de Meijer, Vincent E

de Vries, Yvonne

Porte, Robert J

van Leeuwen, Otto B

English

NARCIS 

Hypothermic machine perfusion before viability testing of previously discarded human livers

Dissertations of the University of Groningen

   University of GroningenHypothermic machine perfusion before viability testing of previously discarded human liversvan Leeuwen, Otto B; de Vries, Yvonne; de Meijer, Vincent E; Porte, Robert JPublished in:Nature CommunicationsDOI:10.1038/s41467-021-21182-8IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):van Leeuwen, O. B., de Vries, Y., de Meijer, V. E., & Porte, R. J. (2021). Hypothermic machine perfusionbefore viability testing of previously discarded human livers. Nature Communications, 12(1), Article 1008.https://doi.org/10.1038/s41467-021-21182-8CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 31-10-2023MATTERS ARISINGHypothermic machine perfusion before viabilitytesting of previously discarded human liversOtto B. van Leeuwen 1, Yvonne de Vries1, Vincent E. de Meijer 1 & Robert J. Porte1✉ARISING FROM H. Mergental et al. Nature Communications https://doi.org/10.1038/s41467-020-16251-3 (2020)The results from the VITTAL study, with back-to-base end-ischemic normothermic machine perfusion (NMP) forviability testing of high-risk donor livers, were eagerlyawaited as in this field different techniques are currently beingused1. Of 31 initially discarded livers, 22 (71%) met the viabilitycriteria during NMP and were transplanted with a 100% 90-daygraft survival; however, three out of ten livers donated after cir-culatory death (DCD) developed biliary complications (30%) andrequired retransplantation. Because the trial was already initiatedin 2016, more recent insights in viability testing should be con-sidered when discussing the design and results of this clinicaltrial. Therefore, there are three issues that needs commenting tointerpret the high rate of biliary complications reported: (1) theviability criteria used in this trial, (2) production of bile duringNMP and (3) the use of end-ischemic NMP alone.Cholangiocyte viability assessment and liver functionbiomarkers for clinical decision making during NMPIn contrast to hypothermic (<12 °C) machine perfusion (HMP),livers are metabolically fully active during NMP. This leads torestoration of hepatobiliary metabolism, such as clearance oflactate, production of (coagulation) proteins, and, importantly,bile production. Two types of viability criteria for donor liversduring NMP have been distinguished: hepatocellular (‘liver par-enchyma’) and cholangiocellular (‘bile duct’) viability criteria(Table 1). In the current study by Mergental et al., only hepato-cellular viability criteria were used to assess ‘transplantability’ ofliver grafts during NMP1. The first reports on the value of bilecomposition as a tool to determine bile duct viability were pub-lished after the initiation of this study2,3. In our experience, asubstantial number of especially high-risk DCD grafts do notmeet the cholangiocellular viability criteria during NMP(Table 1). We therefore do not transplant these livers, as bilecomposition during NMP has been shown to correlate withbiliary injury and thereby the risk of post-transplant cholangio-pathy4. Transplanting high-risk (DCD) donor livers withoutmonitoring bile composition during NMP poses a risk to therecipient, as other investigators have previously shown a high rateof post-transplant cholangiopathy after end-ischemic NMP ofhigh-risk DCD livers3,5. Therefore, with the current knowledge itis not a complete surprise that Mergental et al. have noted a highincidence of post-transplant cholangiopathy (30% after DCDtransplantation) and need for retransplantation in their series1.In another clinical trial on NMP and transplantation of initiallydiscarded human donor livers (DHOPE-COR-NMP trial), wehave monitored bile composition point of care6–8. Following anearly case of post-transplant cholangiopathy, we have learned thatabsolute values of bile pH, bicarbonate, and glucose during NMPare not the most suitable markers for cholangiocellular viabilitytesting. We have learned that the difference between the bile andperfusate levels of