Evolving Trends in Machine Perfusion for Liver Transplantation
2019; Elsevier BV; Volume: 156; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2018.12.037
ISSN1528-0012
AutoresPhillipp Dutkowski, James V. Guarrera, Jeroen de Jonge, Paulo N. Martins, Robert J. Porte, Pierre‐Alain Clavien,
Tópico(s)Organ Donation and Transplantation
ResumoThe imbalance between grafts available for transplantation and demands has moved the focus of many investigators on the search for novel strategies to rescue organs, previously considered to be unsuitable for transplantation. In this setting, machine perfusion is recognized as one of the most significant improvements in the field of transplantation over the past 20 years.1Dutkowski P. Linecker M. Deoliveira M.L. et al.Challenges to liver transplantation and strategies to improve outcomes.Gastroenterology. 2015; 148: 307-323Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar Besides potentially improving organ shortage by repairing putative irreversible injuries, dynamic preservation strategies may offer an opportunity to test organ quality before implantation or to manipulate some functions; for example, by mitigating the immune response.2Clavien P.A. Muller X. de Oliveira M.L. et al.Can immunosuppression be stopped after liver transplantation?.Lancet Gastroenterol Hepatol. 2017; 2: 531-537Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar For livers, 2 main perfusion approaches are currently debated in the clinic: (a) perfusion with blood or alternative oxygen carriers at physiologic normothermic or subnormothermic conditions, or (b) perfusion with cooled oxygenated artificial fluids. The aim and mechanisms of both approaches differ greatly. Normothermic machine perfusion (NMP) is used to minimize the duration of cold storage, and is applied either in situ (eg, in donors before procurement), known as normothermic regional perfusion,3Oniscu G.C. Randle L.V. Muiesan P. et al.In situ normothermic regional perfusion for controlled donation after circulatory death - the United Kingdom experience.Am J Transplant. 2014; 14: 2181-2186Crossref PubMed Scopus (30) Google Scholar or ex situ during or after organ transport to the recipient center.4Ravikumar R. Jassem W. Mergental H. et al.Liver transplantation after ex vivo normothermic machine preservation: a phase 1 (first-in-man) clinical trial.Am J Transplant. 2016; 16: 1779-1787Crossref PubMed Scopus (310) Google Scholar The first randomized NMP trial on predominantly livers donated after brain death (DBD) showed excellent 1-year graft survival (95%) by continuous application of NMP during the entire preservation period with, however, similar survival outcome in the control static preservation group.5Nasralla D. Coussios C.C. Mergental H. et al.A randomized trial of normothermic preservation in liver transplantation.Nature. 2018; 557: 50-56Crossref PubMed Scopus (561) Google Scholar Hypothermic machine perfusion (HOPE)6Guarrera J.V. Henry S.D. Samstein B. et al.Hypothermic machine preservation in human liver transplantation: the first clinical series.Am J Transplant. 2010; 167: e356-e373Google Scholar, 7Guarrera J.V. Henry S.D. Samstein B. et al.Hypothermic machine preservation facilitates successful transplantation of “orphan” extended criteria donor livers.Am J Transplant. 2015; 15: 161-169Crossref PubMed Scopus (232) Google Scholar and dual hypothermic oxygenated perfusion (D-HOPE)8Dutkowski P. Schlegel A. De Oliveira M. et al.HOPE for human liver grafts obtained from donors after cardiac death.J Hepatol. 2014; 60: 765-772Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 9van Rijn R. Karimian N. Matton A.P.M. et al.Dual hypothermic oxygenated machine perfusion in liver transplants donated after circulatory death.Br J Surg. 2017; 104: 907-917Crossref PubMed Scopus (151) Google Scholar, 10van Rijn R. van Leeuwen O. Matton A. Burlage L. et al.Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers.Liver Transplant. 