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A pilot study of low-dose fludarabine in membranous nephropathy refractory to therapy.


Clin Nephrol. 1999 Aug;52(2):67-75. Unique Identifier : AIDSLINE

BACKGROUND: Lymphocytes are believed to play a role in the induction and perpetuation of membranous nephropathy. Fludarabine is a purine nucleoside analog with selective activity against both dividing and resting lymphocytes. We evaluated the tolerance, toxicity, pharmacokinetics, immunologic, and clinical effects of fludarabine in patients with membranous nephropathy in an single arm pilot study. PATIENTS AND METHODS: Eight patients with idiopathic (n = 7) or lupus (n = 1) membranous nephropathy who had failed high-dose prednisone (n = 8) and/or alkylating agents (n = 2), or cyclosporine (n = 1) were treated with 6-monthly cycles of fludarabine (cycles 1-2, 20 mg/m2/day x 2 days, cycles 3-6, 20 mg/m2/day x 3 days). Mean proteinuria was 9 g/day with a mean duration of disease of 25 months (range 12-48). Proteinuria, GFR and effective renal plasma flow were compared before and after completing the treatment. RESULTS: Seven patients completed the protocol. CD3, CD4, CD8 and B cell counts decreased by 53%, 46%, 61% and 84%, respectively, at the end of treatment and remained at lower than pretreatment levels 6 months after completing the trial. Despite lymphopenia, serum immunoglobulin levels remained unchanged. Both naive (CD45RA+) and memory CD4+ T cells (CD45RO+) were reduced (naive > memory). Proteinuria decreased by > or = 50% in 5 out of 7 patients (p = 0.11). Filtration fraction improved in all patients with decreased filtration fraction at baseline. The only side-effect observed was one episode of acute bacterial sinusitis that responded promptly to antibiotic therapy. CONCLUSION: We conclude that low-dose fludarabine treatment in patients with membranous nephropathy is well tolerated and results in significant lymphopenia involving B more than T cells. In this pilot study improvement in proteinuria and filtration rate were observed. Additional studies are required to determine the optimal dose and clinical efficacy of fludarabine.

JOURNAL ARTICLE Adult Alkylating Agents/THERAPEUTIC USE Anti-Inflammatory Agents, Steroidal/THERAPEUTIC USE B-Lymphocytes/DRUG EFFECTS Comparative Study Cyclosporine/THERAPEUTIC USE CD4-Positive T-Lymphocytes/DRUG EFFECTS CD8-Positive T-Lymphocytes/DRUG EFFECTS Drug Administration Schedule Female Follow-Up Studies Glomerular Filtration Rate/DRUG EFFECTS Glomerulonephritis, Membranous/*DRUG THERAPY/IMMUNOLOGY Human IgG/BLOOD Immunologic Memory/DRUG EFFECTS Immunosuppressive Agents/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/ PHARMACOKINETICS/*THERAPEUTIC USE Lupus Nephritis Lymphocyte Count/DRUG EFFECTS Lymphocytes/DRUG EFFECTS Male Middle Age Pilot Projects Prednisone/THERAPEUTIC USE Proteinuria/DRUG THERAPY/URINE Renal Plasma Flow, Effective/DRUG EFFECTS Sinusitis/MICROBIOLOGY Vidarabine/*ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/PHARMACOKINETICS/THERAPEUTIC USE


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