First clinical-grade porcine kidney xenotransplant using a human decedent model

Abstract

A radical solution is needed for the organ supply crisis, and the domestic pig is a promising organ source. In preparation for a clinical trial of xenotransplantation, we developed an in vivo pre‐clinical human model to test safety and feasibility tenets established in animal models. After performance of a novel, prospective compatible crossmatch, we performed bilateral native nephrectomies in a human brain‐dead decedent and subsequently transplanted two kidneys from a pig genetically engineered for human xenotransplantation. The decedent was hemodynamically stable through reperfusion, and vascular integrity was maintained despite the exposure of the xenografts to human blood pressure. No hyperacute rejection was observed, and the kidneys remained viable until termination 74 h later. No chimerism or transmission of porcine retroviruses was detected. Longitudinal biopsies revealed thrombotic microangiopathy that did not progress in severity, without evidence of cellular rejection or deposition of antibody or complement proteins. Although the xenografts produced variable amounts of urine, creatinine clearance did not recover. Whether renal recovery was impacted by the milieu of brain death and/or microvascular injury remains unknown. In summary, our study suggests that major barriers to human xenotransplantation have been surmounted and identifies where new knowledge is needed to optimize xenotransplantation outcomes in humans.

Targeted delivery of galunisertib attenuates fibrogenesis in an integratedex vivorenal transplant and fibrosis model

“…Pretreatment with TGF-β is an effective method to induce the onset of fibrosis in a relative short period of time. Additionally, the great advantage of using porcine kidneys obtained from the abattoir is that they are, genetically, physiologically and heterogeneity wise, very similar to human kidneys (32) , and limit the use of laboratory animals. As a follow-up to the porcine models, donated human kidneys rejected for transplantation could be used, leading to more translatable results.…”

Invited commentary: Initial reflections on the world's first clinical genetically‐engineered pig heart transplant

“…24 In addition, it is difficult to determine whether any adverse effects on the function and/or survival of the pig graft are related to the well-documented pathophysiological changes taking place as a result of brain death 25,26 or as a consequence of the presence of the xenograft, as was illustrated by the inconclusive recent experience reported by the University of Alabama at Birmingham group. 27 Importantly, the recent pig heart transplant, if it is even moderately successful, should stimulate further support to enable clinical trials of pig kidney transplantation to be initiated, in part by attracting funding support and in part by providing the regulatory authorities with some experience on which to base their future decisions. It should also stimulate further efforts to resolve the remaining immunological problems relating to liver, lung, islet, and corneal xenotransplantation.…”

“…These are data that it is not possible to obtain from pig organ transplantation into brain‐dead human subjects, if only because of the limited period of follow‐up that is possible 24 . In addition, it is difficult to determine whether any adverse effects on the function and/or survival of the pig graft are related to the well‐documented pathophysiological changes taking place as a result of brain death 25,26 or as a consequence of the presence of the xenograft, as was illustrated by the inconclusive recent experience reported by the University of Alabama at Birmingham group 27 …”

Bioabsorption of Subcutaneous Nanofibrous Scaffolds Influences the Engraftment and Function of Neonatal Porcine Islets

“…Seven-year follow-up data of thirty-eight patients with T1D transplanted with encapsulated porcine islets indicated no transmission of zoonotic diseases [ 20 ]. Most recently, the first successful attempt of clinical-grade porcine kidneys from genetically modified pigs was transplanted in a human decedent model that showed no observations of hyperacute rejection or transmission of porcine retroviruses [ 21 ]. Furthermore, surgeons from the University of Maryland School of Medicine successfully transplanted a genetically modified pig’s heart into the first human patient [ 22 ].…”