A pilot study of low-dose fludarabine in membranous nephropathy refractoryto therapy

Background: Lymphocytes are believed to play a role in the induction and pe rpetuation of membranous nephropathy. Fludarabine is a purine nucleoside an alog with selective activity against both dividing and resting lymphocytes. We evaluated the tolerance, toxicity, pharmacokinetics, immunologic, and c linical effects of fludarabine in patients with membranous nephropathy in a n single arm pilot study. Patients and methods: Eight patients with idiopat hic (n = 7) or lupus (n = 1) membranous nephropathy who had failed high-dos e 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/ m(2)/day x 2 days, cycles 3 - 6, 20 mg/m(2)/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 a fter completing the treatment. Results: Seven patients completed the protoc ol. CD3, CD4, CD8 and B cell counts decreased by 53%, 46%, 61% and 84%, res pectively, at the end of treatment and remained at lower than pretreatment levels 6 months after completing the trial. Despite lymphopenia, serum immu noglobulin levels remained unchanged. Both naive (CD45RA+) and memory CD4T cells (CD45RO+) were reduced (naive > memory). Proteinuria decreased by g reater than or equal to 50% in 5 out of 7 patients (p = 0.11). Filtration f raction improved in all patients with decreased filtration fraction at base line. The only side-effect observed was one episode of acute bacterial sinu sitis that responded promptly to antibiotic therapy. Conclusion: We conclud e that low-dose fludarabine treatment in patients with membranous nephropat hy is well tolerated and results in significant lymphopenia involving B mor e than T cells. In this pilot study improvement in proteinuria and filtrati on rate were observed. Additional studies are required to determine the opt imal dose and clinical efficacy of fludarabine.