2018; 25: 655-664Crossref Scopus (69) Google Scholar are currently performed after cold storage, that is, just before implantation in a recipient. Recent observational studies reported a 5-year graft survival of 94% in HOPE-treated livers despite using higher risk livers with longer donor warm ischemia.11Schlegel A.A. Muller X. Kalisvaart M. et al.Outcomes of liver transplantations from donation after circulatory death (DCD) treated by hypothermic oxygenated perfusion (HOPE) before implantation.J Hepatol. 2019; 70: 50-57Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar Besides mortality, however, morbidity measured for ≤1 year after transplantation seems to be equally important.12Muller X. Marcon F. Sapisochin G. et al.Defining benchmarks in liver transplantation: a multicenter outcome analysis determining best achievable results.Ann Surg. 2018; 267: 419-425Crossref PubMed Scopus (112) Google Scholar For example, a particularly distressful type of preservation injury occurs on the bile ducts, often weeks after transplantation, and this risk is mainly observed in livers donated after circulatory death (DCD).13Laing R.W. Scalera I. Isaac J. et al.Liver transplantation using grafts from donors after circulatory death: a propensity-matched study from a single centre.Am J Transplant. 2016; 16: 1795-1804Crossref PubMed Scopus (89) Google Scholar Of note, both upfront NMP or NMP after cold storage (eg, an end-ischemic normothermic perfusion) failed to protect significantly DCD liver grafts from such biliary injury.5Nasralla D. Coussios C.C. Mergental H. et al.A randomized trial of normothermic preservation in liver transplantation.Nature. 2018; 557: 50-56Crossref PubMed Scopus (561) Google Scholar, 14Watson C.J.E. Kosmoliaptsis V. Pley C. et al.Observations on the ex situ perfusion of livers for transplantation.Am J Transplant. 2018; 18: 2005-2020Crossref PubMed Scopus (191) Google Scholar In contrast, end-ischemic HOPE has been shown to decrease significantly the histologic signs of bile duct injury after reperfusion10van Rijn R. van Leeuwen O. Matton A. Burlage L. et al.Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers.Liver Transplant. 2018; 25: 655-664Crossref Scopus (69) Google Scholar and achieved a rate of 5000 U/L).22Rosen H.R. Martin P. Goss J. et al.Significance of early aminotransferase elevation after liver transplantation.Transplantation. 1998; 65: 68-72Crossref PubMed Scopus (84) Google Scholar A recent large trial on NMP, unfortunately, chose peak serum AST levels as the primary endpoint,5Nasralla D. Coussios C.C. Mergental H. et al.A randomized trial of normothermic preservation in liver transplantation.Nature. 2018; 557: 50-56Crossref PubMed Scopus (561) Google Scholar which not only poorly reflect whole graft injury, but these markers are washed out together with other cytoplasmic enzymes already during ex situ machine liver perfusion before implantation of the graft in the recipient. This bias is obvious, because washout of any liver enzymes is not part of cold stored grafts (eg, in the control group). Surprisingly, the authors failed to report AST concentrations in the perfusate.5Nasralla D. Coussios C.C. Mergental H. et al.A randomized trial of normothermic preservation in liver transplantation.Nature. 2018; 557: 50-56Crossref PubMed Scopus (561) Google Scholar Second, the availability of more sensitive markers of allograft function would be essential to demonstrate protective effects. Unfortunately, no such markers exist, and the most accurate clinical prediction for liver graft dysfunction after transplantation relies on lactate and bilirubin clearance together with the synthesis of coagulation factors. Importantly, dynamic changes of these laboratory parameters (eg, the slope of the serum international normalized ratio or bilirubin) are superior to any single peak values.23Agopian V.G. Harlander-Locke M.P. Markovic D. et al.Evaluation of early allograft function using the liver graft assessment following transplantation risk score model.JAMA Surg. 2017; 152: 55-64Crossref PubMed Scopus (43) Google Scholar Accordingly, a definition of liver graft dysfunction based on peak transaminases in combination with later (eg, 7-day) single levels of the international normalized ratio and bilirubin at arbitrary cut-off points24Olthoff K.M. Kulik L. Samstein B. et al.Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors.Liver Transplant. 