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Semnep 23 4 355.Pdf Corticosteroids, Cyclophosphamide, and Chlorambucil Therapy of Membranous Nephropathy By Patrizia Passerini and Claudio Ponticelli Corticosteroids and cytotoxic agents have been studied widely in membranous nephropathy (MN). However, controlled studies with corticosteroids have not shown a clear benefit of these agents on the outcome of the disease. Some controlled trials reported that cytotoxic agents can reduce proteinuria significantly, but it was difficult to assess the efficacy of these drugs in protecting renal function because of the short follow-up period of the studies. Three randomized controlled trials showed that a 6-month treatment regimen based on corticoste- roids and a cytotoxic agent, giving each for 1 month at a time in an alternating schedule, could favor remission of the nephrotic syndrome and protect renal function. Taken together, the results of these trials at the end of the follow-up period, 74% of the 174 treated patients were without nephrotic syndrome, 4 patients were on chronic dialysis, and 2 patients died. Good results with cytotoxic drugs, often associated with corticosteroids, also have been reported in progressive membranous nephropathy. However, in patients with renal insufficiency side effects were frequent and severe. Moreover, in most cases renal function improved but did not return to normal. © 2003 Elsevier Inc. All rights reserved. HETHER, HOW, AND WHEN to treat either in the mean urinary protein excretion or in Wmembranous nephropathy (MN) is still a the mean creatinine clearance. Although the size of matter of controversy. In this article we review the the study was adequate, untreated controls had a results with corticosteroids and cytotoxic drugs better outcome than usually reported in the litera- given alone or in combination. ture, probably because of the inclusion of nonne- For the sake of clarity, we use the following phrotic patients. definitions: nephrotic syndrome (NS) was equiva- In a multicenter study in the United States,3 72 lent to proteinuria of 3.5 g/d or greater, partial nephrotic patients with MN were allocated to remission was equivalent to proteinuria between symptomatic therapy or to high-dose alternate-day 0.21 and 2.0 g/d with normal renal function, com- prednisone (mean dose 125 mg) for 2 months with plete remission was equivalent to proteinuria less gradual reduction until withdrawal. During the than 0.2 g/d with normal renal function. study there were significantly more remissions of the NS in steroid-treated patients than in controls CORTICOSTEROIDS (22 versus 11), but because of frequent and early Four randomized trials with these agents have relapses at the end of a mean follow-up period of been published. In these studies, prednisone was 23 months, the number of patients in complete administered either at low doses for 6 months, or at remission was similar in the 2 groups. However, high doses for 8 weeks. the mean creatinine clearance declined more 1 In a small study by Black et al, 19 patients with quickly in controls (Ϫ10% per year) than in treated MN and NS were assigned randomly to symptom- patients (Ϫ2% per year). Treatment was well tol- atic therapy or to prednisone, at a mean dose of 20 erated with major side effects occurring only in 2 to 30 mg/d for at least 6 months. After 2 years, patients. There are some concerns with this study 20% of controls and 40% of the treated patients because the outcome of the control group was had daily proteinuria less than 1 g, the difference worse than that usually observed in patients with being nonsignificant. Side effects were frequent. MN. There were 6 cardiovascular deaths in the treated group versus 1 in the control group. Another protocol, based on moderate doses of From the Division of Nephrology, Istituto Recovero e Cura 2 Carattere Scientifico, Ospedale Maggiore, Milano, Italy. prednisone, was used in a Canadian study in Supported by Project Glomerulonephritis in memory of Pippo which 120 patients with nephrotic proteinuria and Neglia. 38 with nonnephrotic proteinuria were assigned to Address reprint requests to Patrizia Passerini, MD, Divisione receive symptomatic therapy or prednisone at a di Nefrologia e Dialisi, IRCCS Ospedale Maggiore di Milano, dose of 45 mg/m2 every other day for 6 months. Via Commenda 15, 20122, Milano, Italy. E-mail: ponticelli@ policlinico.mi.it Patients were followed-up for up to 4 years. Ther- © 2003 Elsevier Inc. All rights reserved. apy usually was well tolerated. No difference could 0270-9295/03/2304-0005$30.00/0 be seen between the 2 groups at any time point, doi:10.1016/S0270-9295(03)00052-4 Seminars in Nephrology, Vol 23, No 4 (July), 2003: pp 355-361 355 356 PASSERINI AND PONTICELLI More than 10 years later, a multicenter trial tis treated with chlorambucil