TISSUE FACTOR INITIATES GLOMERULAR FIBRIN DEPOSITION AND PROMOTES MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II EXPRESSION IN CRESCENTIC GLOMERULONEPHRITIS

Increased glomerular tissue factor (TF) expression is associated with glomerular fibrin deposition and renal failure in human and experiment al crescentic glomerulonephritis (GN), However, the in vivo functional contribution of TF to the development of glomerular fibrin deposition , crescent formation, and renal failure in GN has not been established . The contribution of TF to fibrin deposition and renal injury was stu died in a rabbit model of crescentic GN in which glomerular macrophage infiltration, augmented TF expression, and fibrin deposition are prom inent. Administration of anti-TF antibody inhibited glomerular TF acti vity in nephritic glomeruli by 96%, without affecting macrophage accum ulation or systemic indices of coagulation. Anti-TF antibody significa ntly reduced glomerular fibrin deposition (fibrin scores, 0.43 +/- 0.1 0 (treated) and 1.40 +/- 0.19 (control); P < 0.0005), crescent formati on (0.33 +/- 0.05 (treated) and 1.0 +/- 0.06 (control) P < 0.0005), an d development of renal failure (serum creatinine, 168 +/- 22 mu mol/l (treated) and 267 +/- 35 mu mol/l (control) P < 0.04). This was associ ated with significant reduction in proteinuria (1189 +/- 277 mg/24 hou rs (treated) and 2060 +/- 336 mg/24 hours (control) P < 0.03) and expr ession of MHC class II antigen in glomeruli (1.25 +/- 0.41 (treated) a nd 2.83 +/- 0.53 (control); P < 0.03) and in tubules and interstitial areas. These data demonstrate that TF is the major in vivo initiator o f fibrin deposition in crescentic GN. The reduction in proteinuria and glomerular major histocompatibility class II antigen expression by TF inhibition suggests that TF may also activate other mediators that co ntribute to glomerular injury.