2010; 16: 943-949Crossref PubMed Scopus (675) Google Scholar must be avoided in perfusion trials. The only completed RCT,5Nasralla D. Coussios C.C. Mergental H. et al.A randomized trial of normothermic preservation in liver transplantation.Nature. 2018; 557: 50-56Crossref PubMed Scopus (561) Google Scholar regrettably, focused on such definitions, and thereby failed to offer any valuable information about the role of NMP on liver graft function. Third, rescuing damaged organs, otherwise discarded, is a major target of new technologies in this area. The policy to discard a graft for transplantation is, however, far from being standardized, greatly differs among centers and individual surgeons, and is prone to major selection biases in clinical trials.25Marcon F. Schlegel A. Bartlett D.C. et al.Utilization of declined liver grafts yields comparable transplant outcomes and previous decline should not be a deterrent to graft use.Transplantation. 2018; 102: e211-e218Crossref PubMed Scopus (32) Google Scholar For example, in the recent perfusion RCT,5Nasralla D. Coussios C.C. Mergental H. et al.A randomized trial of normothermic preservation in liver transplantation.Nature. 2018; 557: 50-56Crossref PubMed Scopus (561) Google Scholar one-quarter of accepted livers were discarded in the cold storage group by the respective recipient centers, although initially randomized because deemed transplantable by the donor surgeon. This figure contrasts with only 12% in the perfusion group.5Nasralla D. Coussios C.C. Mergental H. et al.A randomized trial of normothermic preservation in liver transplantation.Nature. 2018; 557: 50-56Crossref PubMed Scopus (561) Google Scholar Such discrepancy between accepting grafts for the trial, but not for implantation, suggests an additional flaw in the study design. Future trials require a strict commitment in the decision to use or not a liver graft before randomization, regardless of whether perfusion or cold storage is used, to minimize differences in dropouts. In addition, the quality of all grafts need to be documented in terms of donor age, steatosis, and cold and warm ischemia times to increase comparability of discard reasons among centers.15Muller X. Schlegel A. Würdinger M. et al.Can hypothermic oxygenated perfusion (HOPE) rescue futile DCD liver grafts?.HPB. 2019 Feb 15; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (22) Google Scholar Fourth, hospital stay after liver transplantation varies greatly among centers, despite adjusting risk, as illustrated in a recent benchmark analysis in large-volume centers recording a range of hospitalization between 6 and 24 days in low-risk transplants.12Muller X. Marcon F. Sapisochin G. et al.Defining benchmarks in liver transplantation: a multicenter outcome analysis determining best achievable results.Ann Surg. 2018; 267: 419-425Crossref PubMed Scopus (112) Google Scholar The reason behind such considerable differences in hospital stay is mostly not treatment based, but reflects discharge policies of transplant centers, such as in-hospital waiting for rehabilitation places versus unrestricted transfer without rehabilitation. This difference indicates major limitations in interpreting such parameter in studies. Fifth, graft and patient survivals are logically convincing parameters, but there is a need for adequate follow-up to assess safety or superiority in machine perfusion trials. A minimum observation of 1 year seems to be advisable, based on the fact that most graft losses related to preservation injury develop all along the first year after liver transplantation.1Dutkowski P. Linecker M. Deoliveira M.L. et al.Challenges to liver transplantation and strategies to improve outcomes.Gastroenterology. 