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.

Declined Offers for Deceased Donor Kidneys Are Not an Independent Reflection of Organ Quality.

Background: Deceased donor kidney offers are frequently declined multiple times before acceptance for transplantation, despite significant organ shortage and long waiting times. Whether the number of times a kidney has been declined, reflecting cumulative judgments of clinicians, is associated with long-term transplant outcomes remains unclear. Methods: In this national, retrospective cohort study of deceased donor kidney transplants in the United States from 2008 to 2015 (n=78,940), we compared donor and recipient characteristics and short- and long-term graft and patient survival outcomes grouping by the sequence number at which the kidney was accepted for transplantation. We compared outcomes for kidneys accepted within the first seven offers in the match-run, after 8-100 offers, and for hard-to-place kidneys distinguishing those requiring >100 and >1000 offers before acceptance. Results: Harder-to-place kidneys had lower donor quality and higher rates of delayed graft function (46% among kidneys requiring >1000 offers before acceptance versus 23% among kidneys with ≤7 offers). In unadjusted models, later sequence groups had higher hazard of all-cause graft failure, death-censored graft failure, and patient mortality; however, these associations were attenuated after adjusting for Kidney Donor Risk Index (KDRI). After adjusting for donor factors already taken into consideration during allocation, and recipient factors associated with long-term outcomes, graft, and patient survival outcomes were not significantly different for the hardest-to-place kidneys compared with the easiest-to-place kidneys, with the exception of death-censored graft failure (adjusted hazard ratio, 1.16, 95% CI, 1.05 to 1.28). Conclusion: Late sequence offers may represent missed opportunities for earlier successful transplant for the higher-priority waitlisted candidates for whom the offers were declined.

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.

Immune Cell Trafficking to the Liver.

The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body's immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.