Effects of pharmacological intervention on coagulopathy and organ function in xenoperfused kidneys

Abstract

Following pig to primate kidney transplantation, xenogenic activation of the coagulation (XAC) system of the recipient eventually leading to organ dysfunction and disseminated intravascular coagulation (DIC) can be observed. Using an ex-vivo perfusion circuit based on low-dose heparin-mediated anticoagulation and exogenous complement inhibition by C1- Inhibitor (C1-Inh), we have analysed XAC following contact of human blood with porcine endothelium. Porcine kidneys (n = 23) were recovered following in situ cold perfusion with histidine-tryptophan-ketoglutarate (HTK) solution and were connected to a perfusion circuit utilizing freshly drawn pooled human AB blood. Kidney survival during organ perfusion with human blood, CI-Inh, heparin but without any further pharmacological intervention was 126 +/- 78 min. XAC was observed with significantly elevated levels of D-dimer and thrombin antithrombin complexes (TAT). Pharmacological intervention with nitroprusside and prostacycline resulted in increased organ survival (220 +/- 28 min and 180 +/- 85 min respectively) but failed to inhibit XAC. In contrast, addition of activated protein C (APC) significantly reduced the increase in D-dimer and TAT and prolonged organ survival to 240 min (+/-0). On histology, no remarkable signs of XAC were observed. We conclude that exogenous APC is able to reduce XAC in this ex vivo perfusion model.