for at least 1 year, 3 organized in the United Kingdom by the Medical developed malignancy. Research Council4 repeated the same study but in a In an Australian trial,8 54 patients were assigned double-blind fashion. A total of 107 nephrotic pa- to symptomatic therapy or to cyclophosphamide tients with MN were allocated randomly to pred- plus warfarin plus dipyridamole for 3 years. Pa- nisone, 125 mg every other day for 8 weeks, or to tients who completed the 3-year treatment showed placebo. All patients had a potential follow-up significantly lower levels of proteinuria and higher period of at least 3 years. A few treated patients levels of serum albumin when compared with un- had an early but transient reduction of proteinuria. treated controls, while the mean levels of creati- No difference was seen between the 2 groups in the nine clearance did not differ between the 2 groups. mean levels of proteinuria or serum creatinine at 1, Side effects were frequent and several patients had 2, or 3 years. to stop therapy. In summary, controlled trials have not shown a More recently, Murphy et al9 randomized 40 clear benefit of corticosteroids in patients with nonnephrotic patients either to symptomatic ther- MN. This impression has been confirmed by a apy alone or to cyclophosphamide for 6 months meta-analysis that showed that corticosteroids plus dipyridamole and warfarin for 2 years. when compared with symptomatic therapy neither Treated patients showed a significantly greater re- improved the probability of remission of protein- duction of proteinuria and a larger number of com- uria nor reduced the risk for developing renal fail- plete and partial remissions when compared with ure.5 However, in these studies, prednisone was controls. Treatment was well tolerated. given either at low doses or for short periods of Thus, there is the impression that cytotoxic time. One cannot exclude a better efficacy of cor- agents can reduce proteinuria and improve the ticosteroids when given at higher doses or for more chances of remission, but little information is prolonged periods. available about the influence of these treatments on long-term renal function. CYTOTOXIC AGENTS A few randomized trials have evaluated pro- ALTERNATING CORTICOSTEROIDS AND spectively the role of cytotoxic agents in MN. CYTOTOXIC DRUGS Donadio et al6 randomly assigned 22 patients Because MN is a chronic disease with slow with MN to nonspecific therapy or to cyclophos- progression, it is difficult to obtain a sustained phamide at a mean dose of 1.8 mg/kg/d for 1 year. remission of proteinuria and/or protection of renal At the end of treatment, there was a tendency function with short-term treatments. On the other toward a greater reduction of proteinuria in treated hand, prolonged therapies with corticosteroids or patients (mean reduction 4.7 g/d versus 2.6 g/d in cytotoxic agents expose patients to a high risk for controls), but the difference was not significant. side effects. This is why, many years ago, we However, the number of patients enrolled was too decided to alternate a corticosteroid and an alky- small to detect a significant difference, if any. lating agent every other month for 6 months to In a trial including several forms of primary allow a sufficiently long treatment, while reducing glomerulonephritis, Lagrue et al7 randomly allo- the risk for drug-related toxicity. Treatment began cated 41 nephrotic patients with MN either to with a 1-g pulse of intravenous methylpred- chlorambucil (0.2 mg/kg/d for 6 mo then 0.1 mg/ nisolone repeated for 3 consecutive days followed kg/d for a further 6 mo), azathioprine (3 mg/kg/d by oral prednisolone (0.5 mg/kg/d) for 1 month; for 6 mo then 2 mg/kg/d for a further 6 mo), or then steroids were stopped and chlorambucil (0.2 placebo. After a mean follow-up period of 2 years mg/kg/d) was given for 1 month. The cycles of there were 9 complete and 4 partial remissions steroids were given at months 1, 3, and 5, and those among the 16 patients treated with chlorambucil. of chlorambucil at months 2, 4, and 6 (Table 1). In There was only 1 partial remission among the 11 a randomized controlled trial,10 patients with bi- patients receiving azathioprine and there were 2 opsy examination–proven MN and NS were ran- complete and 1 partial remission among the 14 domized to receive this treatment or symptomatic patients who were given placebo. Unfortunately, of therapy (control group). After a mean follow-up 37 patients with various types of glomerulonephri- period of 31 months, we observed that treated TREATMENT OF MEMBRANOUS NEPHROPATHY 357 Table 1. Therapeutic Protocols Adopted in the 3 Italian Multicenter Controlled Trials MP ϩ chlorambucil versus symptomatic therapy Months 1, 3, 5 Methylprednisolone1gIVfor3days, followed by oral
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