{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T18:36:03Z","timestamp":1793298963942,"version":"4.5.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Convergence Health & Technology","award":["HT\/FS\/2022025"],"award-info":[{"award-number":["HT\/FS\/2022025"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:sec>\n                    <jats:title>Background.<\/jats:title>\n                    <jats:p>Cell-free DNA (cfDNA) is a potential biomarker for graft (dys)function during machine perfusion, but its ability to predict posttransplant outcomes in donor kidneys remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods.<\/jats:title>\n                    <jats:p>We analyzed perfusate cfDNA from 57 hypothermic machine-perfused (HMP) and 56 normothermic machine-perfused (NMP) deceased donor kidneys. Nuclear cfDNA and mitochondrial cfDNA (mt-cfDNA) were quantified and compared across immediate graft function (IGF), delayed graft function (DGF), primary nonfunction (PNF), and discarded kidneys. Methylated DNA sequencing was used to analyze the cfDNA methylome during HMP to identify differentially methylated regions between IGF and PNF kidneys. Associations with donor characteristics and transplant outcomes, including serum creatinine, estimated glomerular filtration rate, and DGF duration, were assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results.<\/jats:title>\n                    <jats:p>\n                      Perfusate cfDNA concentrations during HMP were significantly higher in PNF kidneys (0.72\u2009ng\/\u00b5L) compared with both IGF (0.48\u2009ng\/\u00b5L) and DGF kidneys (0.43\u2009ng\/\u00b5L;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2005=\u20050.030 and\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2005=\u20050.031, respectively). mt-cfDNA was more abundant than nuclear cfDNA and was associated with better posttransplant graft outcome during HMP and, independently, predicted better graft outcome during NMP. Methylated DNA sequencing identified 5 differentially methylated regions between IGF and PNF located in pseudogenes or intergenic cytosine-phosphate-guanine dinucleotide islands.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions.<\/jats:title>\n                    <jats:p>cfDNA\u2014especially mt-cfDNA\u2014measured during machine perfusion is associated with posttransplant graft outcome during both HMP and NMP. Therefore, it may serve as a candidate biomarker that warrants validation in larger prospective studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1097\/txd.0000000000001995","type":"journal-article","created":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T19:00:13Z","timestamp":1793214013000},"page":"e1995","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Predictive Value of Perfusate Cell-free DNA During Hypothermic and Normothermic Machine Perfusion of Donor Kidneys"],"prefix":"10.1097","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9510-9002","authenticated-orcid":false,"given":"Karim","family":"Bousnina","sequence":"first","affiliation":[{"name":"Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia S.","family":"Slagter","sequence":"additional","affiliation":[{"name":"Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yitian","family":"Fang","sequence":"additional","affiliation":[{"name":"Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben G.","family":"Boers","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim B.","family":"Boers","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan","family":"Heidt","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilfred F.J.","family":"van IJcken","sequence":"additional","affiliation":[{"name":"Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost","family":"Gribnau","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert C.","family":"Minnee","sequence":"additional","affiliation":[{"name":"Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin J.","family":"Hoogduijn","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Boer","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"R1-20261029","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1097\/TP.0000000000003817","article-title":"Renal normothermic machine perfusion: the road toward clinical implementation of a promising pretransplant organ assessment tool.","volume":"106","author":"Hamelink","year":"2022","journal-title":"Transplantation"},{"key":"R2-20261029","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.1111\/j.1600-6143.2010.03179.x","article-title":"A risk prediction model for delayed graft function in the current era of deceased donor renal transplantation.","volume":"10","author":"Irish","year":"2010","journal-title":"Am J Transplant"},{"key":"R3-20261029","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1111\/ajt.13162","article-title":"Early graft loss after kidney transplantation: risk factors and consequences.","volume":"15","author":"Hamed","year":"2015","journal-title":"Am J Transplant"},{"key":"R4-20261029","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1111\/ajt.14526","article-title":"The duration of asystolic ischemia determines the risk of graft failure after circulatory-dead donor kidney transplantation: a Eurotransplant cohort study.","volume":"18","author":"Heylen","year":"2018","journal-title":"Am J Transplant"},{"key":"R5-20261029","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1111\/ajt.16491","article-title":"OPTN\/SRTR 2019 annual data report: deceased organ donors.","volume":"21","author":"Israni","year":"2021","journal-title":"Am J