Physiology and immunology of a pig-to-human decedent kidney xenotransplant

Abstract

Xenotransplantation of genetically modified pig kidneys offers a solution to the scarcity of organs for patients with end stage renal disease¹. Here we performed a pig kidney thymic autograft transplantation from an α1,3-galactosyltransferase knockout (GGTA1-knockout, GTKO) pig into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification, and somatically supported the decendent for a pre-planned 61-day study. Haemodynamic and electrolyte stability and dialysis independence were achieved. Biopsies from post-operative day (POD) 10 revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype that is not seen in allotransplantation. On POD33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, complement C3 and C3b inhibition, and rabbit anti-thymocyte globulin (rATG) completely reversed xenograft rejection. After the xenotransplant, pre-existing donor-reactive T cell clones expanded progressively in the circulation and acquired an effector transcriptional profile, and were detected in the POD33 rejecting xenograft prior to rATG treatment. This study presents long-term physiological, immunological and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitopes present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiological functions in a human.