Introduction: The only treatment for patients with end-stage renal failure is transplantation of a new replacement kidney. Xenogeneic kidney transplantation can provide an unlimited supply of organs that are lacking. In addition, it is possible to produce patient-tailored transgenic organs using genetic engineering techniques. It can be said to be the fastest realistic way to solve the problem of organ shortage compared to other fields. However, there are several complications that must be overcome in order for a xenogeneic kidney to be used as a replacement organ. Thrombotic microangiopathy(TMA), which causes blood clots to form in and around the transplanted kidney, significantly reducing the survival rate of the transplanted kidney, is known to be a serious complication that can cause loss of transplanted kidney function.
Therefore, this study aims to analyze the results of thrombotic microangiopathy that occurs after transplantation in studies conducted from 2021 to the present.
Method: Konkuk University's xenotransplantation research team has performed 37 xenograft transplants from 2011 to present using transplant kidneys from transgenic pigs based on αGal-knockout(GTKO). Transplantation research conducted from 2021 is based on GTKO, including thrombomodulin(TBM), ectonucleoside triphosphate diphosphohydrolase1(CD39), membrane cofactor protein(CD46), and complement decay accelerating factor(CD55), as well as GGTA1/CMAH/B4galNT2, a combination of various transformations.
A xenograft transplantation study was performed using(Triple-knockout; TKO) and GGTA1/CMAH/iGb3s/B4GalNT2(Quadruple-knockout; QKO)+CD46+TBM transgenic pigs. The immunosuppressant therapy was used by antibody CD-154, rituximab, antibody thymocyte globulin, cobra venom factor(CVF), rapamycin, and the calcineurin inhibitor(CNI) which was changed later to tacrolimus for immunosuppressive therapy.
From the 2023 study, solu-medrol was administered as maintenance therapy through tapering therapy.
Results: In the last three years, transgenic pigs with a combination of various transgenic pigs were used, and thrombotic microangiopathy, which was not observed in previous studies, was observed despite the administration of almost the same immunosuppressant as the same recipient primates. There was also a difference in survival rate, which was analyzed to determine whether thrombotic microangiopathy was not observed in pre-2023 studies or thrombotic microangiopathy was observed with immunosuppressive therapy used in recent studies.
Conclusions: Compared to previous studies, transgenic pigs that underwent xenograft kidney transplantation are more diverse, and clinical results are insufficient to clearly determine the cause of thrombotic microangiopathy. Therefore, to apply it to clinical xenotransplantation in the future, in order to improve the development mechanism of microvascular thrombosis, immunological disorders, and heterogeneous incompatibility at the early stage, which must be resolved, future detailed studies will be conducted to determine which genes combination expression is advantageous for xenotransplantation. We think it needs to be clarified. In addition, if immune rejection can be suppressed and controlled through the development of an optimal immunomodulation protocol that can be applied clinically, it is expected to have a positive impact on the long-term survival and function of transplanted kidneys in the future.