Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP-which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion-will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.

Department of Gastroenterology Metabolic Disorders and Intensive Care University Hospital RWTH Aachen 52074 Aachen Germany

Department of General Visceral and Transplantation Surgery University of Heidelberg 69120 Heidelberg Germany

Department of Hepatology and Gastroenterology Campus Charité Mitte | Campus Virchow Klinikum Charité Universitätsmedizin Berlin 13353 Berlin Germany

Department of Surgery and Transplantation University Hospital RWTH Aachen 52074 Aachen Germany

Department of Surgery Campus Charité Mitte | Campus Virchow Klinikum Charité Universitätsmedizin Berlin 13353 Berlin Germany

Department of Transplant Surgery Institute for Clinical and Experimental Medicine 140 21 Prague Czech Republic

The Liver Unit Queen Elizabeth Hospital Birmingham Birmingham B15 2TH UK

Zobrazit více v PubMed

Land W.G. The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation. Transplantation. 2005;79:505–514. doi: 10.1097/01.TP.0000153160.82975.86. PubMed DOI

Zhang Z., Qiu L., Yan S., Wang J.-J., Thomas P.M., Kandpal M., Zhao L., Iovane A., Liu X.-F., Thorp E.B., et al. A clinically relevant murine model unmasks a “two-hit” mechanism for reactivation and dissemination of cytomegalovirus after kidney transplant. Am. J. Transplant. 2019;19:2421–2433. doi: 10.1111/ajt.15376. PubMed DOI PMC

Tacke F., Kroy D.C., Barreiros A.P., Neumann U.P. Liver transplantation in Germany. Liver Transplant. 2016 doi: 10.1002/lt.24461. PubMed DOI

Eurotransplant. [(accessed on 18 March 2020)]; Waiting List Mortality in 2015, by Country, by Organ. Available online: https://statistics.eurotransplant.org/

Czigany Z., Schoning W., Ulmer T.F., Bednarsch J., Amygdalos I., Cramer T., Rogiers X., Popescu I., Botea F., Fronek J., et al. Hypothermic oxygenated machine perfusion (HOPE) for orthotopic liver transplantation of human liver allografts from extended criteria donors (ECD) in donation after brain death (DBD): A prospective multicentre randomised controlled trial (HOPE ECD-DBD) BMJ Open. 2017;7:e017558. doi: 10.1136/bmjopen-2017-017558. PubMed DOI PMC

Czigany Z., Lurje I., Tolba R.H., Neumann U.P., Tacke F., Lurje G. Machine perfusion for liver transplantation in the era of marginal organs-New kids on the block. Liver Int. 2018 doi: 10.1111/liv.13946. PubMed DOI

Merion R.M., Goodrich N.P., Feng S. How can we define expanded criteria for liver donors? J. Hepatol. 2006;45:484–488. doi: 10.1016/j.jhep.2006.07.016. PubMed DOI

Ploeg R.J., D’Alessandro A.M., Knechtle S.J., Stegall M.D., Pirsch J.D., Hoffmann R.M., Sasaki T., Sollinger H.W., Belzer F.O., Kalayoglu M. Risk factors for primary dysfunction after liver transplantation--a multivariate analysis. Transplantation. 1993;55:807–813. doi: 10.1097/00007890-199304000-00024. PubMed DOI

Busquets J., Xiol X., Figueras J., Jaurrieta E., Torras J., Ramos E., Rafecas A., Fabregat J., Lama C., Ibanez L., et al. The impact of donor age on liver transplantation: Influence of donor age on early liver function and on subsequent patient and graft survival. Transplantation. 2001;71:1765–1771. doi: 10.1097/00007890-200106270-00011. PubMed DOI

Piratvisuth T., Tredger J.M., Hayllar K.A., Williams R. Contribution of true cold and rewarming ischemia times to factors determining outcome after orthotopic liver transplantation. Liver Transplant. Surg. 1995;1:296–301. doi: 10.1002/lt.500010505. PubMed DOI

Czigany Z., Bleilevens C., Beckers C., Stoppe C., Mohring M., Fulop A., Szijarto A., Lurje G., Neumann U.P., Tolba R.H. Limb remote ischemic conditioning of the recipient protects the liver in a rat model of arterialized orthotopic liver transplantation. PLoS ONE. 2018;13:e0195507. doi: 10.1371/journal.pone.0195507. PubMed DOI PMC

Emontzpohl C., Stoppe C., Theissen A., Beckers C., Neumann U.P., Lurje G., Ju C., Bernhagen J., Tolba R.H., Czigany Z. The Role of Macrophage Migration Inhibitory Factor in Remote Ischemic Conditioning Induced Hepatoprotection in A Rodent Model of Liver Transplantation. Shock. 2018 doi: 10.1097/SHK.0000000000001307. PubMed DOI

