A Randomized Pilot Trial Comparing Methylprednisolone Plus a Cytotoxic Agent Versus Synthetic Adrenocorticotropic Hormone in Idiopathic Membranous Nephropathy Claudio Ponticelli, MD, Patrizia Passerini, MD, Maurizio Salvadori, MD, Carlo Manno, MD, Battista Fabio Viola, MD, Sonia Pasquali, MD, Salvatore Mandolfo, MD, and Piergiorgio Messa, MD ● Background: We conducted a pilot trial to compare the effectiveness and safety of 2 different treatments in patients with membranous nephropathy and nephrotic syndrome. Methods: To validate the hypothesis that the 2 treatments were equivalent, patients with biopsy-proven membranous nephropathy and nephrotic syndrome were randomly assigned to methylprednisolone alternated with a cytotoxic drug every other month for 6 months (group A) or to intramuscular synthetic adrenocorticotropic hormone administered twice a week for 1 year (group B). Results: The primary outcome measure is cumulative number of remissions as a first event. Fifteen of 16 patients in group A and 14 of 16 patients in group B entered complete or partial remission as a first event. After a median follow-up of 24 months (interquartile range, 15 to 25 months), there were 4 complete remissions and 8 partial remissions in group A versus 8 complete remissions and 6 partial remissions in group B. Median proteinuria decreased from protein of 5.1 g/d (interquartile range, 4.0 to 7.3 g/d) to 2.1 g/d (interquartile range, 0.4 to 3.8 g/d; P ⴝ 0.004) in group A and 6.0 g/d (interquartile range, 4.4 to 8.5 g/d) to 0.3 g/d (interquartile range, 0.2 to 1.9 g/d; P ⴝ 0.049) in group B. Two patients from each group interrupted treatment because of side effects or inefficacy. Conclusion: Most nephrotic patients with membranous nephropathy responded to either treatment. Proteinuria was significantly decreased with both methylprednisolone and cytotoxic agents or prolonged administration of synthetic adrenocorticotropic hormone, without significant differences between these 2 therapies. Am J Kidney Dis 47: 233-240. © 2005 by the National Kidney Foundation, Inc. INDEX WORDS: Membranous nephropathy; nephrotic syndrome; glomerulonephritis; adrenocorticotropic hormone; cytotoxic treatment.

I

DIOPATHIC MEMBRANOUS nephropathy (MN) is a frequent cause of nephrotic syndrome in adults. The natural course of the disease may be variable, with some patients entering spontaneous remission and others showing slow progression to renal failure.1,2 The greater the proteinuria, the greater the risk for renal failure in the long term.3-5 Conversely, patients who respond to therapy have a fair renal prognosis, even in the long term.6-8 Three multicenter randomized trials showed good efficacy of a 6-month treatment based on methylprednisolone (MP) alternated with either chlorambucil or cyclophosphamide every other month.9-11 A pooled analysis of these trials showed a high probability of remission, with a 92% renal survival rate at 10 years for patients who received this treatment. However, approximately 9% of patients had to stop therapy because of side effects.12 Berg et al13 reported that synthetic adrenocorticotropic hormone (ACTH) administered for 1 year improved lipoprotein profiles and decreased proteinuria in patients with MN. In another report, they showed that 7 or 8 patients with MN responded to 1 year of treatment with ACTH.14 More recently, Picardi

et al15 treated 7 patients with MN with the same schedule of ACTH; 5 patients entered complete remission of proteinuria within 6 months of