2015; 148: 307-323Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 12Muller X. Marcon F. Sapisochin G. et al.Defining benchmarks in liver transplantation: a multicenter outcome analysis determining best achievable results.Ann Surg. 2018; 267: 419-425Crossref PubMed Scopus (112) Google Scholar Finally, measuring morbidity after transplantation is crucial, because it affects the quality of life of patients and influences overall cost.26Vonlanthen R. Slankamenac K. Breitenstein S. et al.The impact of complications on costs of major surgical procedures: a cost analysis of 1200 patients.Ann Surg. 2011; 254: 907-913Crossref PubMed Scopus (297) Google Scholar Capturing complications after surgery, however, is challenging, because multiple definitions of postoperative complications exist. The Clavien-Dindo classification, which relies on the need for treatment to correct a negative event, or its surrogate metric, the comprehensive complication index,27Slankamenac K. Graf R. Barkun J. et al.The comprehensive complication index: a novel continuous scale to measure surgical morbidity.Ann Surg. 2013; 258: 1-7Crossref PubMed Scopus (810) Google Scholar are currently widely used in surgery and transplantation28Dindo D. Demartines N. Clavien P.-A. Classification of surgical complications.Ann Surg. 2004; 240: 205-213Crossref PubMed Scopus (20254) Google Scholar with the availability of reference values provided in a recent multicenter benchmark study covering 1 year after transplantation.12Muller X. Marcon F. Sapisochin G. et al.Defining benchmarks in liver transplantation: a multicenter outcome analysis determining best achievable results.Ann Surg. 2018; 267: 419-425Crossref PubMed Scopus (112) Google Scholar In summary, most of the available endpoints in liver transplantation are weak and should be carefully selected in RCTs. Based on the fact that complications after liver transplant are frequent and have unequivocally the highest clinical relevance in terms of cost and quality of life, we suggest a cumulative assessment of post-transplant complications within 1 year, besides recipient and graft survival, as the preferred primary endpoints for future machine perfusion studies. This is the case, for example, in the 2 ongoing multicentric randomized machine perfusion trials on hypothermic liver perfusion (HOPE, D-HOPE).18Jochmans I. Akhtar M.Z. Nasralla D. et al.Past, present, and future of dynamic kidney and liver preservation and resuscitation.Am J Transplant. 2016; 16: 2545-2555Crossref PubMed Scopus (79) Google Scholar For convincing effectiveness against cold static preservation, any novel perfusion technology should prove superiority in relevant endpoints before claiming its general use (Table 1).Table 1Current observational studies and randomized trials (RCT) on human machine liver perfusionYearRCTGraft typeTechniqueEndpointsClinical RelevanceCompleted studies Bral et al44Bral M. Gala-Lopez B. Bigam D. et al.Preliminary single-center Canadian experience of human normothermic ex vivo liver perfusion: results of a clinical trial.Am J Transplant. 2017; 17: 1071-1080Crossref PubMed Scopus (143) Google Scholar2017NoDBD+DCDNMP (Organox)Graft function and survivalYes De Carlis et al45De Carlis R. Di Sandro S. Lauterio A. et al.Successful donation after cardiac death liver transplants with prolonged warm ischemia time using normothermic regional perfusion.Liver Transplant. 2017; 23: 166-173Crossref PubMed Scopus (68) Google Scholar2018NoDCDNRP + HOPEGraft function, biliary complications, 1-year survivalYes Dutkowski et al46Dutkowski P. Polak W.G. Muiesan P. et al.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: 764-771Crossref PubMed Scopus (239) Google Scholar2015NoDCDHOPEGraft function, 1-year graft survival, biliary complicationsYes Guarrera et al6Guarrera J.V. Henry S.D. Samstein B. et al.Hypothermic machine preservation in human liver transplantation: the first clinical series.Am J Transplant. 2010; 167: e356-e373Google Scholar2010NoDBDHMPPNF, EAD; 1-year graft and patient survival, biliary complicationsYes Guarrera et al7Guarrera J.V. Henry S.D. Samstein B. et al.Hypothermic machine preservation facilitates successful transplantation of “orphan” extended criteria donor livers.Am J Transplant. 2015; 15: 161-169Crossref PubMed Scopus (232) Google Scholar2015NoDBDHMPPNF, EAD; 1-year graft and patient survival, biliary complicationsYes Hessheimer et al47Hessheimer A, Coll E, Valdivieso A, et al. Superior outcomes using normothermic regional perfusion in cDCD liver transplantation. ILTS Conference, Lisbon, Portugal, May 23–26, 2018.Google Scholar2018NoDCDNRPGraft function, biliary complications, 1-year graft survivalYes Nasralla et al5Nasralla D. Coussios C.C. Mergental H. et al.A randomized trial of normothermic preservation in liver transplantation.Nature. 