Gao W., Bentley R.C., Madden J.F., Clavien P.A. Apoptosis of sinusoidal endothelial cells is a critical mechanism of preservation injury in rat liver transplantation. Hepatology. 1998;27:1652–1660. doi: 10.1002/hep.510270626. PubMed DOI

Ploeg R.J., van Bockel J.H., Langendijk P.T., Groenewegen M., van der Woude F.J., Persijn G.G., Thorogood J., Hermans J. Effect of preservation solution on results of cadaveric kidney transplantation. The European Multicentre Study Group. Lancet. 1992;340:129–137. doi: 10.1016/0140-6736(92)93212-6. PubMed DOI

Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am. J. Physiol. Gastrointest. Liver Physiol. 2003;284:G15–G26. doi: 10.1152/ajpgi.00342.2002. PubMed DOI

Hessheimer A.J., Garcia-Valdecasas J.C., Fondevila C. Abdominal regional in-situ perfusion in donation after circulatory determination of death donors. Curr. Opin. Organ Transplant. 2016;21:322–328. doi: 10.1097/MOT.0000000000000315. PubMed DOI

Stewart R.K., Dangi A., Huang C., Murase N., Kimura S., Stolz D.B., Wilson G.C., Lentsch A.B., Gandhi C.R. A novel mouse model of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury. J. Hepatol. 2014;60:298–305. doi: 10.1016/j.jhep.2013.09.013. PubMed DOI PMC

Belzer F.O., Southard J.H. Principles of solid-organ preservation by cold storage. Transplantation. 1988;45:673–676. doi: 10.1097/00007890-198804000-00001. PubMed DOI

Chouchani E.T., Pell V.R., James A.M., Work L.M., Saeb-Parsy K., Frezza C., Krieg T., Murphy M.P. A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury. Cell Metab. 2016;23:254–263. doi: 10.1016/j.cmet.2015.12.009. PubMed DOI

Peralta C., Bartrons R., Riera L., Manzano A., Xaus C., Gelpi E., Rosello-Catafau J. Hepatic preconditioning preserves energy metabolism during sustained ischemia. Am. J. Physiol. Gastrointest. Liver Physiol. 2000;279:G163–G171. doi: 10.1152/ajpgi.2000.279.1.G163. PubMed DOI

Carini R., Bellomo G., Benedetti A., Fulceri R., Gamberucci A., Parola M., Dianzani M.U., Albano E. Alteration of Na+ homeostasis as a critical step in the development of irreversible hepatocyte injury after adenosine triphosphate depletion. Hepatology. 1995;21:1089–1098. PubMed

Zaouali M.A., Ben Abdennebi H., Padrissa-Altes S., Mahfoudh-Boussaid A., Rosello-Catafau J. Pharmacological strategies against cold ischemia reperfusion injury. Expert Opin. Pharmacother. 2010;11:537–555. doi: 10.1517/14656560903547836. PubMed DOI

Niatsetskaya Z.V., Sosunov S.A., Matsiukevich D., Utkina-Sosunova I.V., Ratner V.I., Starkov A.A., Ten V.S. The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice. J. Neurosci. 2012;32:3235–3244. doi: 10.1523/JNEUROSCI.6303-11.2012. PubMed DOI PMC

Chen Q., Moghaddas S., Hoppel C.L., Lesnefsky E.J. Reversible blockade of electron transport during ischemia protects mitochondria and decreases myocardial injury following reperfusion. J. Pharmacol. Exp. Ther. 2006;319:1405–1412. doi: 10.1124/jpet.106.110262. PubMed DOI

Hoyer D.P., Mathe Z., Gallinat A., Canbay A.C., Treckmann J.W., Rauen U., Paul A., Minor T. Controlled Oxygenated Rewarming of Cold Stored Livers Prior to Transplantation: First Clinical Application of a New Concept. Transplantation. 2016;100:147–152. doi: 10.1097/TP.0000000000000915. PubMed DOI

van Golen R.F., Reiniers M.J., Olthof P.B., van Gulik T.M., Heger M. Sterile inflammation in hepatic ischemia/reperfusion injury: Present concepts and potential therapeutics. J. Gastroenterol. Hepatol. 2013;28:394–400. doi: 10.1111/jgh.12072. PubMed DOI

Essani N.A., McGuire G.M., Manning A.M., Jaeschke H. Endotoxin-induced activation of the nuclear transcription factor kappa B and expression of E-selectin messenger RNA in hepatocytes, Kupffer cells, and endothelial cells in vivo. J. Immunol. 1996;156:2956–2963. PubMed

