315.2: Considerations for inclusion/exclusion criteria for clinical pig kidney xenotransplantation

Introduction: Sufficient progress has been made in gene-edited pig-to-nonhuman primate (NHP) kidney transplantation (Tx) to suggest that clinical trials may be justified within the near future. Graft survival >1 year has been achieved. Further improvement can be expected, but the limitations of the pig-to-NHP model are well-known. Conflicting viewpoints are centered around patient selection for the first clinical trial. Methods and Results: We hold the viewpoint that candidates for a pig kidney transplant should be fully acceptable for a human kidney allograft, but who are very unlikely to obtain a deceased human kidney before they die or are removed from the waiting list (because they are no longer suitable candidates). The patient should have no or few comorbidities and a medical history that would suggest an excellent outcome. Patients with a diabetic nephropathy are at significantly increased risk of dying while on the waitlist than others, and so should be given some priority. Ideally, we suggest that the optimal candidate (i) should not have been supported by dialysis for >1 year (because comorbidities increase with time), (ii) should not have had a previous transplant, (iii) be between 55 and 65 years-old but in good physiological condition, and (iv) BMI outliers should be excluded. Preemptive pig kidney Tx should not be carried out (if only to confirm to the patient that he/she is in terminal renal failure and in need of a kidney transplant). Patients of blood group O or B would be preferred, since they wait longer for an allogeneic kidney. The patient’s geographic location should also be considered because, in some parts of the US, the wait time for a deceased human kidney can be up to 10 years. For those subjects not able to list at multiple centers, a pig renal transplant might represent their only opportunity for Tx. Patients with a very high cPRA, but no antibodies that cross-react with pig antigens can be considered. Lack of vascular access might be an additional factor, but these patients have often waited for several years and may have developed multiple comorbidities. The consent process must be exhaustive, including in-depth psychological evaluation to validate the patient’s understanding of the risks and compliance with the intensive follow-up that will be necessary. The regulatory authorities, however, have indicated they would prefer clinical trials to be performed in patients who have experienced failure of a previous kidney allograft. It is well-recognized that clinical outcomes are worse in such patients, and this may detrimentally impact a first-in-human clinical trial, thus perhaps hindering further clinical development of this promising therapy. Conclusions: We suggest that the stakeholders in the planning of clinical trials of pig kidney Tx continue to discuss recipient selection to optimize outcomes. Certain inclusion/exclusion criteria may risk failure of these trials and jeopardize the future of this novel therapy.