Sequential hypothermic and normothermic perfusion preservation and transplantation of expanded criteria donor livers.

BACKGROUND: The purpose of this study was to assess the safety and feasibility of sequential hypothermic oxygenated perfusion and normothermic machine perfusion and the potential benefits of graft viability preservation and assessment before liver transplantation. METHODS: With the Food and Drug Administration and institutional review board approval, 17 expanded criteria donor livers underwent sequential hypothermic oxygenated perfusion and normothermic machine perfusion using our institutionally developed perfusion device. RESULTS: Expanded criteria donor livers were from older donors, donors after cardiac death, with steatosis, hypertransaminasemia, or calcified arteries. Perfusion duration ranged between 1 and 2 hours for the hypothermic oxygenated perfusion phase and between 4 and 9 hours for the normothermic machine perfusion phase. Three livers were judged to be untransplantable during normothermic machine perfusion based on perfusate lactate, bile production, and macro-appearance. One liver was not transplanted because of recipient issue after anesthesia induction and failed reallocation. Thirteen livers were transplanted, including 9 donors after cardiac death livers (donor warm ischemia time 16-25 minutes) and 4 from donors after brain death. All livers had the standardized lactate clearance >60% (perfusate lactate cleared to <4.0 mmol/L) within 3 hours of normothermic machine perfusion. Bile production rate was 0.2 to 10.7 mL/h for donors after brain death livers and 0.3 to 6.1 mL/h for donors after cardiac death livers. After transplantation, 5 cases had early allograft dysfunction (3 donors after cardiac death and 2 donors after brain death livers). No graft failure or patient death has occurred during follow-up time of 6 to 13 months. Two livers developed ischemic cholangiopathy. Compared with our previous normothermic machine perfusion study, the bile duct had fewer inflammatory cells in histology, but the post-transplant outcomes had no difference. CONCLUSION: Sequential hypothermic oxygenated perfusion and normothermic machine perfusion preservation is safe and feasible and has the potential benefits of preserving and evaluating expanded criteria donor livers.

Transient-mixed Chimerism With Nonmyeloablative Conditioning Does Not Induce Liver Allograft Tolerance in Nonhuman Primates.

BACKGROUND: Although short-term outcomes for liver transplantation have improved, patient and graft survival are limited by infection, cancer, and other complications of immunosuppression. Rapid induction of tolerance after liver transplantation would decrease these complications, improving survival and quality of life. Tolerance to kidneys, but not thoracic organs or islets, has been achieved in nonhuman primates and humans through the induction of transient donor chimerism. Since the liver is considered to be tolerogenic, we tested the hypothesis that the renal transplant transient chimerism protocol would induce liver tolerance. METHODS: Seven cynomolgus macaques received immune conditioning followed by simultaneous donor bone marrow and liver transplantation. The more extensive liver surgery required minor adaptations of the kidney protocol to decrease complications. All immunosuppression was discontinued on postoperative day (POD) 28. Peripheral blood chimerism, recipient immune reconstitution, liver function tests, and graft survival were determined. RESULTS: The level and duration of chimerism in liver recipients were comparable to those previously reported in renal transplant recipients. However, unlike in the kidney model, the liver was rejected soon after immunosuppression withdrawal. Rejection was associated with proliferation of recipient CD8 T effector cells in the periphery and liver, increased serum interleukin (IL)-6 and IL-2, but peripheral regulatory T cell (Treg) numbers did not increase. Antidonor antibody was also detected. CONCLUSIONS: These data show the transient chimerism protocol does not induce tolerance to livers, likely due to greater CD8 T cell responses than in the kidney model. Successful tolerance induction may depend on greater control or deletion of CD8 T cells in this model.