Essani N.A., Fisher M.A., Jaeschke H. Inhibition of NF-kappa B activation by dimethyl sulfoxide correlates with suppression of TNF-alpha formation, reduced ICAM-1 gene transcription, and protection against endotoxin-induced liver injury. Shock. 1997;7:90–96. doi: 10.1097/00024382-199702000-00003. PubMed DOI

Jaeschke H., Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver. Am. J. Physiol. 1991;260:G355–G362. doi: 10.1152/ajpgi.1991.260.3.G355. PubMed DOI

Perry B.C., Soltys D., Toledo A.H., Toledo-Pereyra L.H. Tumor necrosis factor-alpha in liver ischemia/reperfusion injury. J. Investig. Surg. 2011;24:178–188. doi: 10.3109/08941939.2011.568594. PubMed DOI

van Golen R.F., van Gulik T.M., Heger M. Mechanistic overview of reactive species-induced degradation of the endothelial glycocalyx during hepatic ischemia/reperfusion injury. Free Radic. Biol. Med. 2012;52:1382–1402. doi: 10.1016/j.freeradbiomed.2012.01.013. PubMed DOI

Cywes R., Packham M.A., Tietze L., Sanabria J.R., Harvey P.R., Phillips M.J., Strasberg S.M. Role of platelets in hepatic allograft preservation injury in the rat. Hepatology. 1993;18:635–647. doi: 10.1002/hep.1840180324. PubMed DOI

Koo A., Komatsu H., Tao G., Inoue M., Guth P.H., Kaplowitz N. Contribution of no-reflow phenomenon to hepatic injury after ischemia-reperfusion: Evidence for a role for superoxide anion. Hepatology. 1992;15:507–514. doi: 10.1002/hep.1840150325. PubMed DOI

Clemens M.G. Nitric oxide in liver injury. Hepatology. 1999;30:1–5. doi: 10.1002/hep.510300148. PubMed DOI

Boecker J., Czigany Z., Bednarsch J., Amygdalos I., Meister F., Santana D.A.M., Liu W.J., Strnad P., Neumann U.P., Lurje G. Potential value and limitations of different clinical scoring systems in the assessment of short- and long-term outcome following orthotopic liver transplantation. PLoS ONE. 2019;14:e0214221. doi: 10.1371/journal.pone.0214221. PubMed DOI PMC

Boteon Y.L., Boteon A., Attard J., Mergental H., Mirza D.F., Bhogal R.H., Afford S.C. Ex situ machine perfusion as a tool to recondition steatotic donor livers: Troublesome features of fatty livers and the role of defatting therapies. A systematic review. Am. J. Transplant. 2018;18:2384–2399. doi: 10.1111/ajt.14992. PubMed DOI

Ijaz S., Yang W., Winslet M.C., Seifalian A.M. Impairment of hepatic microcirculation in fatty liver. Microcirculation. 2003;10:447–456. doi: 10.1038/sj.mn.7800206. PubMed DOI

Fernandez L., Carrasco-Chaumel E., Serafin A., Xaus C., Grande L., Rimola A., Rosello-Catafau J., Peralta C. Is ischemic preconditioning a useful strategy in steatotic liver transplantation? Am. J. Transplant. 2004;4:888–899. doi: 10.1111/j.1600-6143.2004.00447.x. PubMed DOI

Ben Mosbah I., Alfany-Fernandez I., Martel C., Zaouali M.A., Bintanel-Morcillo M., Rimola A., Rodes J., Brenner C., Rosello-Catafau J., Peralta C. Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemia-reperfusion. Cell Death Dis. 2010;1:e52. doi: 10.1038/cddis.2010.29. PubMed DOI PMC

Ijaz S., Yang W., Winslet M.C., Seifalian A.M. The role of nitric oxide in the modulation of hepatic microcirculation and tissue oxygenation in an experimental model of hepatic steatosis. Microvasc. Res. 2005;70:129–136. doi: 10.1016/j.mvr.2005.08.001. PubMed DOI

Hayashi M., Tokunaga Y., Fujita T., Tanaka K., Yamaoka Y., Ozawa K. The effects of cold preservation on steatotic graft viability in rat liver transplantation. Transplantation. 1993;56:282–287. doi: 10.1097/00007890-199308000-00005. PubMed DOI

Kron P., Schlegel A., Mancina L., Clavien P.A., Dutkowski P. Hypothermic oxygenated perfusion (HOPE) for fatty liver grafts in rats and humans. J. Hepatol. 2017 doi: 10.1016/j.jhep.2017.08.028. PubMed DOI

Jay C.L., Lyuksemburg V., Ladner D.P., Wang E., Caicedo J.C., Holl J.L., Abecassis M.M., Skaro A.I. Ischemic cholangiopathy after controlled donation after cardiac death liver transplantation: A meta-analysis. Ann. Surg. 2011;253:259–264. doi: 10.1097/SLA.0b013e318204e658. PubMed DOI