2018; 557: 50-56Crossref PubMed Scopus (561) Google Scholar2018YesDBD + DCDNMP (Organox)Peak AST, EAD, graft useNo Ravikumar et al4Ravikumar R. Jassem W. Mergental H. et al.Liver transplantation after ex vivo normothermic machine preservation: a phase 1 (first-in-man) clinical trial.Am J Transplant. 2016; 16: 1779-1787Crossref PubMed Scopus (310) Google Scholar2016NoDBD + DCDNMPPeak AST, EADNo Liver Revive trial18Jochmans I. Akhtar M.Z. Nasralla D. et al.Past, present, and future of dynamic kidney and liver preservation and resuscitation.Am J Transplant. 2016; 16: 2545-2555Crossref PubMed Scopus (79) Google Scholar2016YesDCDNMP (OCS)Number of donor livers preserved in a near physiological state, serious adverse eventsNo Schlegel et al11Schlegel A.A. Muller X. Kalisvaart M. et al.Outcomes of liver transplantations from donation after circulatory death (DCD) treated by hypothermic oxygenated perfusion (HOPE) before implantation.J Hepatol. 2019; 70: 50-57Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar2018NoDCDHOPE5-year graft survival, biliary complicationsYes Van Rijn et al9van Rijn R. Karimian N. Matton A.P.M. et al.Dual hypothermic oxygenated machine perfusion in liver transplants donated after circulatory death.Br J Surg. 2017; 104: 907-917Crossref PubMed Scopus (151) Google Scholar2017NoDCDD-HOPEHistology of bile ducts during implantationYes Van Rijn et al10van Rijn R. van Leeuwen O. Matton A. Burlage L. et al.Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers.Liver Transplant. 2018; 25: 655-664Crossref Scopus (69) Google Scholar2018NoDCDD-HOPELiver function, liver ATP, biliary complications, 1-year graft and patient survivalYes Watson et al48Watson C, Hunt F, Butler A, et al. Normothermic regional perfusion (NRP) for DCD liver transplantation in the UK: better graft survival with no cholangiopathy. ILTS Conference Lisbon, Portugal, May 23–26, 2018.Google Scholar2018NoDCDNRPPeak ALT, graft function, 90-day survivalNo Watson et al14Watson C.J.E. Kosmoliaptsis V. Pley C. et al.Observations on the ex situ perfusion of livers for transplantation.Am J Transplant. 2018; 18: 2005-2020Crossref PubMed Scopus (191) Google Scholar2018NoDBD + DCDNMP (liver assist)Postreperfusion syndrome, PNF, bile duct histology, biliary complications, graft survivalYesOngoing RCTs Dutkowski et al18Jochmans I. Akhtar M.Z. Nasralla D. et al.Past, present, and future of dynamic kidney and liver preservation and resuscitation.Am J Transplant. 2016; 16: 2545-2555Crossref PubMed Scopus (79) Google ScholarOngoingYesDBDHOPE1-year cumulative Clavien grade ≥III, CCI∗Clinical relevance not yet available. Porte et al18Jochmans I. Akhtar M.Z. Nasralla D. et al.Past, present, and future of dynamic kidney and liver preservation and resuscitation.Am J Transplant. 2016; 16: 2545-2555Crossref PubMed Scopus (79) Google ScholarOngoingYesDCDD-HOPE6-month biliary complications∗Clinical relevance not yet available. Lurje et al49Czigany Z. Lurje I. Tolba R.H. et al.Machine perfusion for liver transplantation in the era of marginal organs—new kids on the block.Liver Int. 2019; 39: 228-249Crossref PubMed Scopus (55) Google ScholarOngoingYesECD DBDHOPEPeak ALTNo Liver Protect trial18Jochmans I. Akhtar M.Z. Nasralla D. et al.Past, present, and future of dynamic kidney and liver preservation and resuscitation.Am J Transplant. 2016; 16: 2545-2555Crossref PubMed Scopus (79) Google ScholarOngoingYesDBD+ DCDNMP (OCS)EAD, serious adverse eventsNoALT, alanine aminotransferase; AST, aspartate aminotransferase; ATP: adenosine triphosphate; CCI, comprehensive complication index; DBD, donation after brain death; DCD, donation after circulatory death; D-HOPE, dual hypothermic oxygenated perfusion; HOPE, hypothermic oxygenated perfusion; NMP, normothermic machine perfusion; NRP, normothermic regional perfusion; OCS, organ care system; PNF, primary nonfunction.