{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:24:33Z","timestamp":1791915873533,"version":"4.3.4"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"The University of Osaka"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Artif Organs"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Kidney transplantation is the only curative option for patients with chronic renal failure, significantly improving their survival and quality of life. However, this treatment remains limited by the shortage of organ donors. The shortage of kidney donors remains a serious problem all over the world, and is particularly severe in Japan. While advancements in immunosuppressive therapies and histocompatibility testing have improved outcomes in allogeneic kidney transplantation, the rising number of dialysis patients has worsened the gap between the demand for and supply of suitable donor organs. In response to this pressing need, xenotransplantation has gained attention as a promising alternative solution. Recent progress driven by gene-editing technologies, including CRISPR-Cas9, has facilitated the development of genetically modified pigs suitable for potential human transplantation. This review provides an overview of the key differences in immune response and infection risks between xenogeneic and allogeneic kidney transplants. In addition, it comprehensively examines the challenges and potential of xenogeneic kidney transplantation from multiple perspectives, including differences in immunosuppressive therapies between allogeneic and xenogeneic transplantation. We also discuss the feasibility of xenogeneic kidney transplantation as a solution to the organ shortage in Japan and present directions for addressing challenges toward clinical application. We hope this review will provide valuable insights into the potential of xenogeneic kidney transplantation as a new treatment option for chronic renal failure and contribute to efforts to address the donor shortage problem in Japan.<\/jats:p>","DOI":"10.1007\/s10047-025-01506-x","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T12:34:20Z","timestamp":1746189260000},"page":"336-342","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Differences between xenotransplantation and allogeneic kidney transplantation: the current situation and future challenges in Japan"],"prefix":"10.1007","volume":"28","author":[{"given":"Soichi","family":"Matsumura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5339-4312","authenticated-orcid":false,"given":"Yoichi","family":"Kakuta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Maegawa-Higa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shota","family":"Fukae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeaki","family":"Nakazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuaki","family":"Yamanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuji","family":"Miyagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Nonomura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"issue":"3","key":"1506_CR1","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1093\/ckj\/sfab273","volume":"15","author":"R Boenink","year":"2021","unstructured":"Boenink R, Astley ME, Huijben JA, et al. The ERA Registry Annual Report 2019: summary and age comparisons. Clin Kidney J. 2021;15(3):452\u201372.","journal-title":"Clin Kidney J"},{"key":"1506_CR2","doi-asserted-by":"publisher","first-page":"126","DOI":"10.21037\/tau.2019.03.05","volume":"8","author":"M Okumi","year":"2019","unstructured":"Okumi M, Kakuta Y, Unagami K, et al. Current protocols and outcomes of ABO-incompatible kidney transplantation based on a single-center experience. Transl Androl Urol. 2019;8:126\u201333.","journal-title":"Transl Androl Urol"},{"key":"1506_CR3","doi-asserted-by":"crossref","unstructured":"Tanjala S Purnell, Priscilla Auguste, Deidra C Crews, et al. Comparison of life participation activities among adults treated by hemodialysis, peritoneal dialysis, and kidney transplantation: a systematic review. Am J Kidney Dis 2013;62(5):953\u201373.","DOI":"10.1053\/j.ajkd.2013.03.022"},{"key":"1506_CR4","doi-asserted-by":"publisher","DOI":"10.1111\/ctr.13591","volume":"33","author":"Y Kakuta","year":"2019","unstructured":"Kakuta Y, Okumi M, Unagami K, et al. Outcomes, complications, and economic impact of ABO-incompatible living kidney transplantation: a single- center Japanese cohort study. Clin Transplant. 