Complement independent nephrotoxic nephritis in the guinea pig

Abstract

Immunologic mechanisms of proteinuria were investigated in guinea pigs (GP) injected with sheep antiserum (NTS) to GP glomerular basement membrane (GBM). Linear deposition of sheep γ1 and γ2 IgG led to a prompt but transient (36 hr) increase in albumin excretion from control values of 0.026±0.013 mg/hr to maximal values of 26.3±12.1 mg/hr at 6 hr without detectable histologic or electron microscopic changes except for decreased staining for glomerular polyanion and epithelial cell foot process fusion. GBM permeability to anionic ferritin was not increased during proteinuria. Anti-GBM antibody deposits did not fix GP C3 or C4 in vivo or in vitro. NTS-induced proteinuria was the same in guinea pigs that were normal, >95% depleted of C3 through C9, gentically deficient in C4, and depleted of circulating polymorphonuclear leukocytes (PMN). Prior administration of antihistamines, steroids, azathioprine, colchicine, indomethacin, heparin, aprotinin (Trasylol), and niridazole also failed to reduce proteinuria. Initial proteinuria subsided by 36 hr, did not recur despite linear deposition of GP γ1 and γ2 after day 7, and could not be produced by large or repeated doses of rabbit or GP antibody to GBM-bound sheep globulin. In the GP nephrotoxic nephritis model, anti-GBM antibody deposits apparently mediate increased permeability to albumin by a currently undefined mechanism which is independent of complement, PMN and other known mediators of inflammation.