pH, bicarbonate, and glucose should be used toidentify alkalization of the bile and reabsorption of glucose by thebiliary epithelium (biomarkers of bile duct viability; Table 1)8.Currently, we have performed over 50 DHOPE-COR-NMPprocedures of initially nation-wide discarded, high-risk DCDlivers and after using the delta pH, bicarbonate, and glucose ascholangiocellular viability criteria during NMP, we have notobserved any case of post-transplant cholangiopathy.Bile production during NMPIn the study by Mergental et al., 23% of the livers did not appearto produce bile1. In our experience, we have always been able toexplain low or absent bile flow during NMP by a technical issuewith the biliary drain. Regularly, the tip of the biliary drain can bestuck against the bile duct wall, leading to obstruction of thelumen and limiting bile flow. We have tested biliary drainsextensively in preclinical experiments, and observed that bile flowinitiates more rapidly when a small diameter drain is used, as aresult of increased capillary force. As a result, we have been usinga small feeding tube catheter (8 French) with an open tip and sideholes as a biliary drain9.Combination of end-ischemic HMP and NMP versus NMPaloneIn the study by Mergental et al., it was chosen to perform end-ischemic NMP only1. Since the VITTAL study was initiated in2016, other centers shared similar experiences showing highhttps://doi.org/10.1038/s41467-021-21182-8 OPEN1 Department of Surgery, Section of Hepatobiliary Surgery & Liver Transplantation, University Medical Center Groningen, University of Groningen,Groningen, Netherlands. ✉email: r.j.porte@umcg.nlNATURE COMMUNICATIONS |         (2021) 12:1008 | https://doi.org/10.1038/s41467-021-21182-8 | www.nature.com/naturecommunications 11234567890():,;percentages of biliary complications after NMP for high-risk(DCD) donor livers3,5. End-ischemic NMP exposes a donororgan to ischemia-reperfusion injury, to which the bile ducts areextremely sensible. It has been shown before that a short period ofdual hypothermic oxygenated machine perfusion (DHOPE)reduces reperfusion injury of the liver and biliary tree10. Severalstudies have demonstrated a beneficial effect of performingDHOPE prior to either direct transplantation or NMP11–15. Aftercombined DHOPE and NMP, hepatic adenosine triphosphatecontent and biliary bicarbonate and bilirubin were higher incomparison to livers that underwent NMP only15. As a result, in2017, the DHOPE-COR-NMP trial was initiated with a combi-nation of one-hour DHOPE, followed by one-hour controlledoxygenated rewarming, and subsequent NMP, with the aim toreduce ischemia-reperfusion injury at the start of NMP6–8.Interestingly, all livers in the DHOPE-COR-NMP trial met thehepatocellular viability criteria used in the VITTAL study, despitethe fact that all livers were derived from high-risk DCD donorswith a substantially higher median age, compared to the VITTALstudy8. This could suggest that a short period of DHOPE prior toNMP is very effective in preventing additional reperfusion injuryof the liver parenchyma (hepatocytes) at the start of NMP. Onlylivers that have suffered too much (warm) ischemic injury of thebile ducts during and after the DCD procedure may no longer besalvageable with DHOPE and will not meet the biliary viabilitycriteria during the NMP phase.In conclusion, in a rapidly advancing field of liver machine per-fusion, we are all still learning and it is through sharing of ourexperiences that we can collective determine the most optimal use ofthe new technology in the benefit or our patients. From the emer-ging evidence, it becomes clear that end-ischemic NMP is animportant tool to assess and select donor livers that, based on tra-ditional criteria, were initially considered not suitable for trans-plantation. Yet, end-ischemic NMP alone, as applied in the VITTALstudy, does not protect the bile ducts against ischemia-reperfusioninjury. Therefore, a short period of HMP prior the NMP, as well asthe use of cholangiocellular viability criteria during machine perfu-sion, are important modifications that may help avoid post-transplant morbidity and graft loss due to cholangiopathy.Received: 18 June 2020; Accepted: 18 January 2021;References1. Mergental, H. et al. Transplantation of discarded livers following viabilitytesting with normothermic machine perfusion. Nat. Commun. 