From the Istituto Scientifico Auxologico Italiano; Unità Operativa Nefrologia, Istituto Scientifico Ospedale Maggiore, Milano; Unità Operativa Nefrologia, Ospedale Policlinico Careggi, Firenze; Cattedra Nefrologia, Università di Bari; Cattedra e Divisione Nefrologia, Università e Spedali Civili Brescia; Unità Operativa Nefrologia, Ospedale Civile Lodi; and Unità Operativa Nefrologia, Sant’Orsola-Malpighi, Bologna, Italy. Received July 13, 2005; accepted in revised form October 10, 2005. Originally published online as doi:10.1053/j.ajkd.2005.10.016 on December 22, 2005. Support: This was a spontaneous clinical trial sponsored by the grant “Project Glomerulonephritis” in memory of Pippo Neglia. Potential conflicts of interest: C.P. is serving as an external consultant to Novartis, which produces tetracosactide used in this study. Address reprint requests to Claudio Ponticelli, MD, Istituto Scientifico Auxologico Italiano, Division of Immunology, Via Ampere 126, Milano 20131, Italy. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4702-0004$30.00/0 doi:10.1053/j.ajkd.2005.10.016

American Journal of Kidney Diseases, Vol 47, No 2 (February), 2006: pp 233-240

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treatment with ACTH, whereas 2 patients had to interrupt treatment because of side effects. To compare the efficacy and safety of a regimen based on 6 months of treatment with MP alternated with a cytotoxic drug versus synthetic ACTH administered for 1 year, we organized an exploratory multicenter randomized trial. METHODS

Study Design and Study Population We conducted a multicenter, prospective, randomized, open trial aimed to verify the feasibility of a new therapeutic protocol in comparison with the standard protocol used for patients with MN in our centers. The study protocol met criteria required by the Declaration of Helsinki and was approved by the ethics committees of each center. Each patient gave informed written consent.

Participants Patients with biopsy-proven MN and nephrotic syndrome (defined as urinary protein excretion ⬎ 3.5 g/d, with plasma albumin concentration ⬍ 2.5 g/dL [⬍25 g/L]) were eligible for the trial. Patients younger than 16 years, those with serum creatinine concentrations greater than 1.9 mg/dL (⬎168 ␮mol/L), those who previously received treatment with corticosteroids or cytotoxic agents, and those with conditions associated with secondary MN were not admitted to the study. The pathologist at each study center examined each renal biopsy specimen by using light microscopy and immunofluorescence. Electron microscopy was performed in approximately half the patients. Glomerular stages were classified according to Ehrenreich and Churg.16 Mesangial glomerular sclerosis and interstitial fibrosis with tubular atrophy were classified as absent or present.

Interventions Patients assigned to group A (MP plus cytotoxic drugs) underwent 3 cycles of treatment with MP, 1 g, administered intravenously on 3 consecutive days, and then 0.4 mg/kg body weight per day for 27 days, administered orally in a single morning dose. Each cycle was followed by 1 month of treatment with either chlorambucil (0.2 mg/kg/d orally) or cyclophosphamide (2.5 mg/kg/d orally). This 2-month treatment was repeated 3 times for a total treatment duration of 6 months. If a patient’s leukocyte count decreased to less than 5,000/␮L (5 ⫻ 109/L), the chlorambucil or cyclophosphamide dose was halved, and the drug was discontinued for the remainder of that cycle if leukocyte count was less than 3,000/␮L (3 ⫻ 109/L). Patients in group B were administered tetracosactide, a synthetic analogue of ACTH, in a slow release preparation. ACTH was administered by means of an intramuscular injection of 1 mg between 7:00 and 9:00 AM. Administration of ACTH was increased from 1 injection every other week to 2 injections per week for a total treatment period of 1 year, as reported by Berg et al.13 After the assigned treatment was

completed, no patient received additional “specific” therapy in group A or B. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), as well as hypolipemic drugs, were used at the discretion of the investigator.

Objective The objective of the study is to validate the hypothesis that the 2 treatments are equivalent.

Sample Size Based on previous data, we estimated that approximately 75% of patients assigned to either group A9-11 or B13,14 would enter complete or partial remission as a first event within 1 year after starting treatment. The number of patients enrolled was too large to validate this assumption; thus, we decided to perform a pilot study with a limited number of patients.