Foley D.P., Fernandez L.A., Leverson G., Anderson M., Mezrich J., Sollinger H.W., D’Alessandro A. Biliary complications after liver transplantation from donation after cardiac death donors: An analysis of risk factors and long-term outcomes from a single center. Ann. Surg. 2011;253:817–825. doi: 10.1097/SLA.0b013e3182104784. PubMed DOI PMC

Dawson P.A., Lan T., Rao A. Bile acid transporters. J. Lipid Res. 2009;50:2340–2357. doi: 10.1194/jlr.R900012-JLR200. PubMed DOI PMC

Hertl M., Harvey P.R.C., Swanson P.E., West D.D., Howard T.K., Shenoy S., Strasberg S.M. Evidence of preservation injury to bile ducts by bile salts in the pig and its prevention by infusions of hydrophilic bile salts. Hepatology. 1995;21:1130–1137. doi: 10.1002/hep.1840210436. PubMed DOI

Durand F., Levitsky J., Cauchy F., Gilgenkrantz H., Soubrane O., Francoz C. Age and liver transplantation. J. Hepatol. 2019;70:745–758. doi: 10.1016/j.jhep.2018.12.009. PubMed DOI

Bertuzzo V.R., Cescon M., Odaldi F., Di Laudo M., Cucchetti A., Ravaioli M., Del Gaudio M., Ercolani G., D’Errico A., Pinna A.D. Actual Risk of Using Very Aged Donors for Unselected Liver Transplant Candidates: A European Single-center Experience in the MELD Era. Ann. Surg. 2017;265:388–396. doi: 10.1097/SLA.0000000000001681. PubMed DOI

Detelich D., Markmann J.F. The dawn of liver perfusion machines. Curr. Opin. Organ Transplant. 2018;23:151–161. doi: 10.1097/MOT.0000000000000500. PubMed DOI PMC

Diaz Jaime F., Berenguer M. Pushing the donor limits: Deceased donor liver transplantation using organs from octogenarian donors. Liver Transplant. 2017;23:S22–S26. doi: 10.1002/lt.24841. PubMed DOI

Starzl T.E., Groth C.G., Brettschneider L., Penn I., Fulginiti V.A., Moon J.B., Blanchard H., Martin A.J., Jr., Porter K.A. Orthotopic homotransplantation of the human liver. Ann. Surg. 1968;168:392–415. doi: 10.1097/00000658-196809000-00009. PubMed DOI PMC

Vogel T., Brockmann J.G., Coussios C., Friend P.J. The role of normothermic extracorporeal perfusion in minimizing ischemia reperfusion injury. Transplant. Rev. 2012;26:156–162. doi: 10.1016/j.trre.2011.02.004. PubMed DOI

Reddy S.P., Bhattacharjya S., Maniakin N., Greenwood J., Guerreiro D., Hughes D., Imber C.J., Pigott D.W., Fuggle S., Taylor R., et al. Preservation of porcine non-heart-beating donor livers by sequential cold storage and warm perfusion. Transplantation. 2004;77:1328–1332. doi: 10.1097/01.TP.0000119206.63326.56. PubMed DOI

Mergental H., Laing R.W., Kirkham A.J., Perera T.P.R., Boteon Y., Attard J., Barton D., Wilkhu M., Curbishley S., Neil D.A., et al. Transplantation after Viability Testing of Discarded Livers with Normothermic Machine Perfusion (NMP): The Vittal (VIability Testing and Transplantation of mArginal Livers) Trial 90-Day Outcomes. Hepatology. 2018;68 doi: 10.1002/hep.30256. DOI

Nasralla D., Coussios C.C., Mergental H., Akhtar M.Z., Butler A.J., Ceresa C.D.L., Chiocchia V., Dutton S.J., Garcia-Valdecasas J.C., Heaton N., et al. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018;557:50–56. doi: 10.1038/s41586-018-0047-9. PubMed DOI

Czigany Z., Tacke F., Lurje G. Evolving Trends in Machine Liver Perfusion: Comments on Clinical End Points and Selection Criteria. Gastroenterology. 2019;157:1166–1167. doi: 10.1053/j.gastro.2019.02.051. PubMed DOI

Eshmuminov D., Becker D., Bautista Borrego L., Hefti M., Schuler M.J., Hagedorn C., Muller X., Mueller M., Onder C., Graf R., et al. An integrated perfusion machine preserves injured human livers for 1 week. Nat. Biotechnol. 2020 doi: 10.1038/s41587-019-0374-x. PubMed DOI PMC

op den Dries S., Karimian N., Sutton M.E., Westerkamp A.C., Nijsten M.W., Gouw A.S., Wiersema-Buist J., Lisman T., Leuvenink H.G., Porte R.J. Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers. Am. J. Transplant. 2013;13:1327–1335. doi: 10.1111/ajt.12187. PubMed DOI