Transplant"},{"key":"R6-20261029","doi-asserted-by":"crossref","first-page":"487","DOI":"10.3390\/jcm11030487","article-title":"A review of current and emerging trends in donor graft-quality assessment techniques.","volume":"11","author":"Warmuzi\u0144ska","year":"2022","journal-title":"J Clin Med"},{"key":"R7-20261029","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1590\/s1677-5538.ibju.2024.0166","article-title":"Clinical outcomes prediction in kidney transplantation by use of biomarkers from hypothermic machine perfusion.","volume":"50","author":"de Almeida Leite","year":"2024","journal-title":"Int Braz J Urol"},{"key":"R8-20261029","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1111\/tri.13593","article-title":"A systematic review to identify whether perfusate biomarkers produced during hypothermic machine perfusion can predict graft outcomes in kidney transplantation.","volume":"33","author":"Guzzi","year":"2020","journal-title":"Transpl Int"},{"key":"R9-20261029","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1016\/j.transproceed.2024.05.032","article-title":"Diagnostic and prognostic value of machine perfusion biomarkers in kidney graft evaluation.","volume":"56","author":"Avramidou","year":"2024","journal-title":"Transplant Proc"},{"key":"R10-20261029","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1111\/ajt.13655","article-title":"Associations of perfusate biomarkers and pump parameters with delayed graft function and deceased donor kidney allograft function.","volume":"16","author":"Parikh","year":"2016","journal-title":"Am J Transplant"},{"key":"R11-20261029","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.clim.2012.04.006","article-title":"The origin and properties of extracellular DNA: from PAMP to DAMP.","volume":"144","author":"Pisetsky","year":"2012","journal-title":"Clin Immunol"},{"key":"R12-20261029","doi-asserted-by":"crossref","first-page":"9110","DOI":"10.3390\/ijms22179110","article-title":"Properties and application of cell-free DNA as a clinical biomarker.","volume":"22","author":"de Miranda","year":"2021","journal-title":"Int J Mol Sci"},{"key":"R13-20261029","doi-asserted-by":"crossref","first-page":"S90","DOI":"10.1016\/S0140-6736(08)61887-5","article-title":"Epigenetics in evolution and disease.","volume":"372","author":"Esteller","year":"2008","journal-title":"Lancet"},{"key":"R14-20261029","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1038\/nchem.2064","article-title":"5-Hydroxymethylcytosine is a predominantly stable DNA modification.","volume":"6","author":"Bachman","year":"2014","journal-title":"Nat Chem"},{"key":"R15-20261029","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1038\/nbt.1685","article-title":"Epigenetic modifications and human disease.","volume":"28","author":"Portela","year":"2010","journal-title":"Nat Biotechnol"},{"key":"R16-20261029","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nrg3230","article-title":"Functions of DNA methylation: islands, start sites, gene bodies and beyond.","volume":"13","author":"Jones","year":"2012","journal-title":"Nat Rev Genet"},{"key":"R17-20261029","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13148-020-00969-4","article-title":"Circulating cell-free nucleosomes as biomarker for kidney transplant rejection: a pilot study.","volume":"13","author":"Verhoeven","year":"2021","journal-title":"Clin Epigenetics"},{"key":"R18-20261029","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1097\/MOT.0000000000000833","article-title":"Variations in DNA methylation and allograft rejection.","volume":"26","author":"Boer","year":"2021","journal-title":"Curr Opin Organ Transplant"},{"key":"R19-20261029","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s13148-016-0288-0","article-title":"Variations in DNA methylation of interferon gamma and programmed death 1 in allograft rejection after kidney transplantation.","volume":"8","author":"Boer","year":"2016","journal-title":"Clin Epigenetics"},{"key":"R20-20261029","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13148-022-01241-7","article-title":"The applications of DNA methylation as a biomarker in kidney transplantation: a systematic review.","volume":"14","author":"Cristoferi","year":"2022","journal-title":"Clin Epigenetics"},{"key":"R21-20261029","doi-asserted-by":"crossref","first-page":"861498","DOI":"10.3389\/fimmu.2022.861498","article-title":"Epigenetic regulation in kidney transplantation.","volume":"13","author":"Xiang","year":"2022","journal-title":"Front Immunol"},{"key":"R22-20261029","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.jtcvs.2020.08.008","article-title":"Cell-free DNA in human ex vivo lung perfusate as a potential biomarker to predict the risk of primary graft dysfunction in lung transplantation.","volume":"162","author":"Kanou","year":"2021","journal-title":"J Thorac Cardiovasc Surg"},{"key":"R23-20261029","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1097\/TP.0000000000004842","article-title":"Graft-derived cfDNA monitoring in plasma and bile during normothermic machine perfusion in liver transplantation is feasible and a potential tool for assessing graft viability.","volume":"108","author":"Cox","year":"2024","journal-title":"Transplantation"},{"key":"R24-20261029","doi-asserted-by":"crossref","first-page":"e1768","DOI":"10.1097\/TXD.0000000000001768","article-title":"Soluble DNA concentration in the perfusate is a predictor of posttransplant renal function in hypothermic machine perfused kidney allografts.","volume":"11","author":"Duarte","year":"2025","journal-title":"Transplant Direct"},{"key":"R25-20261029","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.ajt.2025.12.021","article-title":"Normothermic