Porcine kidney xenotransplantation: From primate models to clinical reality

The escalating global incidence of end-stage renal disease has exacerbated the critical shortage of kidneys from human donors. Porcine kidney xenotransplantation has emerged as the most promising alternative solution to providing an unlimited organ supply. In this review, we examine the historical evolution, current breakthroughs and future directions of kidney xenotransplantation. We probe the milestones from early attempts and non-human primate (NHP) experiments to recent clinical trials involving both brain-dead and living human recipients. The core of this review provides an in-depth discussion of the significant barriers in kidney xenotransplantation, including immune rejection, physiological incompatibilities and the risk of cross-species infection. Next, we systematically outline the multifaceted strategies developed to overcome these barriers. The rapid development of gene editing technology has enabled the establishment of multigene-edited pigs. These donors feature knockout of key carbohydrate antigen genes and expression of various human proteins, including complement regulators, anticoagulants, and immunomodulators. These genetic modifications have extended xenograft survival in NHP models to over 750 days. This is synergized with novel immunosuppressive regimens, tolerance-induction protocols, cellular therapies, and emerging adjuncts like bioengineering materials and organoid-on-a-chip technologies. Finally, we discuss future directions, raising concerns about potential complications arising from the biomechanical incompatibility between pigs and human in xenotransplantation, highlighting the need to deploy advanced multi-omics to identify unknown xenoantigens, optimize bioengineering materials for local immunomodulation, and validate extracellular vesicles as non-invasive biomarkers. While challenges for long-term xenograft survival remain, kidney xenotransplantation is rapidly advancing from preclinical research to clinical reality, holding huge potential to resolve the organ shortage crisis.