Outcomes The primary outcome measure is cumulative number of remissions (either complete or partial) as a primary event. Secondary outcome measures are cumulative number of remissions, number of relapses, amount of daily proteinuria, and mean serum cholesterol levels at the end of follow-up.

Randomization The coordinating center assigned patients consecutively by telephone to 1 of the 2 treatment regimens in a centralized randomized order, with assignation produced by a table from a statistical textbook. The sequence was concealed until intervention was assigned. Data were collected by the local pathologist and sent at the end of the study to the coordinating center (Nephrology, Ospedale Maggiore, Milan, Italy).

Response Criteria Clinical response is defined as complete or partial remission, according to Troyanov et al.8 Complete remission is defined as a decrease in urinary protein excretion to 0.3 g/d or less, and partial remission, as a decrease of at least 50% in daily protein excretion, leading to proteinuria with less than 3.5 g/d with a normal serum creatinine concentration. To avoid false results caused by fluctuations in proteinuria, remission had to last at least 1 month. No response is defined as a decrease in urinary protein excretion of less than 50% greater than basal and/or proteinuria with protein greater than 3.5 g/d with a normal serum creatinine concentration. Relapse is defined as an increase in proteinuria to protein of 3.5 g/d or more for at least 1 month in patients who attained remission. Worsening condition is defined as doubling of baseline serum creatinine level. Hypertension is defined as blood pressure greater than either 140 mm Hg systolic or 90 mm Hg diastolic without specific therapy.

Follow-Up Patients were followed up for at least 1 year after starting therapy. All patients were examined at study entry, then every month for 1 year and every 3 months thereafter. At each visit, patients were questioned about their symptoms

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and possible side effects of therapy. The general medical examination included measurements of blood pressure and body weight. Serum creatinine, 24-hour urinary protein excretion, and other laboratory parameters were evaluated at each visit. Leukocyte, erythrocyte, and platelet counts were performed weekly during administration of chlorambucil or cyclophosphamide.

Statistical Analysis This was a pilot study, and target sample size was set to 32 patients. Primary and secondary variables for evaluation of efficacy were defined with the aim of exploring factors more likely to influence the outcome of MN. Descriptive analysis was based on arithmetical means and SDs for normally distributed continuous variables and percentiles (median and interquartile range) for nonnormally distributed continuous variables, such as proteinuria and follow-up times to remission. Independent t-test was used to compare differences between groups for normally distributed continuous variables. Paired t-test was performed to analyze the evolution during follow-up of normal continuous variables in the overall study population or within each group. Similarly, Mann-Whitney and Wilcoxon signed ranks test were used for between- and within-group comparisons in case of nonnormally distributed continuous variables, respectively. Chi-square tests were performed on the cumulative proportion of patients with complete or partial remissions and relapses. An additional index of efficacy was obtained as the percentage of remission time (complete or partial) on total follow-up for each patient. The trial was designed by the investigators. The investigators also managed the database and data accrual, analyzed data, and interpreted results.

RESULTS

The study started in September 2001. Participant flow was slow and did not change over time (16 participants per year). Therefore, enrollment was stopped in December 2003. Thirty-two patients met criteria for enrollment and agreed to participate in the trial. Of these patients, 16 were assigned to administration of MP plus chlorambucil9 or cyclophosphamide7 (group A), and 16 were randomly assigned to administration of ACTH (group B). There was no difference at presentation between the 2 groups in the main clinical, biological, and histological features. However, only 44% of participants were male in group A versus 75% in group B (P ⫽ not significant). Nine patients per group had mild to moderate hypertension at presentation (Table 1). In all hypertensive patients, blood pressure could be maintained within normal values with antihypertensive treatment. Eleven patients in group A and 12 patients

235 Table 1. Demographic and Histological Characteristics of Patients at Presentation Characteristic

Group A (n ⫽ 16)

Group B (n ⫽ 16)

