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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.

Any xenograft trial in the United States and the facility that supplies the organs are regulated by the US Food and Drug Administration. The FDA has assigned regulatory responsibility for Xenotransplantation to the Center for Biologics Evaluation and Research. As a novel therapeutic, the Investigational New Drug Application will likely be subjected to review by a review committee assembled by the Office of Cellular, Tissue, and Gene Therapies. The agency will utilize several guidance documents and key reference publications to evaluate proposed facilities against industry expectation for source animal facilities and products originating from these facilities. The University of Alabama at Birmingham and its partners have utilized a pragmatic approach to design and renovate a compliant source animal facility. Design standards, renovation strategies, and aspects of xeno guidance document compliance are discussed. Additionally, UAB has proposed a nucleic acid testing approach to pathogen screening for a streamlined list of pathogens of interest. UAB believes that the four principles of designated pathogen-free pig production for xenotransplantation include all-in/all-out production, modular facilities or design principles, designated pathogen freedom and response, and establishing a new paradigm aided by technology and outside expertise. Quality of the “product,” defined as a kidney with known genetics that is free from pathogenic agents of concern, is the primary concern in producing kidneys for use in humans. A flexible, adaptable design is the foundation of the vision for producing clinical-quality pig kidneys, as this is the first-in-human use of genetically modified pigs for organ transplantation.