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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