Guarrera J.V., Henry S.D., Samstein B., Reznik E., Musat C., Lukose T.I., Ratner L.E., Brown R.S., Jr., Kato T., Emond J.C. Hypothermic machine preservation facilitates successful transplantation of “orphan” extended criteria donor livers. Am. J. Transplant. 2015;15:161–169. doi: 10.1111/ajt.12958. PubMed DOI

Moers C., Smits J.M., Maathuis M.H., Treckmann J., van Gelder F., Napieralski B.P., van Kasterop-Kutz M., van der Heide J.J., Squifflet J.P., van Heurn E., et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N. Engl. J. Med. 2009;360:7–19. doi: 10.1056/NEJMoa0802289. PubMed DOI

Guarrera J.V., Henry S.D., Samstein B., Odeh-Ramadan R., Kinkhabwala M., Goldstein M.J., Ratner L.E., Renz J.F., Lee H.T., Brown J.R.S., et al. Hypothermic Machine Preservation in Human Liver Transplantation: The First Clinical Series. Am. J. Transplant. 2010;10:372–381. doi: 10.1111/j.1600-6143.2009.02932.x. PubMed DOI

Henry S.D., Nachber E., Tulipan J., Stone J., Bae C., Reznik L., Kato T., Samstein B., Emond J.C., Guarrera J.V. Hypothermic machine preservation reduces molecular markers of ischemia/reperfusion injury in human liver transplantation. Am. J. Transplant. 2012;12:2477–2486. doi: 10.1111/j.1600-6143.2012.04086.x. PubMed DOI

Balzan S., Belghiti J., Farges O., Ogata S., Sauvanet A., Delefosse D., Durand F. The “50-50 Criteria” on Postoperative Day 5: An Accurate Predictor of Liver Failure and Death After Hepatectomy. Ann. Surg. 2005;242:824–829. doi: 10.1097/01.sla.0000189131.90876.9e. PubMed DOI PMC

de Rougemont O., Breitenstein S., Leskosek B., Weber A., Graf R., Clavien P.A., Dutkowski P. One hour hypothermic oxygenated perfusion (HOPE) protects nonviable liver allografts donated after cardiac death. Ann. Surg. 2009;250:674–683. doi: 10.1097/SLA.0b013e3181bcb1ee. PubMed DOI

Dutkowski P., Schlegel A., de Oliveira M., Mullhaupt B., Neff F., Clavien P.A. HOPE for human liver grafts obtained from donors after cardiac death. J. Hepatol. 2014;60:765–772. doi: 10.1016/j.jhep.2013.11.023. PubMed DOI

Dutkowski P., Polak W.G., Muiesan P., Schlegel A., Verhoeven C.J., Scalera I., DeOliveira M.L., Kron P., Clavien P.A. First Comparison of Hypothermic Oxygenated PErfusion Versus Static Cold Storage of Human Donation After Cardiac Death Liver Transplants: An International-matched Case Analysis. Ann. Surg. 2015;262:764–771. doi: 10.1097/SLA.0000000000001473. PubMed DOI

Schlegel A., Muller X., Kalisvaart M., Muellhaupt B., Perera M., Isaac J.R., Clavien P.A., Muiesan P., Dutkowski P. Outcomes of DCD liver transplantation using organs treated by hypothermic oxygenated perfusion before implantation. J. Hepatol. 2019;70:50–57. doi: 10.1016/j.jhep.2018.10.005. PubMed DOI

van Rijn R., Karimian N., Matton A.P.M., Burlage L.C., Westerkamp A.C., van den Berg A.P., de Kleine R.H.J., de Boer M.T., Lisman T., Porte R.J. Dual hypothermic oxygenated machine perfusion in liver transplants donated after circulatory death. Br. J. Surg. 2017;104:907–917. doi: 10.1002/bjs.10515. PubMed DOI PMC

van Rijn R., van Leeuwen O.B., Matton A.P.M., Burlage L.C., Wiersema-Buist J., van den Heuvel M.C., de Kleine R.H.J., de Boer M.T., Gouw A.S.H., Porte R.J. Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers. Liver Transplant. 2018;24:655–664. doi: 10.1002/lt.25023. PubMed DOI PMC

Patrono D., Surra A., Catalano G., Rizza G., Berchialla P., Martini S., Tandoi F., Lupo F., Mirabella S., Stratta C., et al. Hypothermic Oxygenated Machine Perfusion of Liver Grafts from Brain-Dead Donors. Sci. Rep. 2019;9:9337. doi: 10.1038/s41598-019-45843-3. PubMed DOI PMC