∗ Clinical relevance not yet available. Open table in a new tab ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATP: adenosine triphosphate; CCI, comprehensive complication index; DBD, donation after brain death; DCD, donation after circulatory death; D-HOPE, dual hypothermic oxygenated perfusion; HOPE, hypothermic oxygenated perfusion; NMP, normothermic machine perfusion; NRP, normothermic regional perfusion; OCS, organ care system; PNF, primary nonfunction. Future machine perfusion trials should compare the different competing techniques using clinically relevant endpoints. To properly conduct such studies, an objective and adequate knowledge of the various perfusion technologies is mandatory, and thus should optimally be restricted to few experienced centers. We would urge the transplant community, including the industry, to rather focus on supporting current research in highly engaged perfusion teams, instead of suggesting widespread use of one specific perfusion technology. Accessible registries to allow research in long-term outcome should also be implemented.29Quintini C. Martins P.N. Shah S. et al.Implementing an innovated preservation technology: The American Society of Transplant Surgeons’ (ASTS) Standards Committee white paper on ex situ liver machine perfusion.Am J Transplant. 2018; 18: 1865-1874Crossref PubMed Scopus (15) Google Scholar The precise underlying mechanism for protection of liver grafts by machine perfusion remains under debate. For NMP, the current explanation is a reduction of cold ischemia by minimizing the anaerobic metabolism with less accumulation of citric acid cycle products and improved ATP restoration.30Ceresa C.D.L. Nasralla D. Coussios C.C. et al.The case for normothermic machine perfusion in liver transplantation.Liver Transpl. 2018; 24: 269-275Crossref PubMed Scopus (35) Google Scholar The extreme of such strategy is an ischemia-free organ transplantation, where donor livers are put on a normothermic circuit even before procurement, similar to normothermic regional perfusion, but with continuing normothermic perfusion until implantation.31He X. Guo Z. Zhao Q. et al.The first case of ischemia-free organ transplantation in humans: a proof of concept.Am J Transplant. 2018; 18: 737-744Crossref PubMed Scopus (80) Google Scholar It might be more efficient to develop repair strategies of pretransplant or procurement injuries, which are common in the clinic (eg, fatty liver, prolonged cold or warm ischemia times). Endischemic NMP in discarded human livers with longer periods of cold ischemia failed to protect against biliary injury, the most prevalent cause of graft loss after DCD liver transplantation.14Watson C.J.E. Kosmoliaptsis V. Pley C. et al.Observations on the ex situ perfusion of livers for transplantation.Am J Transplant. 2018; 18: 2005-2020Crossref PubMed Scopus (191) Google Scholar Continuous or endischemic NMP after ischemia triggers an inflammatory cascade, mostly related to mitochondrial derived reactive oxygen species32Chouchani E.T. Pell V.R. Gaude E. et al.Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.Nature. 2014; 515: 431-435Crossref PubMed Scopus (1512) Google Scholar, 33Murphy M.P. How mitochondria produce reactive oxygen species.Biochem J. 2009; 417: 1-13Crossref PubMed Scopus (5238) Google Scholar (Figure 1), which resemble in vivo conditions.34Van 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: 1382-1402Crossref PubMed Scopus (161) Google Scholar Evidence for an activation of “danger” signals by normothermic perfusion techniques is also well-described in normothermic perfusion of other organs including heart,35Kearns M.J. Miller S.D. Cheung A. et al.A rodent model of cardiac donation after circulatory death and novel biomarkers of cardiac viability during ex vivo heart perfusion.Transplantation. 