Age (y) 51.4 ⫾ 9.5 (38-66) 48 ⫾ 12.9 (26-69) Sex (M/F) 7/9 12/4 Serum creatinine (mg/dL) 0.9 ⫾ 0.17 1.0 ⫾ 0.36 Urinary protein excretion (g/d) 5.5 ⫾ 2.0 6.7 ⫾ 2.8 Hypertension 9 9 Glomerular stage at renal biopsy I-II 12 14 III-IV 4 2 Mesangial sclerosis 1 1 Tubulointerstitial lesions Yes 3 3 No 13 13 Follow-up (mo) 21.8 ⫾ 7.5 21.8 ⫾ 7.6 NOTE. Values expressed as mean ⫾ SD (range) or number of patients. To convert serum creatinine in mg/dL to ␮mol/L, multiply by 88.4.

in group B were treated with ACE inhibitors and/or ARBs during the study. Average doses of ACE inhibitors ranged from approximately 20 mg/d of enalapril (or equivalent doses for other ACE inhibitors). Average doses of ARBs ranged from approximately 50 mg/d of losartan (or equivalent doses for other ARBs). In all cases, these drugs were started at first presentation and continued in the case of persistent proteinuria, whereas they were discontinued in the case of proteinuria with protein less than 0.2 g/d. Seven patients in group A and 11 patients in group B were administered statins at a mean dose of 10 to 20 mg at night for simvastatin or equivalent doses for other statins until complete remission. Response to Therapy Data are reported according to intention-totreat analysis. Complete or partial remission as a first event was attained by 93% of patients in group A (5 patients, complete remission; 10 patients, partial remission) and 87% in group B (10 patients, complete remission; 4 patients, partial remission). There was no significant difference between the 2 groups in the probability of cumulative, complete, or partial remissions or remission between patients administered ACE

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Fig 1. Clinical outcome of 16 patients treated with MP and an alkylating agent for 6 months. White lines, complete remission; crossed lines, partial remission; black lines, no response; (ⴱ), patients treated with ACE inhibitors and/or ARBs; (●), patients administereded statins; (ⴙ), patients who withdrew from cytotoxic therapy because of side effects.

inhibitors and/or ARBs or statins and those not administered either of these drugs. At the last observation, 75% of patients in group A were in remission; 4 patients (25%) in complete remission and 8 patients (50%) in partial remission (Fig 1). No patient showed deterioration in renal function. In group B, there were 8 patients (50%) in complete remission and 6 patients (37%) in partial remission. The difference in remissions at the last observation was not significant. One patient in group B had worsening renal function and had to undergo regular dialysis after 18 months of follow-up (Fig 2). Median time to response was 2.0 months (interquartile range, 1.0 to 5.3 months) in group A versus 3.0 months (interquartile range, 1.0 to 3.0) in group B (P ⫽ not significant). Of 15 patients in group A who experienced at least partial remission, 7 patients experienced a relapse, transient and spontaneously reversible in 5 patients. Of 14 patients who experienced remission in group B, 3 patients had a transient relapse (P ⫽ not significant). In group A, median proteinuria decreased from a basal protein value of 5.1 g/d (interquartile range, 4.0 to 7.3 g/d) to 2.1 g/d (interquartile range, 0.4 to 3.8 g/d; P ⫽ 0.004) at the last

follow-up visit (Fig 3). In group B, median proteinuria decreased from protein of 6.0 g/d (interquartile range, 4.4 to 8.5 g/d) at baseline to 0.3 g/d (interquartile range, 0.2 to 1.9 g/d; P ⫽ 0.049) at the last follow-up visit (Fig 4). There was no difference between the 2 groups in median decrease in proteinuria. Patients in group A spent 224 of 348 months of their follow-up (65%) without nephrotic syndrome versus 254 of 349 months (73%) for patients in group B (P ⫽ 0.028). In group A, median serum creatinine level was 0.9 mg/dL (interquartile range, 0.8 to 0.9 mg/dL [79 ␮mol/L; interquartile range, 70 to 79 ␮mol/ L]) at randomization and 1.0 mg/dL (interquartile range, 0.8 to 1.0 mg/dL [88 ␮mol/L; interquartile range, 70 to 88 ␮mol/L]) at the last follow up visit. In group B, median serum creatinine level was 0.9 mg/dL (interquartile range, 0.7 to 1.2 mg/dL [79 ␮mol/L; interquartile range, 61 to 106 ␮mol/L]) at randomization and 1.0 mg/dL (interquartile range, 0.8 to 1.2 mg/dL [88 ␮mol/L; interquartile range, 70 to 106 ␮mol/L]), at the last follow up visit. In group A, mean serum cholesterol level decreased from a median of 323 mg/dL (interquartile range, 265 to 426 mg/dL [8.3 mmol/L; inter-

