Z. Hruby et al., EFFECT OF ANTIPROTEOLYTIC DRUGS - EPSILON-AMINOCAPROIC ACID (EACA) AND APROTININ ON EXPERIMENTAL ANTI-GBM NEPHRITIS, Nephrology, dialysis, transplantation, 11(1), 1996, pp. 32-39
Background. Given the evidence accrued by other authors on beneficial
effect of protease inhibitors on experimental immune nephritis, and fo
llowing our preliminary report on abrogation of immune glomerulopathy
in the rat by an antifibrinolytic and antiproteolytic drug, epsilon-am
inocaproic acid (EACA), we investigated the effect of this drug on the
rat autologous anti-GEM nephritis. Along with the EACA we evaluated a
nother protease inhibitor, aprotinin, anantagonist of serine proteases
. Methods. EACA (0.3 g/kg) or aprotinin (5000 kallikrein inhibition un
its, KIU/kg) was administered intraperitoneally (t.i.d.) from day 0 (p
reventive protocol) or day 3 (therapeutic protocol) of autologous anti
-GEM nephritis induced in Wistar rats. Proteinuria, creatinine clearen
ce and renal histopathology were assessed as markers of disease activi
ty, while glomerular fibrin deposits (immunoperoxidase staining) and s
tandard parameters of coagulation/fibrinolysis of peripheral blood ena
bled insight into local and systemic haemostatic mechanisms. Glomerula
r binding of anti-GEM antibodies (immunofluorescence) and serum titres
of autologous nephrotoxic antibodies (haemagglutination assay) repres
ented conditions of immune induction of glomerulopathy. Results. Our e
xperiments indicate that the EACA, and to a lesser extent also aprotin
in, are capable of preventing proteinuria (EACA, reduction by 57.6%; a
protinin, reduction by 26.8%, compared to untreated nephritic rats, da
y 3 post-induction) and glomerular histopathological changes, without
affecting endogenous creatinine clearence, otherwise depressed in this
model of glomerulonephritis. More importantly, both drugs significant
ly ameliorated glomerular lesions and proteinuria, even when the treat
ment 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 glome
rular injury did not cause any appreciable fibrin deposition in glomer
uli of nephritic rats, nor did it modify parameters of systemic coagul
ation and fibrinolysis in these animals. EACA and aprotinin did not in
terfere with serum titres of nephrotoxic antibody, nor with the intens
ity of its binding to the glomerular basement membrane in vivo. Conclu
sions. Antiproteolytic drugs utilized in our studies exert their benef
icial effect on autologous anti-GBM nephritis through interference wit
h inflammatory phase of the disease, while sparing its immune inductio
n and mechanisms of coagulation/fibrinolysis.