11, 2939 (2020).2. Op den Dries, S. et al. Ex vivo normothermic machine perfusion andviability testing of discarded human donor livers. Am. J. Transplant. 13,1327–1335 (2013).3. Watson, C. J. E. et al. Observations on the ex situ perfusion of livers fortransplantation. Am. J. Transplant. 18, 2005–2020 (2018).4. Matton, A. P. M. et al. Biliary bicarbonate, pH and glucose are suitablebiomarkers of biliary viability during ex situ normothermic machine perfusionof human donor livers. Transplantation 103, 1405–1413 (2019).5. Watson, C. J. E. et al. Normothermic perfusion in the assessment andpreservation of declined livers before transplantation: hyperoxia andvasoplegia—important lessons from the first 12 cases. Transplantation 101,1084–1098 (2017).6. De Vries, Y. et al. Transplantation of high-risk donor livers after resuscitationand viability assessment using a combined protocol of oxygenatedhypothermic, rewarming and normothermic machine perfusion: studyprotocol for a prospective, single-arm study (DHOPE-COR-NMP trial). BMJOpen. 9, e028596 (2019).7. De Vries, Y. et al. Pretransplant sequential hypo and normothermic machineperfusion of suboptimal livers donated after circulatory death using ahemoglobin-based oxygen carrier perfusion solution. Am. J. Transplant. 19,1202–1211 (2019).8. van Leeuwen, O. B. et al. Transplantation of high-risk donor livers after ex situresuscitation and assessment using combined hypo- and normothermicmachine perfusion: a prospective trial. Ann. Surg. 270, 906–914 (2019).9. Van Leeuwen, O. B., de Meijer, V. E. & Porte, R. J. Viability criteria forfunctional assessment of donor livers during normothermic machineperfusion. Liver Transpl. 24, 1333–1335 (2018).10. Van Rijn, R. et al. Hypothermic oxygenated machine perfusion reduces bileduct reperfusion injury after transplantation of donation after circulatorydeath livers. Liver Transpl. 24, 655–664 (2018).11. Guarrera, J. V. et al. Hypothermic machine preservation in human livertransplantation: the first clinical series. Am. J. Transplant. 10, 372–381 (2010).12. Dutkowski, P. et al. HOPE for human liver grafts obtained from donors aftercardiac death. J. Hepatol. 60, 765–772 (2014).13. van Rijn, R. et al. Dual hypothermic oxygenated machine perfusion inliver transplants donated after circulatory death. Br. J. Surg. 104, 907–917(2017).14. Burlage, L. C. et al. Oxygenated hypothermic machine perfusion after staticcold storage improves endothelial function of extended criteria donor livers.HPB (Oxford) 19, 538–546 (2017).15. Westerkamp, A. C. et al. Oxygenated hypothermic machine perfusion afterstatic cold storage improves hepatobiliary function of extended criteria donorlivers. Transplantation 100, 825–835 (2016).Author contributionsO.B.v.L., Y.d.V., V.E.d.M., and R.J.P. wrote and critically revised the manuscript.Competing interestsThe authors declare no competing interests.Additional informationCorrespondence and requests for materials should be addressed to R.J.P.Peer review information Nature Communications thanks Renato Romagnoli and StefanSchneeberger for their contribution to the peer review of this work.Reprints and permission information is available at http://www.nature.com/reprintsPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2021Table 1 Hepatocellular and cholangiocellular viability criteriafor human donor livers during NMPa.VITTAL criteria Groningen criteriaHepatocellular criteria HepatocellularcriteriaCholangiocellularcriteriaLactate clearance Lactate clearance Delta bile pHAt least two of the followingcriteriaPerfusate pHstabilizationDelta bile bicarbonateBile production Delta bile glucose- Bile production- Perfusate pH stabilization- Metabolism of glucose- Stable flows- Homogenous perfusionaThe VITTAL criteria had to be met within 4 h of NMP, the Groningen criteria within 2.5 h ofNMP1,8.MATTERS ARISING NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21182-82 NATURE COMMUNICATIONS |         (2021) 12:1008 | https://doi.org/10.1038/s41467-021-21182-8 | www.nature.com/naturecommunications