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Fig 2. Clinical outcomes of 16 patients treated with ACTH. White lines, complete remission; crossed lines, partial remission; black lines, no response; (ⴱ), patients treated with ACE inhibitors and/or ARBs; (●), patients administered statins; (ⴙ), patient who discontinued therapy because of side effects; (ⴙⴙ), patient who withdrew therapy after 3 months because of inefficacy.

quartile range, 6.8 to 10.9 mmol/L]) to 234 mg/dL (interquartile range, 218 to 279 mg/dL [6.0 mmol/L; interquartile range, 5.6 to 7.2 mmol/ L]) at last follow-up (P ⫽ 0.003). In group B, serum cholesterol level decreased from 291 mg/dL (interquartile range, 208 to 343 mg/dL [7.5 mmol/L; interquartile range, 5.3 to 8.8 mmol/ L]) to 202 mg/dL (interquartile range, 183 to 216 mg/dL [5.2 mmol/L; interquartile range, 4.7 to 5.5 mmol/L]; P ⬍ 0.0001). The difference between the 2 groups was not significant (Fig 5).

Fig 3. Outcome of daily proteinuria in group A. Black dots, patients with nephrotic proteinuria; gray dots, patients in partial remission; white dots, patients in complete remission (see definitions).

Side Effects In group A, 2 patients did not complete treatment because of severe leukopenia. Both patients continued without chlorambucil, and leukocyte counts increased within a few days. In group B, 2 patients stopped ACTH therapy. One patient could not tolerate treatment because of dizziness. In the other patient, treatment was considered to be ineffective by the clinician because of severe persisting nephrotic syndrome and the patient was shifted to another therapy.

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Fig 4. Outcome of daily proteinuria in group B. Black dots, patients with nephrotic proteinuria; gray dots, patients in partial remission; white dots, patients in complete remission (see definitions).

Two patients from each group developed glucose intolerance during treatment, which reversed after completion of treatment. In group B, 1 patient had diarrhea, 1 patient developed onycodystrophy, 1 patient developed folliculitis, and 6 patients developed bronze color of the skin. In both groups, side effects completely disappeared after the end of therapy. DISCUSSION

In this randomized pilot trial, we compared effects of 6 months of therapy with MP alternated with an alkylating agent versus a 12-month

course of synthetic ACTH in patients with MN and nephrotic syndrome. Because a previous randomized trial did not show significant differences between patients assigned to MP and cyclophosphamide therapy and those assigned to MP and chlorambucil therapy,11 the investigators were free to administer either alkylating agent in patients assigned to receive MP/cytotoxic therapy. Most patients reached the primary end point without differences between the 2 groups, and there were no significant differences between the 2 treatments in number of remissions at last follow-up visit, mean time of response, number

Fig 5. Mean serum cholesterol levels in groups A (●) and B (). To convert cholesterol in mg/dL to mmol/L, multiply by 0.02586.

