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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\u2010human primate (NHP) experiments to recent clinical trials involving both brain\u2010dead and living human recipients. The core of this review provides an in\u2010depth discussion of the significant barriers in kidney xenotransplantation, including immune rejection, physiological incompatibilities and the risk of cross\u2010species 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\u2010edited 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\u2009days. This is synergized with novel immunosuppressive regimens, tolerance\u2010induction protocols, cellular therapies, and emerging adjuncts like bioengineering materials and organoid\u2010on\u2010a\u2010chip 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\u2010omics to identify unknown xenoantigens, optimize bioengineering materials for local immunomodulation, and validate extracellular vesicles as non\u2010invasive biomarkers. While challenges for long\u2010term xenograft survival remain, kidney xenotransplantation is rapidly advancing from preclinical research to clinical reality, holding huge potential to resolve the organ shortage crisis.<\/jats:p>","DOI":"10.1002\/ame2.70195","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T05:03:46Z","timestamp":1778303026000},"page":"1142-1166","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Porcine kidney xenotransplantation: From primate models to clinical reality"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8984-0045","authenticated-orcid":false,"given":"Zihang","family":"Guo","sequence":"first","affiliation":[{"name":"Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Sciences, National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, National Health Commission of China (NHC) Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Sciences, National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, National Health Commission of China (NHC) Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoulong","family":"Deng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Sciences, National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, National Health Commission of China (NHC) Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College  Beijing China"},{"name":"National Science Center for Model Animals China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6261-1232","authenticated-orcid":false,"given":"Chuan","family":"Qin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Sciences, National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, National Health Commission of China (NHC) Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"189","article-title":"Can man live with a pig 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