2019;33: e13591.","journal-title":"Clin Transplant"},{"key":"1506_CR5","unstructured":"Japan Society for Dialysis Therapy. Current status of chronic dialysis treatment in Japan (as of December 31, 2021); 2023. https:\/\/docs.jsdt.or.jp\/overview\/Accsessed. Written in Japanese"},{"key":"1506_CR6","unstructured":"The Japan Society for Transplantation. Fact. Accsessed 2023; 2022. http:\/\/www.asas.or.jp\/jst\/pdf\/factbook\/factbook2022.pdf. Written in Japanese"},{"issue":"2","key":"1506_CR7","doi-asserted-by":"publisher","first-page":"S21","DOI":"10.1016\/j.ajt.2023.02.004","volume":"23","author":"KL Lentine","year":"2023","unstructured":"Lentine KL, Smith JM, Miller JM, et al. OPTN\/SRTR 2021 annual data report: kidney. Am J Transplant. 2023;23(2):S21\u2013120.","journal-title":"Am J Transplant"},{"issue":"6","key":"1506_CR8","doi-asserted-by":"publisher","first-page":"3196","DOI":"10.3390\/ijms22063196","volume":"22","author":"N Ryczek","year":"2021","unstructured":"Ryczek N, Hryhorowicz M, Zeyland J, et al. CRISPR\/Cas technology in pig-to-human xenotransplantation research. Int J Mol Sci. 2021;22(6):3196.","journal-title":"Int J Mol Sci"},{"issue":"6616","key":"1506_CR9","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1126\/science.abo7935","volume":"378","author":"M Sykes","year":"2022","unstructured":"Sykes M. Developing pig-to-human organ transplants. Science. 2022;378(6616):135\u20136.","journal-title":"Science"},{"key":"1506_CR10","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1056\/NEJMoa2120238","volume":"386","author":"RA Montgomery","year":"2022","unstructured":"Montgomery RA, Stern JM, Lonze BE, et al. Results of two cases of pig-to-human kidney xenotransplantation. N Engl J Med. 2022;386:1889\u201398.","journal-title":"N Engl J Med"},{"key":"1506_CR11","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1111\/ajt.16930","volume":"22","author":"PM Porrett","year":"2022","unstructured":"Porrett PM, Orandi BJ, Kumar V, et al. First clinical-grade porcine kidney xenotransplant using a human decedent model. Am J Transplant. 2022;22:1037\u201353.","journal-title":"Am J Transplant"},{"key":"1506_CR12","unstructured":"Massachusetts General Hospital Founding Member, Mass General Brigham. World\u2019s first genetically-edited pig kidney transplant into living recipient performed at Massachusetts General Hospital. 2024. https:\/\/www.massgeneral.org\/news\/press-release\/worlds-first-genetically-edited-pig-kidney-transplant-into-living-recipient"},{"key":"1506_CR13","doi-asserted-by":"publisher","first-page":"899657","DOI":"10.3389\/fimmu.2022.899657","volume":"13","author":"DL Eisenson","year":"2022","unstructured":"Eisenson DL, Hisadome Y, Yamada K, et al. Progress in xenotransplantation: immunologic barriers, advances in gene editing, and successful tolerance induction strategies in pig-to-primate transplantation. Front Immunol. 2022;13:899657.","journal-title":"Front Immunol"},{"key":"1506_CR14","doi-asserted-by":"publisher","first-page":"3865","DOI":"10.3390\/cells11233865","volume":"11","author":"TY Lu","year":"2022","unstructured":"Lu TY, Xu XL, Du XG, et al. Advances in innate immunity to overcome immune rejection during xenotransplantation. Cells. 2022;11:3865.","journal-title":"Cells"},{"key":"1506_CR15","doi-asserted-by":"publisher","first-page":"941880","DOI":"10.3389\/fimmu.2022.941880","volume":"13","author":"KJ Lopez","year":"2022","unstructured":"Lopez KJ, Cross-Najafi AA, Farag K, et al. Strategies to induce natural killer cell tolerance in xenotransplantation. Front Immunol. 2022;13:941880.","journal-title":"Front Immunol"},{"key":"1506_CR16","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1111\/j.1365-2567.2010.03253.x","volume":"130","author":"TJ Kim","year":"2010","unstructured":"Kim TJ, Kim N, Kim EO, et al. Suppression of human anti-porcine natural killer cell xenogeneic responses by combinations of monoclonal antibodies Immunology 130. Immunology. 2010;130:545\u201355.","journal-title":"Immunology"},{"issue":"1","key":"1506_CR17","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1097\/TP.0b013e318191c784","volume":"87","author":"EH Weiss","year":"2009","unstructured":"Weiss EH, Lilienfeld BG, M\u00fcller S, et al. HLA-E\/human beta2-microglobulin transgenic pigs: protection against xenogeneic human anti-pig natural killer cell cytotoxicity. Transplantation. 