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of relapses, or amount of decrease in proteinuria, whereas time spent without nephrotic syndrome was longer for patients in group B. In group A, at the last follow-up visit, 75% of patients were still in complete or partial remission. In 2 of 16 patients, treatment was interrupted because of leukopenia, and 2 other patients experienced a transient intolerance to glucose that did not lead to withdrawal of treatment. In all cases, these side effects completely reversed. Mean serum creatinine levels remained unchanged. If we look at these data together, we see that beneficial results and side effects were similar to those observed in our previous trials of Italian patients selected with the same inclusion and exclusion criteria.9-11 The longer period without “specific” therapy in group A was associated with a nonsignificantly greater number of relapses than in group B, but in most cases, proteinuria decreased without further “specific” therapy. In group B, at last follow-up, 87% of patients were in complete or partial remission, similar to that reported in 2 previous uncontrolled studies.14,15 Prolonged administration of ACTH was not devoid of side effects, which were mild and reversible. Only 1 patient had to stop ACTH treatment because of dizziness. Mean serum creatinine level remained unchanged, with the exception of 1 patient who progressed to end-stage renal failure. Although favorable effects of MP/cytotoxic therapy may be caused by the anti-inflammatory and immunosuppressive effects of these drugs, how ACTH decreases proteinuria in patients with MN is still unknown. It is unlikely that the antiproteinuric effect of ACTH is related to the increased release of cortisol because corticosteroids alone, even when administered at high doses, are unable to modify the natural course of MN, shown by studies of meta-analysis.1,17 Berg et al18 showed that ACTH has a pronounced lipid-lowering effect in healthy individuals, which is mediated primarily by modification of apolipoprotein metabolism. We hypothesize that by modifying apolipoprotein metabolism, ACTH might restore glomerular expression of apolipoprotein J (also called clusterin), which is inappropriate in patients with MN.19 Experimental studies showed that clusterin competes with the terminal components of complement, C5b-9, for the same receptor in podocytes, namely megalin,

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which has been identified as the target of the C5b-9 injury in experimental models of MN.20 Therefore, the presence of clusterin in glomeruli would represent a limitation to the lesions caused by complement, whereas deficient expression could enhance these lesions. It also is possible to speculate that the addition of statins may have contributed to decreasing proteinuria, as shown by a previous controlled trial of patients with MN.21 However, there was no significant difference in probability of remission between patients administered and not administered statins. Whatever the mechanism(s), this study confirms the original data of Berg et al13,14 on the efficacy of ACTH administration in patients with MN. After treatment, there were fluctuations in proteinuria, with some patients showing relapse of nephrotic syndrome followed by spontaneous remission in groups A and B. Although mean follow-up was relatively short, the high rate of response obtained with either treatment seems to be of great clinical impact because there now is evidence that, independently from relapses, not only complete remission,6 but also partial remission,7,8 is associated with a fair long-term renal outcome in patients with MN. In conclusion, while waiting for more extensive randomized studies with longer follow-up, this pilot trial confirms the benefit of 6 months of treatment with MP and a cytotoxic agent and shows that prolonged synthetic ACTH therapy may represent an effective therapeutic option in patients with idiopathic MN and nephrotic syndrome. Neither treatment is free of iatrogenic toxicity. Although no irreversible adverse events were seen with MP/cytotoxic treatment in this study, it should be remembered that such treatment potentially may lead to side effects, needing interruption of treatment in 9% of patients.12 Conversely, prolonged ACTH administration, by increasing the release of cortisol from the adrenal cortex, might cause glucose intolerance, osteoporosis, and other steroid-related side effects or anaphylactic reactions in exceptional cases. Caution and careful monitoring of the patient is recommended with either treatment. ACKNOWLEDGMENT The authors thank their colleagues Francesco Scolari (Nephrology Brescia), Enrico Imbasciati (Nephrology Lodi), and Francesca Pansini (Nephrology Bari) for helpful contri-

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butions and Dr Simeone Andrulli (Nephrology Lecco) for reviewing the statistical analysis.