2017; 101: e231-e239Crossref PubMed Scopus (22) Google Scholar kidney,36Hosgood S.A. Moore T. Kleverlaan T. et al.Haemoadsorption reduces the inflammatory response and improves blood flow during ex vivo renal perfusion in an experimental model.J Transl Med. 2017; 15: 216Crossref PubMed Scopus (37) Google Scholar and lung.37Sadaria M.R. Smith P.D. Fullerton D.A. et al.Cytokine expression profile in human lungs undergoing normothermic ex-vivo lung perfusion.Ann Thorac Surg. 2011; 92: 478-484Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar The target of all ex situ normothermic interventions is, therefore, to capture reactive oxygen species and “danger” molecules (danger associated molecular patterns and proinflammatory cytokines), for example, by perfusate scavengers33Murphy M.P. How mitochondria produce reactive oxygen species.Biochem J. 2009; 417: 1-13Crossref PubMed Scopus (5238) Google Scholar or by the implementation of cytokine filters into the circuit. In contrast, hypothermic perfusion techniques mitigate oxidative stress despite high availability of oxygen in the cold,38Dufour S. Rousse N. Canioni P. et al.Top-down control analysis of temperature effect on oxidative phosphorylation.Biochem J. 1996; 314: 743-751Crossref PubMed Scopus (86) Google Scholar probably owing to changes in mitochondrial electron transfer (eg, down-regulated electron transfer at temperatures below the Arrhenius break point temperature of 15°C). At the same time, metabolism of accumulated electron donors, such as NADH and succinate, leads to ATP resynthesis39Westerkamp A.C. Mahboub P. Meyer S.L. et al.End-ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature.Liver Transplant. 2015; 21: 1300-1311Crossref PubMed Scopus (48) Google Scholar, 40Op Den Dries S. Westerkamp A.C. Karimian N. et al.Injury to peribiliary glands and vascular plexus before liver transplantation predicts formation of non-anastomotic biliary strictures.J Hepatol. 2014; 60: 1172-1179Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar with surprisingly high efficiency, compared with normothermic conditions, possibly owing to less electron and proton leakage in the cold.38Dufour S. Rousse N. Canioni P. et al.Top-down control analysis of temperature effect on oxidative phosphorylation.Biochem J. 1996; 314: 743-751Crossref PubMed Scopus (86) Google Scholar End-ischemic cold oxygenated perfusion, therefore, allows for a higher upload of cellular energetic levels in DCD liver grafts, compared with normothermic perfusion41Schlegel A. Kron P. Graf R. et al.Warm vs. cold perfusion techniques to rescue rodent liver grafts.J Hepatol. 2014; 61: 1267-1275Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar (Figure 1). These observations support possible complementary effects of, for example, combining first hypothermic and afterwards NMP, when applied after a period of cold ischemic storage.42Burlage L.C. Karimian N. Westerkamp A.C. et al.Oxygenated hypothermic machine perfusion after static cold storage improves endothelial function of extended criteria donor livers.HPB. 2017; 19: 538-546Abstract Full Text Full Text PDF Scopus (27) Google Scholar, 43Boteon Y.L. Laing R.W. Schlegel A. et al.Combined hypothermic and normothermic machine perfusion improves functional recovery of extended criteria donor livers.Liver Transplant. 2018; 24: 1699-1715Crossref PubMed Scopus (60) Google Scholar Future investigations on perfusion should include the search for protective mechanisms and evaluation of effective repair of injured organs. Thereby, perfusion technologies convey a great potential to influence cellular metabolism before implantation, modulating inflammation, immune response and perhaps triggering anticancer pathways. It is central that expensive and cumbersome RCTs in the field of organ perfusion select exclusively clinically relevant endpoints. Additionally, the prediction of organ function during machine perfusion will likewise be possible by detailed perfusate analysis including metabolomics and proteomics, leading to safer use of marginal grafts. We anticipate that within the next few years a far better understanding will be available about which perfusion strategies should be applied best and for which liver graft. Evolving Trends in Machine Liver Perfusion: Comments on Clinical End Points and Selection CriteriaGastroenterologyVol. 157Issue 4PreviewWe read with great interest the article on current and evolving trends in machine perfusion (MP) for orthotopic liver transplantation (OLT) by Dutkowski et al.1 We compliment this group of pioneering experts on their in-depth summary of advances in liver MP and would like to contribute to the debate on this current topic from a different angle. Full-Text PDF
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