patients. At the last follow up visit, 26 of 42 versus 13 of 39 controls were in either complete or partial remission.

It is important to note the ten year survival probability with a functioning kidney was 60% in patients who received no treatment however, these patients had nephrotic syndrome 80% of the time. This is in contrast to the treated patients who had a ten year survival probability with a functioning kidney of 92% with stable renal function for the first 90 months. Even when the renal function deteriorated, it did so significantly slower than the untreated controls. The authors conclude that a course of six months with methylprednisolone and chlorambucil not only increases the likelihood of remission from nephrotic syndrome but can reduce the risk of dialysis or death within ten years to about 1/3 of patients with both membranous nephropathy and nephrotic syndrome.

The authors discuss the possibility that their untreated controls had particularly bad outcomes when compared with other studies in which membranous nephropathy patients underwent significant rates of spontaneous remission. They pointed out that several of these studies included non-nephrotic patients accounting for the differences. They also point out how infrequently treated patients developed iatrogenic complications, especially neoplasia. One of their treated patients, a heavy smoker developed lung cancer following randomization and no cases of leukemia were seen. This study strongly supports the use of the Ponticelli protocol, utilizing a six month treatment plan with alternating months of methylprednisolone/prednisone and chlorambucil in the treatment of membranous nephropathy with nephrotic syndrome. (Krane)

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Proteinuria/Hematuria : Membranous GN