Brüggenwirth I.M.A., Burlage L.C., Porte R.J., Martins P.N. Is single portal vein perfusion the best approach for machine preservation of liver grafts? J. Hepatol. 2016;64:1194–1195. doi: 10.1016/j.jhep.2015.12.025. PubMed DOI

van Rijn R., van den Berg A.P., Erdmann J.I., Heaton N., van Hoek B., de Jonge J., Leuvenink H.G.D., Mahesh S.V.K., Mertens S., Monbaliu D., et al. Study protocol for a multicenter randomized controlled trial to compare the efficacy of end-ischemic dual hypothermic oxygenated machine perfusion with static cold storage in preventing non-anastomotic biliary strictures after transplantation of liver grafts donated after circulatory death: DHOPE-DCD trial. BMC Gastroenterol. 2019;19:40. doi: 10.1186/s12876-019-0956-6. PubMed DOI PMC

van Leeuwen O.B., de Vries Y., Fujiyoshi M., Nijsten M.W.N., Ubbink R., Pelgrim G.J., Werner M.J.M., Reyntjens K., van den Berg A.P., de Boer M.T., et al. Transplantation of High-risk Donor Livers After Ex Situ Resuscitation and Assessment Using Combined Hypo- and Normothermic Machine Perfusion: A Prospective Clinical Trial. Ann. Surg. 2019;270:906–914. doi: 10.1097/SLA.0000000000003540. PubMed DOI

Boteon Y.L., Laing R.W., Schlegel A., Wallace L., Smith A., Attard J., Bhogal R.H., Reynolds G., Pr Perera M.T., Muiesan P., et al. The impact on the bioenergetic status and oxidative-mediated tissue injury of a combined protocol of hypothermic and normothermic machine perfusion using an acellular haemoglobin-based oxygen carrier: The cold-to-warm machine perfusion of the liver. PLoS ONE. 2019;14:e0224066. doi: 10.1371/journal.pone.0224066. PubMed DOI PMC

Mergental H., Stephenson B.T.F., Laing R.W., Kirkham A.J., Neil D.A.H., Wallace L.L., Boteon Y.L., Widmer J., Bhogal R.H., Perera M., et al. Development of Clinical Criteria for Functional Assessment to Predict Primary Nonfunction of High-Risk Livers Using Normothermic Machine Perfusion. Liver Transplant. 2018;24:1453–1469. doi: 10.1002/lt.25291. PubMed DOI PMC

Brockmann J., Reddy S., Coussios C., Pigott D., Guirriero D., Hughes D., Morovat A., Roy D., Winter L., Friend P.J. Normothermic perfusion: A new paradigm for organ preservation. Ann. Surg. 2009;250:1–6. doi: 10.1097/SLA.0b013e3181a63c10. PubMed DOI

Selten J., Schlegel A., de Jonge J., Dutkowski P. Hypo- and normothermic perfusion of the liver: Which way to go? Best Pract. Res. Clin. Gastroenterol. 2017;31:171–179. doi: 10.1016/j.bpg.2017.04.001. PubMed DOI

Muller X., Schlegel A., Kron P., Eshmuminov D., Wurdinger M., Meierhofer D., Clavien P.A., Dutkowski P. Novel Real-time Prediction of Liver Graft Function During Hypothermic Oxygenated Machine Perfusion Before Liver Transplantation. Ann. Surg. 2019;270:783–790. doi: 10.1097/SLA.0000000000003513. PubMed DOI

Bhogal R.H., Mirza D.F., Afford S.C., Mergental H. Biomarkers of Liver Injury during Transplantation in an Era of Machine Perfusion. Int. J. Mol. Sci. 2020;21 doi: 10.3390/ijms21051578. PubMed DOI PMC

Boteon Y.L., Wallace L., Boteon A., Mirza D.F., Mergental H., Bhogal R.H., Afford S. An effective protocol for pharmacological defatting of primary human hepatocytes which is non-toxic to cholangiocytes or intrahepatic endothelial cells. PLoS ONE. 2018;13:e0201419. doi: 10.1371/journal.pone.0201419. PubMed DOI PMC

Yagi S., Nagai K., Kadaba P., Afify M., Teramukai S., Uemoto S., Tolba R.H. A novel organ preservation for small partial liver transplantations in rats: Venous systemic oxygen persuf fl ation with nitric oxide gas. Am. J. Transplant. 2013;13:222–228. doi: 10.1111/j.1600-6143.2012.04310.x. PubMed DOI

Jochmans I., O’Callaghan J.M., Pirenne J., Ploeg R.J. Hypothermic machine perfusion of kidneys retrieved from standard and high-risk donors. Transplant. Int. 2015;28:665–676. doi: 10.1111/tri.12530. PubMed DOI