2009;87(1):35\u201343.","journal-title":"Transplantation"},{"key":"1506_CR18","doi-asserted-by":"publisher","first-page":"5062","DOI":"10.1073\/pnas.0609661104","volume":"104","author":"K Ide","year":"2007","unstructured":"Ide K, Wang H, Tahara H, et al. Role for CD47-SIRPalpha signaling in xenograft rejection by macrophages. Proc Natl Acad Sci U S A. 2007;104:5062\u20136.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1506_CR19","doi-asserted-by":"publisher","first-page":"3361","DOI":"10.1038\/s41467-024-47679-6","volume":"15","author":"Yu Daniel Eisenson","year":"2024","unstructured":"Daniel Eisenson Yu, Hisadome MS, et al. Consistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs. Nat Commun. 2024;15:3361.","journal-title":"Nat Commun"},{"key":"1506_CR20","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12396","volume":"25","author":"HT Wang","year":"2018","unstructured":"Wang HT, Maeda A, Sakai R, et al. Human CD31 on porcine cells suppresses xenogeneic neutrophil-mediated cytotoxicity via the inhibition of NETosis. Xenotransplantation. 2018;25: e12396.","journal-title":"Xenotransplantation"},{"key":"1506_CR21","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1097\/MOT.0000000000000466","volume":"22","author":"K Yamada","year":"2017","unstructured":"Yamada K, Sykes M, Sachs DH. Tolerance in xenotransplantation. Curr Opin Organ Transplant. 2017;22:522\u20138.","journal-title":"Curr Opin Organ Transplant"},{"key":"1506_CR22","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1172\/JCI27155","volume":"116","author":"H Xu","year":"2006","unstructured":"Xu H, Zhang X, Mannon RB, Kirk AD. Platelet-derived or soluble CD154 induces vascularized allograft rejection independent of cell-bound CD154. J Clin Invest. 2006;116:769\u201374.","journal-title":"J Clin Invest"},{"issue":"6","key":"1506_CR23","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1097\/TP.0b013e3182802f88","volume":"95","author":"AA Vo","year":"2013","unstructured":"Vo AA, Petrozzino J, Yeung K, et al. Efficacy, outcomes, and cost-effectiveness of desensitization using IVIG and rituximab. Transplantation. 2013;95(6):852\u20138.","journal-title":"Transplantation"},{"issue":"1","key":"1506_CR24","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1056\/NEJMoa2201422","volume":"387","author":"BP Griffith","year":"2022","unstructured":"Griffith BP, Goerlich CE, Singh AK, et al. Genetically modified porcine-to-human cardiac xenotransplantation. N Engl J Med. 2022;387(1):35\u201344.","journal-title":"N Engl J Med"},{"key":"1506_CR25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.861471","volume":"13","author":"S Perrin","year":"2022","unstructured":"Perrin S, Magill M. The inhibition of CD40\/CD154 costimulatory signaling in the prevention of renal transplant rejection in nonhuman primates: a systematic review and meta analysis. Front Immunol. 2022;13: 861471.","journal-title":"Front Immunol"},{"issue":"3","key":"1506_CR26","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1124\/jpet.123.001771","volume":"387","author":"M Samant","year":"2023","unstructured":"Samant M, Ziemniak J, Paolini JF. First-in-human phase 1 randomized trial with the anti-CD40 monoclonal antibody KPL-404: safety, tolerability, receptor occupancy, and suppression of T-cell-dependent antibody response. J Pharmacol Exp Ther. 2023;387(3):306\u201314.","journal-title":"J Pharmacol Exp Ther"},{"issue":"4","key":"1506_CR27","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1111\/ajt.16288","volume":"21","author":"H Sakai","year":"2021","unstructured":"Sakai H, Tanaka Y, Tanaka A, et al. TLR-MyD88 signaling blockades inhibit refractory B-1b cell immune responses to transplant-related glycan antigens. Am J Transplant. 2021;21(4):1427\u201339.","journal-title":"Am J Transplant"},{"issue":"1","key":"1506_CR28","doi-asserted-by":"publisher","first-page":"11747","DOI":"10.1038\/s41598-020-68505-1","volume":"10","author":"T Yamamoto","year":"2020","unstructured":"Yamamoto T, Cui Y, Patel D, et al. Effect of intravenous immunoglobulin (IVIg) on primate complement-dependent cytotoxicity of genetically engineered pig cells: relevance to clinical xenotransplantation. Sci Rep. 2020;10(1):11747.","journal-title":"Sci Rep"},{"issue":"1","key":"1506_CR29","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1053\/j.ajkd.2011.04.010","volume":"58","author":"K De Keyzer","year":"2011","unstructured":"De Keyzer K, Van Laecke S, Peeters P, et al. Human cytomegalovirus and kidney transplantation: a clinician\u2019s update. Am J Kidney Dis. 