Mechanism of the antiproteinuric effect of cyclosporine in membranous nephropathy.

Abstract

Forty-one patients with a nephrotic syndrome and biopsy-proven membranous nephropathy were administered a 3 to 6-month course of cyclosporine (CsA;4 to 5 mg/kg per day). Differential solute clearances were used to evaluate glomerular function, before and after therapy. CsA lowered median proteinuria by 56%, from 7.3 to 3.2 g/24 h (P < 0.0001). Corresponding mean increments in serum albumin, immunoglobulin G, and oncotic pressure values were 31, 32, and 26%, respectively (all P < 0.0001). Arterial pressure, GFR, and renal plasma flow remained constant, but CsA restored the dextran-sieving curve toward normal, lowering the computed fraction of shunt-like pores by 25% (P < 0.05). In 14 instances, a cross-over design was used to randomly assign patients to 3 months of CsA versus 3 months of enalapril (10 to 30 mg daily), separated by a 1-month washout interval. Although enalapril lowered arterial pressure by 8 mm Hg (P < 0.01), it had no effect on proteinuria, plasma protein composition, filtration dynamics, or dextran sieving (all P = not significant). CsA dependence of proteinuria, indicated by relapsing nephrosis after CsA withdrawal, required additional courses of CsA to maintain proteinuria subnephrotic in most patients. In six patients with declining GFR during prolonged CsA treatment, a repeat biopsy showed more prominent immune deposits and a thicker glomerular basement membrane than at baseline. It was concluded that: (1) CsA lowers proteinuria in MN in part, by enhancing barrier size-selectivity; (2) lack of comparable efficacy of enalapril suggests that the antiproteinuric effect of CsA is related to its immuno-suppressive rather than glomerulodepressor properties; but (3) judged by repeat biopsy, CsA does not prevent continuing autoantibody formation in this disorder.