{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T15:33:41Z","timestamp":1776440021618,"version":"3.51.2"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Ischemia\u2013reperfusion injury (IRI) is a mechanism based on inflammatory mediators\u2019 release and activation of effectors of damage. Studies showed a correlation between cytokine, severity of damage, and post-operative outcomes. Ex situ perfusion may work as a platform for the treatment of IRI mechanisms, such as the removal of cytokines using cytokine adsorption (CA). We assessed the safety and benefits of an integrated CA during ex situ dual-oxygenated hypothermic (D-HOPE) and normothermic perfusion (NMP). During the period of July 2021\u2013December 2023, 84 octogenarian liver grafts, suitable for transplantation, were considered: 12 were randomized to D-HOPE or NMP with or without CA (D-HOPE + CA, D-HOPE, NMP + CA, NMP groups, n = 3 each) and compared to 72 performed using grafts preserved in static cold storage (SCS). IL-1, IL-6, IL-10, and TNF-a perfusate concentrations were evaluated together with perfusion parameters and post-operative outcomes. Perfusion procedures were unaffected by CA integration. In NMP, cytokine levels were 10\u201340 times higher than in healthy subjects and 20\u201350 times higher than D-HOPE. Cytokines were removed both in D-HOPE and NMP, but the concentration-dependent mechanisms of action of CA led to more remarkable removal in NMP. IL-10 and TNF-a concentrations were significantly lower in NMP + CA than in NMP. The application of CA was associated with significantly higher arterial flows both in D-HOPE and NMP, and reduced neutrophil infiltration in NMP. No differences in post-operative outcomes were found among groups. In conclusion, cytokine adsorption during ex situ machine perfusion of liver grafts from elderly donors is safe and feasible and is associated with modulation of inflammatory mediators and perfusion dynamics. These findings are hypothesis-generating, and larger studies are required to determine the clinical impact of this strategy.<\/jats:p>","DOI":"10.3390\/life16010167","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T09:24:34Z","timestamp":1768901074000},"page":"167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cytokines Adsorption During Ex Situ Machine Perfusion of Liver Grafts from Elderly Donors: A Pilot, Prospective, Randomized Study"],"prefix":"10.3390","volume":"16","author":[{"given":"Giulia","family":"Cirillo","sequence":"first","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0272-7559","authenticated-orcid":false,"given":"Lorenzo","family":"Bernardi","sequence":"additional","affiliation":[{"name":"Department of Surgery, Lausanne University Hospital (CHUV), University of Lausanne, 1011 Lausanne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniele","family":"Pezzati","sequence":"additional","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9496-9370","authenticated-orcid":false,"given":"Maria","family":"Franzini","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Hospital, 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Balzano","sequence":"additional","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Tincani","sequence":"additional","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Bronzoni","sequence":"additional","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caterina","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6075-175X","authenticated-orcid":false,"given":"Arianna","family":"Trizzino","sequence":"additional","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Petagna","sequence":"additional","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8117-8796","authenticated-orcid":false,"given":"Paola","family":"Carrai","sequence":"additional","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Petruccelli","sequence":"additional","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ranka","family":"Vukotic","sequence":"additional","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erlis","family":"Uruci","sequence":"additional","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matilde","family":"Masini","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Hospital, 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1528-4184","authenticated-orcid":false,"given":"Serena","family":"Babboni","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3722-8861","authenticated-orcid":false,"given":"Serena","family":"Del Turco","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riccardo","family":"Morganti","sequence":"additional","affiliation":[{"name":"Department of Statistical Support to Clinical Study, Azienda Ospedaliera Universitaria Pisana (AOUP), University of Pisa, 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"De Tata","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Hospital, 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aldo","family":"Paolicchi","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Hospital, 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giandomenico","family":"Biancofiore","sequence":"additional","affiliation":[{"name":"Division of Anesthesia, Azienda Ospedaliera Universitaria Pisana (AOUP), University of Pisa, 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriano","family":"Peris","sequence":"additional","affiliation":[{"name":"Regional Transplant Authority of Tuscany (OTT), 50139 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Lazzeri","sequence":"additional","affiliation":[{"name":"Regional Transplant Authority of Tuscany (OTT), 50139 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0809-4374","authenticated-orcid":false,"given":"Giuseppina","family":"Basta","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7933-8941","authenticated-orcid":false,"given":"Davide","family":"Ghinolfi","sequence":"additional","affiliation":[{"name":"Division of Hepato-Biliary Surgery and Liver Transplantation, Azienda Ospedaliera Universitaria Pisana (AOUP), 56121 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100549","DOI":"10.1016\/j.trre.2020.100549","article-title":"Implications of liver donor age on ischemia reperfusion injury and clinical outcomes","volume":"34","author":"Dickson","year":"2020","journal-title":"Transplant. 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Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"122","DOI":"10.4240\/wjgs.v6.i7.122","article-title":"Mechanisms of hepatic ischemia-reperfusion injury and protective effects of nitric oxide","volume":"6","author":"Guan","year":"2014","journal-title":"World J. Gastrointest. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100639","DOI":"10.1016\/j.trre.2021.100639","article-title":"Extended criteria grafts and emerging therapeutics strategy in liver transplantation. The unstable balance between damage and repair","volume":"35","author":"Ghinolfi","year":"2021","journal-title":"Transplant. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"371","DOI":"10.2174\/1871530321666211124102837","article-title":"Emerging Role of Interleukins for the Assessment and Treatment of Liver Diseases","volume":"22","author":"Ali","year":"2022","journal-title":"Endocr. Metab. Immune Disord. 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