Xenotransplantation: Where Are We with Potential Kidney Recipients? Recent Progress and Potential Future Clinical Trials

Abstract

Purpose Inter-species transplantation, xenotransplantation, is becoming a realistic strategy to solve the organ shortage crisis. Here we focus on seminal publications that have driven research in xenotransplantation, as well as recently published literature and future endeavors. Recent Findings Advances in gene editing technology have allowed for the efficient production of multi-transgenic porcine donors leading improved xenograft survival in baboons, up to 2-years following heterotopic heart xenotransplantation and from weeks to several months following life-supporting kidney xenotransplanation. As technology evolves, additional challenges have arisen, including the development of proteinuria, early graft loss associated with porcine CMV, disparities in organ growth between donors and recipients as well as high-dose continuous immunosuppression requirements. To address these issues, our laboratory developed a tolerance-inducing protocol which has allowed for >6 months survival of a life-supporting kidney with further approaches currently underway to address the challenges mentioned above. Summary Our recent findings, reviewed in this article, led us to develop methods to overcome obstacles, which, in conjunction with the work of others, are promising for future clinical applications of xenotransplantation.

Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

“…However, the survival of pig skin grafts in baboons was extended if the grafts expressed hCD47, and the transgenic expression of hCD47 enhanced engraftment in an experimental model of pig‐to‐human hematopoietic cell transplantation . There is also a preliminary report that there is less proteinuria in baboons if a GTKO pig kidney graft expresses hCD47 and CD55 …”

IXA Honorary Member Lecture, 2017: The long and winding road to tolerance

“…Both approaches led, for the first time, to long‐term survival of GalT knockout pig kidneys in baboons . Survival of animals receiving this treatment has been limited by thrombotic complications of anti‐CD40L and by proteinuria due to a minimal change disease‐like glomerulopathy, which can be avoided using non‐thrombogenic anti‐CD40 and by administering rituximab and CTLA4Ig, respectively. Interestingly, work presented at this meeting suggests that transgenic expression of human CD47 on porcine glomeruli also appears to mitigate proteinuria due to this glomerulopathy .…”

Immunogenetics of xenotransplantation

“…Indeed, transgenic pig cells expressing human CD47 avoid phagocytosis by baboon macrophages, preventing xenograft injury and proteinuria (Nomura et al., 2019). Furthermore, the use of Rituximab in the preoperative period has shown to provide a certain level of protection against proteinuria (Yamada et al., 2017). Likewise, podocytes have antigen‐presenting functions and may express CD80 which has been associated with proteinuria in patients suffering from minimal change disease.…”

“…avoid phagocytosis by baboon macrophages, preventing xenograft injury and proteinuria (Nomura et al, 2019). Furthermore, the use of Rituximab in the preoperative period has shown to provide a certain level of protection against proteinuria (Yamada et al, 2017).…”