Introduction: Xenotransplantation represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. However, concerns remain about safe clinical translation of these results, given the inconsistency in published survival. Although there have been multiple examples of long-term survival in NHP studies in kidney xenotransplantation, there has not been demonstration of consistent (>60%) survival beyond six months in consecutive experiments of three or more recipients, which may be important as clinical trials are considered.
Methods: Source pigs were genetically modified with 10 gene edits (10GE), including removal of three known carbohydrate antigen targets of pre-formed natural antibodies plus addition of human complement regulatory proteins and human anti-coagulant proteins (Revivicor Inc, Blacksburg, VA). Six baboon recipients enrolled in this study were assessed for preformed natural antibodies by complement dependent cytotoxicity (using triple knockout porcine PBMCs) and IgM/IgG binding (initially assessed using triple knockout porcine PBMCs, later assessed using 10GE PBMCs). All cases were performed consecutively and no cases were excluded. Both native baboon kidneys were removed at the time of transplantation, and the xenografts were immediately life-supporting, producing urine on the operating table.
Results: Recipients 1-5 were low-risk for hyperacute graft loss based on our preformed natural antibody screening algorithm. Recipient 6 was high-risk according to this algorithm due to high donor specific IgG binding to source pig (10GE) PBMCs, and experienced hyperacute xenograft rejection.  In contrast, all 5 recipients in the low-risk group accepted their grafts and maintained stable graft function for 337, 285, 278, 252, and 165 days. Among these low-risk recipients, mean survival was 263 days (± 49.5 [CI: 213 – 313 days]) and median was 278 days.
Conclusion: This is the first demonstration of consistent survival in consecutive cases of pig-to-baboon kidney transplantation, and underscores the importance of donor-specific pre-transplant recipient screening. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation.