MECHANISM OF THE ANTIPROTEINURIC EFFECT OF CYCLOSPORINE IN MEMBRANOUSNEPHROPATHY

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