Yao C.G., Martins P.N. Nanotechnology Applications in Transplantation Medicine. Transplantation. 2019 doi: 10.1097/TP.0000000000003032. PubMed DOI

Tietjen G.T., Hosgood S.A., DiRito J., Cui J., Deep D., Song E., Kraehling J.R., Piotrowski-Daspit A.S., Kirkiles-Smith N.C., Al-Lamki R., et al. Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys. Sci. Transl. Med. 2017;9 doi: 10.1126/scitranslmed.aam6764. PubMed DOI PMC

Gillooly A.R., Perry J., Martins P.N. First Report of siRNA Uptake (for RNA Interference) During Ex Vivo Hypothermic and Normothermic Liver Machine Perfusion. Transplantation. 2019;103:e56–e57. doi: 10.1097/TP.0000000000002515. PubMed DOI

Thijssen M.F., Bruggenwirth I.M.A., Gillooly A., Khvorova A., Kowalik T.F., Martins P.N. Gene Silencing With siRNA (RNA Interference): A New Therapeutic Option During Ex Vivo Machine Liver Perfusion Preservation. Liver Transplant. 2019;25:140–151. doi: 10.1002/lt.25383. PubMed DOI

Van Raemdonck D., Neyrinck A., Rega F., Devos T., Pirenne J. Machine perfusion in organ transplantation: A tool for ex-vivo graft conditioning with mesenchymal stem cells? Curr. Opin. Organ Transplant. 2013;18:24–33. doi: 10.1097/MOT.0b013e32835c494f. PubMed DOI

Kalenski J., Mancina E., Paschenda P., Beckers C., Bleilevens C., Tothova L., Boor P., Gross D., Tolba R.H., Doorschodt B.M. Comparison of Aerobic Preservation by Venous Systemic Oxygen Persufflation or Oxygenated Machine Perfusion of Warm-Ischemia-Damaged Porcine Kidneys. Eur. Surg. Res. Eur. Chir. Forsch. Rech. Chir. Eur. 2016;57:10–21. doi: 10.1159/000444851. PubMed DOI

Karimian N., Yeh H. Opportunities for Therapeutic Intervention During Machine Perfusion. Curr. Transplant. Rep. 2017;4:141–148. doi: 10.1007/s40472-017-0144-y. PubMed DOI PMC

Huang V., Karimian N., Detelich D., Raigani S., Geerts S., Beijert I., Fontan F.M., Aburawi M.M., Ozer S., Banik P., et al. Split-Liver Ex Situ Machine Perfusion: A Novel Technique for Studying Organ Preservation and Therapeutic Interventions. J. Clin. Med. 2020;9 doi: 10.3390/jcm9010269. PubMed DOI PMC

Schlegel A., de Rougemont O., Graf R., Clavien P.A., Dutkowski P. Protective mechanisms of end-ischemic cold machine perfusion in DCD liver grafts. J. Hepatol. 2013;58:278–286. doi: 10.1016/j.jhep.2012.10.004. PubMed DOI

Peralta C., Jimenez-Castro M.B., Gracia-Sancho J. Hepatic ischemia and reperfusion injury: Effects on the liver sinusoidal milieu. J. Hepatol. 2013;59:1094–1106. doi: 10.1016/j.jhep.2013.06.017. PubMed DOI

Upadhya G.A., Topp S.A., Hotchkiss R.S., Anagli J., Strasberg S.M. Effect of cold preservation on intracellular calcium concentration and calpain activity in rat sinusoidal endothelial cells. Hepatology. 2003;37:313–323. doi: 10.1053/jhep.2003.50069. PubMed DOI

Abudhaise H., Davidson B.R., DeMuylder P., Luong T.V., Fuller B. Evolution of dynamic, biochemical, and morphological parameters in hypothermic machine perfusion of human livers: A proof-of-concept study. PLoS ONE. 2018;13:e0203803. doi: 10.1371/journal.pone.0203803. PubMed DOI PMC

Martinez-Mier G., Toledo-Pereyra L.H., Ward P.A. Adhesion molecules in liver ischemia and reperfusion. J. Surg. Res. 2000;94:185–194. doi: 10.1006/jsre.2000.6006. PubMed DOI

Lazeyras F., Buhler L., Vallee J.P., Hergt M., Nastasi A., Ruttimann R., Morel P., Buchs J.B. Detection of ATP by “in line” 31P magnetic resonance spectroscopy during oxygenated hypothermic pulsatile perfusion of pigs’ kidneys. MAGMA. 2012;25:391–399. doi: 10.1007/s10334-012-0319-6. PubMed DOI