2011;58(1):118\u201326.","journal-title":"Am J Kidney Dis"},{"issue":"20","key":"1506_CR30","doi-asserted-by":"publisher","first-page":"3652","DOI":"10.1016\/j.cell.2022.08.026","volume":"185","author":"B Damania","year":"2022","unstructured":"Damania B, Kenney SC, Raab-Traub N. Epstein-Barr virus: biology and clinical disease. Cell. 2022;185(20):3652\u201370.","journal-title":"Cell"},{"issue":"10","key":"1506_CR31","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1097\/00007890-199911270-00015","volume":"68","author":"CV Paya","year":"1999","unstructured":"Paya CV, Fung JJ, Nalesnik MA, et al. Epstein-Barr virus-induced posttransplant lymphoproliferative disorders. ASTS\/ASTP EBV-PTLD Task Force and The Mayo Clinic organized international consensus development meeting. Transplantation. 1999;68(10):1517\u201325.","journal-title":"Transplantation"},{"issue":"8","key":"1506_CR32","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1111\/nep.12728","volume":"21","author":"JS Jamboti","year":"2016","unstructured":"Jamboti JS. BK virus nephropathy in renal transplant recipients. Nephrology. 2016;21(8):647\u201354.","journal-title":"Nephrology"},{"issue":"3","key":"1506_CR33","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.ajt.2022.12.013","volume":"23","author":"SA Mehta","year":"2023","unstructured":"Mehta SA, Saharia KK, Nellore A, et al. Infection and clinical xenotransplantation: guidance from the Infectious Disease Community of Practice of the American Society of Transplantation. Am J Transplant. 2023;23(3):309\u201315.","journal-title":"Am J Transplant"},{"issue":"6357","key":"1506_CR34","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1126\/science.aan4187","volume":"357","author":"D Niu","year":"2017","unstructured":"Niu D, Wei H-J, Lin L, et al. Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9. Science. 2017;357(6357):1303\u20137.","journal-title":"Science"},{"key":"1506_CR35","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1126\/science.285.5431.1236","volume":"285","author":"K Paradis","year":"1999","unstructured":"Paradis K, Langford G, Long Z, et al. Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig The XEN 111 Study Group. Science. 1999;285:1236\u201341.","journal-title":"Science"},{"key":"1506_CR36","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1111\/xen.12180","volume":"22","author":"J Denner","year":"2015","unstructured":"Denner J. Xenotransplantation and porcine cytomegalovirus. Xenotransplantation. 2015;22:329\u201335.","journal-title":"Xenotransplantation"},{"issue":"1","key":"1506_CR37","doi-asserted-by":"publisher","first-page":"17531","DOI":"10.1038\/s41598-020-73150-9","volume":"10","author":"J Denner","year":"2020","unstructured":"Denner J, L\u00e4ngin M, Reichart B, et al. Impact of porcine cytomegalovirus on long-term orthotopic cardiac xenotransplant survival. Sci Rep. 2020;10(1):17531.","journal-title":"Sci Rep"},{"issue":"1","key":"1506_CR38","doi-asserted-by":"publisher","first-page":"21545","DOI":"10.1038\/s41598-022-25624-1","volume":"12","author":"S Halecker","year":"2022","unstructured":"Halecker S, Hansen S, Krabben L, et al. How, where and when to screen for porcine cytomegalovirus (PCMV) in donor pigs for xenotransplantation. Sci Rep. 2022;12(1):21545.","journal-title":"Sci Rep"},{"key":"1506_CR39","unstructured":"The Japanese Society for Xenotransplantation. World Health Organization World Congress on consultation on regulatory requirements for xenotransplantation clinical trials; 2023. http:\/\/square.umin.ac.jp\/xeno\/img\/110.pdf. Written in Japanese. Accsessed 1 Aug 2023"}],"container-title":["Journal of Artificial Organs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10047-025-01506-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10047-025-01506-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10047-025-01506-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T12:47:43Z","timestamp":1757162863000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10047-025-01506-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,2]]},"references-count":39,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["1506"],"URL":"https:\/\/doi.org\/10.1007\/s10047-025-01506-x","relation":{},"ISSN":["1434-7229","1619-0904"],"issn-type":[{"value":"1434-7229","type":"print"},{"value":"1619-0904","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,2]]},"assertion":[{"value":"10 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}