Hyperacute renal allograft rejection in the primate. Intrarenal effects of heparin and associated net release of factor VIII activity and kallikrein activation.
Two groups of specifically presensitized Macaca speciosa monkeys received renal allografts via anastomosis to an indwelling arteriovenous (A-V) shunt. One group was pretreated with heparin (2 mg/kg) intravenously and the other was also treated with constant heparin infusion (1 mg/kg/hr) directly into the renal artery. These studies were performed to evaluate the effects of heparin within the kidney on total and compartmental blood flow, complement (C3) levels, sequestration of formed elements, and activation of the coagulation, fibrinolytic, and kinin-forming systems during the initial 3 hours of hyperacute rejection. The results are compared with those previously reported in unmodified control allografts. Heparin prolonged blood clotting time to infinity, markedly prolonged total renal venous blood flow, and normalized compartmental distribution in both groups despite antibody deposition similar to that in controls. With heparin pretreatment only, initial morphologic injury was much reduced but then progressed rapidly. Marked initial cortical cyanosis with mottling appeared to change constantly and was associated with fluctuations in renal turgor, total blood flow, and sequestration of formed elements, all of which suggested repetitive local cortical arterial spasm and incremental destruction of the grafts. Activation of coagulation Factors II and XII was also revealed and marked net Factor VIII activity was observed in the venous effluent. The latter reflects either formation and release of this factor by the injured kidney, or provides in vivo documentation of the "hyperactivation" of Factor VIII by thrombin known to occur in vitro. The addition of intrarenal artery heparin infusion resulted in greater improvement in early total blood flow rates and more uniformly progressive cyanosis and loss of turgor, but the diffuse initial morphologic injury suggested more uniform perfusion of injured areas. Intrarenal consumption of C3 and sequestration of formed elements was similar to that in controls. Paradoxically, prompt activation and consumption of all coagulation factors, plasminogen, and prekallikrein were observed, but formed fibrin was sparse. The exess amount of Factor XIIa present during heparin blockade may have been diverted to production of plasminogen activator and kallikrein formation. The enormous numbers of neutrophils observed within vessels of grafts which showed the greatest kallikrein activation provide the probable in vivo demonstration of the chemotactic properties of kallikrein noted by others in vitro. Heparin-induced platelet aggregation may have played an important role in the failure of these grafts. These studies elucidate the intrarenal effects of heparin during hyperacute rejection and again suggest that vasoconstriction is the most important early determinant of graft failure, as blood flow appeared unrelated to the degree of vascular injury and apparent obstruction. Also, heparin may exer a beneficial effect on blood flow by other than its known action on coagulation.
D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001706:Biopsy; D003176:Complement C3 / Q000032:analysis; D005169:Factor VIII / Q000032:analysis*; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D006084:Graft Rejection; D006400:Hematocrit; D006493:Heparin / Q000494:pharmacology*; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007610:Kallikreins / Q000032:analysis*; D007668:Kidney / Q000276:immunology / Q000473:pathology; D016030:Kidney Transplantation; D008251:Macaca; D008297:Male; D009929:Organ Size; D012039:Regional Blood Flow; D012077:Renal Artery / Q000473:pathology; D012082:Renal Veins / Q000473:pathology; D012709:Serum Albumin / Q000032:analysis; D013997:Time Factors; D014184:Transplantation, Homologous
D003176:Complement C3; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D012709:Serum Albumin; D005169:Factor VIII; D005340:Fibrinogen; D006493:Heparin; D007610:Kallikreins