REFERENCES 1. Hogan S, Muller KE, Jennette JC, Falk RJ: A review of therapeutic studies of idiopathic membranous nephropathy. Am J Kidney Dis 25:862-875, 1995 2. Cattran DC: Idiopathic membranous glomerulonephritis. Kidney Int 59:1983-1994, 2001 3. Davison AM, Cameron JS, Kerr DNS, Ogg CS, Wilkinson RW: The natural history of renal function in untreated idiopathic membranous glomerulonephritis in adults. Clin Nephrol 22:61-67, 1984 4. Donadio JV, Torres VE, Velosa JA, et al: Idiopathic membranous nephropathy: The natural history of untreated patients. Kidney Int 33:708-715, 1988 5. Cattran DC, Pei Y, Greenwood CM, Ponticelli C, Passerini P, Honkanen E: Validation of a predictive model of idiopathic membranous nephropathy; Its clinical and research implications. Kidney Int 51:901-907, 1997 6. Passerini P, Pasquali S, Cesana B, Zucchelli P, Ponticelli C: Long-term outcome of patients with membranous nephropathy after complete remission of proteinuria. Nephrol Dial Transplant 4:525-529, 1989 7. Ponticelli C, Passerini P, Altieri P, Locatelli F, Pappalettera M: Remission and relapses in idiopathic membranous nephropathy. Nephrol Dial Transplant 7:S85-S90, 1992 (suppl 1) 8. Troyanov S, Wall CA, Miller JA, Scholey JW, Cattran DC: Idiopathic membranous nephropathy: Definition and relevance of a partial remission. Kidney Int 66:1199-1205, 2004 9. Ponticelli C, Zucchelli P, Passerini P, et al: A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med 320:8-13, 1989 10. Ponticelli C, Zucchelli P, Passerini P, Cesana B, for the Italian Idiopathic Membranous Treatment Study Group: Methylprednisolone and chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy. N Engl J Med 327:599-603, 1992

11. Ponticelli C, Altieri P, Scolari F, et al: A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol 9:444450, 1998 12. Passerini P, Ponticelli C: Corticosteroids, cyclophosphamide, and chlorambucil therapy for membranous nephropathy. Semin Nephrol 23:355-361, 2003 13. Berg AL, Nilsson-Ehle P, Arnadottir M: Beneficial effects of ACTH on the serum lipoprotein profile and glomerular function in patients with membranous nephropathy. Kidney Int 56:1534-1543, 1999 14. Berg AL, Arnadottir M: ACTH-induced improvement in the nephrotic syndrome in patients with a variety of diagnoses. Nephrol Dial Transplant 19:1305-1307, 2004 15. Picardi L, Villa G, Galli F, et al: ACTH therapy in nephritic syndrome induced by idiopathic membranous nephropathy. Clin Nephrol 62:403-404, 2004 (letter) 16. Ehrenreich T, Churg J: Pathology of membranous nephropathy, in Sommers SC (ed): Pathology Annual, vol II. New York, NY, Appleton-Century-Crofts, 1968, pp 145-186 17. Perna A, Schieppati A, Zamora J, et al: Immunosuppressive treatment for idiopathic membranous nephropathy: A systematic review. Am J Kidney Dis 44:385-401, 2004 18. Berg AL, Nilsson-Ehle P: Direct effects of ACTH on plasma lipoprotein metabolism in man: Studies in vivo and in vitro. Metabolism 43:90-97, 1994 19. Ghiggeri GM, Bruschi M, Candiano G, et al: Depletion of clusterin in renal diseases causing nephrotic syndrome. Kidney Int 62:2184-2194, 2002 20. Orlando RA, Kerjashki D, Farquhar MG: Megalin (gp330) possesses an antigenic epitope capable of inducing passive Heymann nephritis independent of the nephritogenic epitope in receptor-associated protein. J Am Soc Nephrol 6:61-66, 1995 21. Rayner BL, Byrne MJ, van Zyl Smit R: A prospective clinical trial comparing the treatment of idiopathic membranous nephropathy and nephritic syndrome with simvastatin and diet versus diet alone. Clin Nephrol 46:219-224, 1996