Genetically engineered pig kidney transplantation in a brain‐dead human subject

Abstract

In September 2021, a kidney (with donor‐specific thymic tissue) from an α1, 3‐galactosyltransferase gene‐knockout (GTKO) pig was transplanted into the groin (with anastomoses to the femoral vessels) of a brain‐dead subject by a surgical team at New York University Langone Health (NYU). It was reported to function immediately, passing urine and excreting creatinine. The experiment was terminated after 54 h and, during this period, the kidney did not show macroscopic features of rejection. Does this experiment provide information not available to us previously and does it move the field forward to clinical trials? The information provided was very limited, but the following points are worthy of note. (i) Numerous in vivo studies in nonhuman primates have predicted that the pig kidney would function immediately. (ii) Numerous in vitro studies have predicted that a GTKO pig kidney would not be rejected within the first few days after transplantation into a human subject. (iii) GTKO kidneys are not optimal for clinical transplantation, and the transplantation of a triple‐knockout (TKO) pig kidney would have been more relevant. (iv) There was no purpose in transplanting a “thymokidney” without pre‐transplant conditioning therapy and follow‐up for several months. (v) Because the native kidneys were retained, it is difficult to determine whether the function of the graft was sufficient to support life. (vi) The experiment was announced to the media rather than published in a peer‐reviewed medical journal (although hopefully this will follow), suggesting that it was primarily carried out to gain attention to the great potential of xenotransplantation (and/or possibly to NYU). In this respect the experiment was successful. Because of the very limited period of time for which a brain‐dead subject can be maintained in a metabolically and hemodynamically stable state, the value of experiments in such subjects will remain very limited. It is hoped that any future similar experiments will be planned to be more relevant to the clinical situation. Nevertheless, the report has stimulated public attention towards xenotransplantation which, unless there is an adverse response to what some might consider to be a bizarre experiment, should be of significant benefit to future progress.

Recent Advances in Liver Engineering With Decellularized Scaffold

“…Due to the shortage of discarded human livers, some researchers have proposed to populate human cells into the decellularized animal liver scaffolds to mimic human livers for transplantation. Xenotransplantation of genetically modified pig organs has attracted significant attention in recent years, particularly following the recent transplantation of a genetically modified pig kidney into a brain-dead human ( Lu et al, 2019 ; Cooper, 2021 ). In contrast to the unsatisfactory microstructure of discarded human livers, animal livers are ideal and readily available.…”

“…Removing the a-Gal gene epitope reduced the adverse immune response of the recipient associated with prolonged exposure to decellularized xenografts ( Stahl et al, 2018 ). Nevertheless, substantial concern has been expressed regarding the possibility of transmitting porcine endogenous retroviruses to the recipient and caregivers ( Cooper, 2021 ).…”

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

“…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 …”

Serum Antibody Binding and Cytotoxicity to Pig Cells in Chinese Subjects: Relevance to Clinical Renal Xenotransplantation

“…Subjects with brain-death (DBD subjects) are a frequent source of organs for transplantation, and transplantation of a pig organ into a brain-dead human recipient has recently been carried out (19). However, brain death is associated with dysfunction of the cardiovascular, pulmonary, endocrine, thermoregulation, renal, hematologic and inflammatory systems (20)(21)(22)(23).…”