An ex vivo Perfusion Model to Evaluate Hyperacute Rejection in a Discordant Pig-to-Human Combination

Inadequate supplies of human organs for transplantation have evoked an escalating interest in human xenotransplantation. Hyperacute rejection precludes use of discordant organs. We have developed an ex vivo perfusion model in order to evaluate hyperacute rejection in a pig-to-human combination. Pig kidneys (n = 6) perfused with human blood deteriorated rapidly and rejection was seen after 70 (60–87) min (median, 95% confidence interval). Kidneys perfused with pig blood survived 300 (216–360) min, corresponding to the upper time limit of the model. Increases in prostaglandin E 2 and 6-keto-prostaglandin F 1α indicated endothelial activation. Sequential blood samples revealed a strong progressive inflammatory response with reduced leukocyte and platelet counts, granulocyte activation indicated by increased myeloperoxidase, and complement activation, shown by an increase in C3 activation products and the terminal SC5b-9 complement complex. A significant role for classical pathway activation was indicated by formation of C1rs-C1 inhibitor complexes and activation of C4, whereas factor B was not significantly activated. Biopsies at rejection demonstrated hyperacute rejection with inflammatory changes involving the vessels as well as the nephrons. Where the inflammatory markers could be studied in pig blood, activation was less than in human blood. The present discordant xenotransplant model is a valuable adjunct for evaluation of changes occurring in the human blood perfusate as well as in the pig kidney during hyperacute rejection.