versus hypothermic machine perfusion in kidney transplantation: a randomized controlled trial.","volume":"26","author":"Slagter","year":"2026","journal-title":"Am J Transplant"},{"key":"R26-20261029","doi-asserted-by":"crossref","first-page":"e27122","DOI":"10.1016\/j.heliyon.2024.e27122","article-title":"Mitochondrial DNA levels in perfusate and bile during ex vivo normothermic machine correspond with donor liver quality.","volume":"10","author":"Westhaver","year":"2024","journal-title":"Heliyon"},{"key":"R27-20261029","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1101\/gr.222885.117","article-title":"Genome-wide DNA methylation profiling using the methylation-dependent restriction enzyme LpnPI.","volume":"28","author":"Boers","year":"2018","journal-title":"Genome Res"},{"key":"R28-20261029","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1186\/s13148-021-01177-4","article-title":"High-throughput and affordable genome-wide methylation profiling of circulating cell-free DNA by methylated DNA sequencing (MeD-seq) of LpnPI digested fragments.","volume":"13","author":"Deger","year":"2021","journal-title":"Clin Epigenetics"},{"key":"R30-20261029","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S0968-0004(00)01688-1","article-title":"Mitochondrial genetics and disease.","volume":"25","author":"Schon","year":"2000","journal-title":"Trends Biochem Sci"},{"key":"R31-20261029","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1111\/aor.14910","article-title":"Circulating cell-free DNA in liver transplantation: a pre- and post-transplant biomarker of graft dysfunction.","volume":"49","author":"Sorbini","year":"2025","journal-title":"Artif Organs"},{"key":"R32-20261029","doi-asserted-by":"crossref","first-page":"8060949","DOI":"10.1155\/2017\/8060949","article-title":"Mitochondrial nucleoid: shield and switch of the mitochondrial genome.","volume":"2017","author":"Lee","year":"2017","journal-title":"Oxid Med Cell Longev"},{"key":"R33-20261029","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1097\/TP.0000000000002597","article-title":"Circulating donor mitochondrial DNA: tales the dead may tell.","volume":"103","author":"Menon","year":"2019","journal-title":"Transplantation"},{"key":"R34-20261029","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1097\/MOT.0b013e3283510817","article-title":"The super-rapid technique in Maastricht category III donors: has it developed enough for marginal liver grafts from donors after cardiac death?","volume":"17","author":"Perera","year":"2012","journal-title":"Curr Opin Organ Transplant"},{"key":"R35-20261029","doi-asserted-by":"crossref","first-page":"7523","DOI":"10.3390\/ijms22147523","article-title":"How machine perfusion ameliorates hepatic ischaemia reperfusion injury.","volume":"22","author":"Clarke","year":"2021","journal-title":"Int J Mol Sci"},{"key":"R36-20261029","doi-asserted-by":"crossref","first-page":"6670579","DOI":"10.1155\/2021\/6670579","article-title":"The role of mitochondria in liver ischemia-reperfusion injury: from aspects of mitochondrial oxidative stress, mitochondrial fission, mitochondrial membrane permeable transport pore formation, mitophagy, and mitochondria-related protective measures.","volume":"2021","author":"Zhang","year":"2021","journal-title":"Oxid Med Cell Longev"},{"key":"R37-20261029","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S0168-9525(98)01636-9","article-title":"The DNA methylation paradox.","volume":"15","author":"Jones","year":"1999","journal-title":"Trends Genet"},{"key":"R38-20261029","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1681\/ASN.2017091027","article-title":"Ischemia-induced DNA hypermethylation during kidney transplant predicts chronic allograft injury.","volume":"29","author":"Heylen","year":"2018","journal-title":"J Am Soc Nephrol"},{"key":"R39-20261029","doi-asserted-by":"crossref","first-page":"117673","DOI":"10.1016\/j.cca.2023.117673","article-title":"Comparative study of droplet-digital PCR and absolute Q digital PCR for ctDNA detection in early-stage breast cancer patients.","volume":"552","author":"S\u00e1nchez-Mart\u00edn","year":"2024","journal-title":"Clin Chim Acta"},{"key":"R40-20261029","doi-asserted-by":"crossref","first-page":"100926","DOI":"10.1016\/j.medj.2025.100926","article-title":"The comings and goings of cell-free DNA: biological and clinical implications.","volume":"7","author":"Malki","year":"2026","journal-title":"Med"},{"key":"R41-20261029","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging.","volume":"153","author":"L\u00f3pez-Ot\u00edn","year":"2013","journal-title":"Cell"},{"key":"R42-20261029","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.canlet.2008.02.026","article-title":"Oxidative stress, DNA methylation and carcinogenesis.","volume":"266","author":"Franco","year":"2008","journal-title":"Cancer Lett"}],"container-title":["Transplantation Direct"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.1097\/TXD.0000000000001995","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T18:02:33Z","timestamp":1793296953000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.1097\/TXD.0000000000001995"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":41,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.1097\/txd.0000000000001995","relation":{},"ISSN":["2373-8731"],"issn-type":[{"value":"2373-8731","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]},"assertion":[{"value":"2026-04-19","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-08","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}