Schlegel A., Kron P., Graf R., Clavien P.A., Dutkowski P. Hypothermic Oxygenated Perfusion (HOPE) downregulates the immune response in a rat model of liver transplantation. Ann. Surg. 2014;260:931–937. doi: 10.1097/SLA.0000000000000941. PubMed DOI

Schlegel A., Muller X., Dutkowski P. Hypothermic Machine Preservation of the Liver: State of the Art. Curr. Transplant. Rep. 2018;5:93–102. doi: 10.1007/s40472-018-0183-z. PubMed DOI PMC

Mitchell P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature. 1961;191:144–148. doi: 10.1038/191144a0. PubMed DOI

Gallinat A., Hoyer D.P., Sotiropoulos G., Treckmann J., Benkoe T., Belker J., Saner F., Paul A., Minor T. Oxygen Persufflation in Liver Transplantation Results of a Randomized Controlled Trial. Bioengineering. 2019;6 doi: 10.3390/bioengineering6020035. PubMed DOI PMC

Koetting M., Luer B., Efferz P., Paul A., Minor T. Optimal time for hypothermic reconditioning of liver grafts by venous systemic oxygen persufflation in a large animal model. Transplantation. 2011;91:42–47. doi: 10.1097/TP.0b013e3181fed021. PubMed DOI

Murphy M.P. How mitochondria produce reactive oxygen species. Biochem. J. 2009;417:1–13. doi: 10.1042/BJ20081386. PubMed DOI PMC

Murphy M.P. Understanding and preventing mitochondrial oxidative damage. Biochem. Soc. Trans. 2016;44:1219–1226. doi: 10.1042/BST20160108. PubMed DOI PMC

Hirst J., King M.S., Pryde K.R. The Production of Reactive Oxygen Species by Complex I. Portland Press Ltd.; London, UK: 2008. PubMed

Luer B., Koetting M., Efferz P., Minor T. Role of oxygen during hypothermic machine perfusion preservation of the liver. Transplant. Int. 2010;23:944–950. doi: 10.1111/j.1432-2277.2010.01067.x. PubMed DOI

Chouchani E.T., Pell V.R., Gaude E., Aksentijevic D., Sundier S.Y., Robb E.L., Logan A., Nadtochiy S.M., Ord E.N.J., Smith A.C., et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014;515:431–435. doi: 10.1038/nature13909. PubMed DOI PMC

Dutkowski P., Guarrera J.V., de Jonge J., Martins P.N., Porte R.J., Clavien P.A. Evolving Trends in Machine Perfusion for Liver Transplantation. Gastroenterology. 2019;156:1542–1547. doi: 10.1053/j.gastro.2018.12.037. PubMed DOI

t Hart N.A., van der Plaats A., Faber A., Leuvenink H.G., Olinga P., Wiersema-Buist J., Verkerke G.J., Rakhorst G., Ploeg R.J. Oxygenation during hypothermic rat liver preservation: An in vitro slice study to demonstrate beneficial or toxic oxygenation effects. Liver Transplant. 2005;11:1403–1411. doi: 10.1002/lt.20510. PubMed DOI

Meister F.A., Czigany Z., Bednarsch J., Bocker J., Amygdalos I., Morales Santana D.A., Rietzler K., Moeller M., Tolba R., Boor P., et al. Hypothermic Oxygenated Machine Perfusion of Extended Criteria Kidney Allografts from Brain Dead Donors: Protocol for a Prospective Pilot Study. JMIR Res. Protoc. 2019;8:e14622. doi: 10.2196/14622. PubMed DOI PMC

Lurje I., Czigany Z., Bednarsch J., Roderburg C., Isfort P., Neumann U.P., Lurje G. Treatment Strategies for Hepatocellular Carcinoma—A Multidisciplinary Approach. Int. J. Mol. Sci. 2019;20 doi: 10.3390/ijms20061465. PubMed DOI PMC

Imber C.J., St Peter S.D., de Cenarruzabeitia I.L., Lemonde H., Rees M., Butler A., Clayton P.T., Friend P.J. Optimisation of bile production during normothermic preservation of porcine livers. Am. J. Transplant. 2002;2:593–599. doi: 10.1034/j.1600-6143.2002.20703.x. PubMed DOI

Nativ N.I., Yarmush G., So A., Barminko J., Maguire T.J., Schloss R., Berthiaume F., Yarmush M.L. Elevated sensitivity of macrosteatotic hepatocytes to hypoxia/reoxygenation stress is reversed by a novel defatting protocol. Liver Transplant. 2014;20:1000–1011. doi: 10.1002/lt.23905. PubMed DOI PMC

Improved outcomes after hypothermic oxygenated machine perfusion in liver transplantation-Long-term follow-up of a multicenter randomized controlled trial