Effect of antiproteolytic drugs: epsilon-aminocaproic acid (EACA) and aprotinin on experimental anti-GBM nephritis.
BACKGROUND: Given the evidence accrued by other authors on beneficial effect of protease inhibitors on experimental immune nephritis, and following our preliminary report on abrogation of immune glomerulopathy in the rat by antifibrinolytic and antiproteolytic drug, epsilon-aminocaproic acid (EACA), we investigated the effect of this drug on the rat autologous anti-GBM nephritis. Along with the EACA we evaluated another protease inhibitor, aprotinin, an antagonist of serine proteases. METHODS: EACA (0.3g/kg) or aprotinin (5000 kallkrein inhibition units, KIU/kg) was administered intraperitoneally (t.i.d.) from day 0 (preventive protocol) or day 3 (therapeutic protocol) of autologous anti-GBM nephritis induced in Wistar rats. Proteinuria, creatinine clearance and renal histopathology were assessed as markers of disease activity, while glomerular fibrin deposits (immunoperoxidase staining) and standard parameters of coagulation/fibrinolysis of peripheral blood enabled insight into local and systemic haemostatic mechanisms. Glomerular binding of anti-GBM antibodies (immunofluorescence) and serum titres of autologus nephrotoxic antibodies (haemagglutination assay) represented conditions of immune induction of glomerulopathy. RESULTS: Our experiments indicated that EACA, and to a lesser extent also aprotinin, are capable of preventing proteinuria (EACA, reduction by 57.6%; aprotinin, reduction by 26.8%, compared to untreated nephritic rats, day 3 post-induction) and glomerular histopathological changes, without affecting endogenous creatinine clearance, otherwise depressed in this model of glomerulonephritis. More importantly, both drugs significantly ameliorated glomerular lesions and proteinuria, even when the treatment was initiated on day 3 post-induction, after the injury has begun (EACA reduced proteinuria by 32.0%, and aprotinin reduced it by 20.9% day 7). Administration of EACA and aprotinin at doses reducing glomerular injury did not cause appreciable fibrin deposition in glomeruli of nephritic rats, nor did it modify parameters of systemic coagulation and fibrinolysis in these animals, EACA and aprotinin did not interfere with serum titres of nephrotoxic antibody, nor with the intensity of its binding to the glomerular basement membrane in vivo. CONCLUSIONS: Antiproteolytic drugs utilized in our studies exert their beneficial effect on autologous anti-GBM nephritis through interference with inflammatory phase of the disease, while sparing its immune induction and mechanisms of coagulation/fibrinolysis.