Experimental discordant hepatic xenotransplantation in the recipient with liver failure: Implications for clinical bridging trials

Background: Clinical xenotransplantation might start with bridge-to-bridge trials. Situations where hyperacute rejection is avoided would provide oppo rtunities for the initiation of bridging trials. Patients with liver failur e have a diminished capacity to initiate antibody and complement-induced in jury of xenogeneic endothelium. Hyperacute rejection of a liver xenograft m anifests as a coagulopathy. We examined the ability of a recipient with liv er failure to hyperacutely reject a liver xenograft in the dog-to-pig model in the immediate postoperative period. Study Design: Liver failure in pigs tvas induced with galactosamine. Canine livers were transplanted into pigs with liver failure and into healthy pig s. The postoperative course was monitored for 1 hour for histologic changes in the xenograft, changes in platelet counts, and whole blood clotting wit h Sonoclot analysis. In vitro assays with pig serum and canine hepatic sinu soidal endothelial cells were used to assess the effect of liver failure on serum cytotoxicity and xenoreactive antibody levels. Results: All untreated pig recipients of liver xenografts died from a coagu lopathy. Recipients with liver failure manifested no signs of coagulopathy, and had minimal change in platelet counts or Sonoclot (Sienco Inc., Morris on, CO) tracings. Liver xenograft biopsies from recipients with liver failu re showed no evidence of the tissue injury that characterized the biopsies of control recipients. Serum from pigs was less cytotoxic to the canine hep atic sinusoidal endothelium after induction of liver failure. The xenoreact ive antibody levels and repertoire were similar in the pig serum before and after liver failure was induced. CH,, (total complement) level were dimini shed in pigs after the induction of liver Failure. Conclusions: Liver xenotransplantation used in bridging trials in recipient s with liver failure might not face the barrier of hyperacute rejection. (J Am Coil Surg 2000;191:54-64. (C) 2000 by the American College of Surgeons) .