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Preserving Renal Function in Patients with Membranous Nephropathy: Daily Oral Chlorambucil Compared with Intermittent Monthly Pulses of Cyclophosphamide

Louis J. M. Reichert; Frans Th. M. Huysmans; Karel Assmann; Robert A. P. Koene; and Jack F. M. Wetzels
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From University Hospital Nijmegen, Nijmegen, the Netherlands. Requests for Reprints: Louis J. M. Reichert, MD, Department of Medicine, Division of Nephrology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands. Acknowledgments: The authors thank Drs. J. Jordans, R. Go, M. Schuurmans, H. van Roermund, G. Schrijver, M. den Hartog, V. Verstappen, P. Hillen, P. van Boven, F. van Liebergen, J. Jansen, and J. Berden for participation in this study and Dr. A. J. Hoitsma for his statistical advice. Grant Support: By NWO grant 900/716-111 from the Netherlands Foundation of Scientific Research.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1994;121(5):328-333. doi:10.7326/0003-4819-121-5-199409010-00003
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Objective: To compare oral chlorambucil and intravenous cyclophosphamide-based drug regimens in the treatment of patients with membranous nephropathy and deteriorating renal function.

Design: Randomized study.

Setting: University hospital and teaching hospitals.

Patients: 18 patients with membranous nephropathy, a nephrotic syndrome, and deteriorating renal function.

Intervention: 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).

Measurements: Serum creatinine, serum cholesterol, serum albumin, and urinary protein levels.

Results: 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 µmol/L to 186 ± 74 µmol/L (P = 0.003) and had increased in the group treated with intravenous cyclophosphamide and methylprednisolone from 218 ± 85 µmol/L to 297 ± 143 µmol/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.

Conclusions: 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.


Grahic Jump Location
Figure 1.
Renal function as shown by 1000/serum creatinine level in individual patients treated with chlorambucil, methylprednisolone, and prednisone.

Treatment was started at t = 0 months. * = start of renal replacement therapy; Triangle = start of retreatment with immunosuppressive therapy. The Y-axis represents the reciprocal of serum creatinine ÷ 1000. This ratio reflects renal function.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Renal function as shown by 1000/serum creatinine level in individual patients treated with intravenous pulses of cyclophosphamide and methylprednisolone.

Treatment was started at t = 0 months. * = start of renal replacement therapy in a single patient. † = patient died. Triangle = start of retreatment with immunosuppressive therapy.

Grahic Jump Location




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