ARTS repository - University of Groningen

   University of GroningenHypothermic machine perfusion before viability testing of previously discarded human liversvan Leeuwen, Otto B; de Vries, Yvonne; de Meijer, Vincent E; Porte, Robert JPublished in:Nature CommunicationsDOI:10.1038/s41467-021-21182-8IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):van Leeuwen, O. B., de Vries, Y., de Meijer, V. E., & Porte, R. J. (2021). Hypothermic machine perfusionbefore viability testing of previously discarded human livers. Nature Communications, 12(1), Article 1008.https://doi.org/10.1038/s41467-021-21182-8CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 10-09-2023MATTERS ARISINGHypothermic machine perfusion before viabilitytesting of previously discarded human liversOtto B. van Leeuwen 1, Yvonne de Vries1, Vincent E. de Meijer 1 & Robert J. Porte1✉ARISING FROM H. Mergental et al. Nature Communications https://doi.org/10.1038/s41467-020-16251-3 (2020)The results from the VITTAL study, with back-to-base end-ischemic normothermic machine perfusion (NMP) forviability testing of high-risk donor livers, were eagerlyawaited as in this field different techniques are currently beingused1. Of 31 initially discarded livers, 22 (71%) met the viabilitycriteria during NMP and were transplanted with a 100% 90-daygraft survival; however, three out of ten livers donated after cir-culatory death (DCD) developed biliary complications (30%) andrequired retransplantation. Because the trial was already initiatedin 2016, more recent insights in viability testing should be con-sidered when discussing the design and results of this clinicaltrial. Therefore, there are three issues that needs commenting tointerpret the high rate of biliary complications reported: (1) theviability criteria used in this trial, (2) production of bile duringNMP and (3) the use of end-ischemic NMP alone.Cholangiocyte viability assessment and liver functionbiomarkers for clinical decision making during NMPIn contrast to hypothermic (<12 °C) machine perfusion (HMP),livers are metabolically fully active during NMP. This leads torestoration of hepatobiliary metabolism, such as clearance oflactate, production of (coagulation) proteins, and, importantly,bile production. Two types of viability criteria for donor liversduring NMP have been distinguished: hepatocellular (‘liver par-enchyma’) and cholangiocellular (‘bile duct’) viability criteria(Table 1). In the current study by Mergental et al., only hepato-cellular viability criteria were used to assess ‘transplantability’ ofliver grafts during NMP1. The first reports on the value of bilecomposition as a tool to determine bile duct viability were pub-lished after the initiation of this study2,3. In our experience, asubstantial number of especially high-risk DCD grafts do notmeet the cholangiocellular viability criteria during NMP(Table 1). We therefore do not transplant these livers, as bilecomposition during NMP has been shown to correlate withbiliary injury and thereby the risk of post-transplant cholangio-pathy4. Transplanting high-risk (DCD) donor livers withoutmonitoring bile composition during NMP poses a risk to therecipient, as other investigators have previously shown a high rateof post-transplant cholangiopathy after end-ischemic NMP ofhigh-risk DCD livers3,5. Therefore, with the current knowledge itis not a complete surprise that Mergental et al. have noted a highincidence of post-transplant cholangiopathy (30% after DCDtransplantation) and need for retransplantation in their series1.In another clinical trial on NMP and transplantation of initiallydiscarded human donor livers (DHOPE-COR-NMP trial), wehave monitored bile composition point of care6–8. Following anearly case of post-transplant cholangiopathy, we have learned thatabsolute values of bile pH, bicarbonate, and glucose during NMPare not the most suitable markers for cholangiocellular viabilitytesting. We have learned that the difference between the bile andperfusate levels of pH, bicarbonate, and glucose should be used toidentify alkalization of the bile and reabsorption of glucose by thebiliary epithelium (biomarkers of bile duct viability; Table 1)8.Currently, we have performed over 50 DHOPE-COR-NMPprocedures of initially nation-wide discarded, high-risk DCDlivers and after using the delta pH, bicarbonate, and glucose ascholangiocellular viability criteria during NMP, we have notobserved any case of post-transplant cholangiopathy.Bile production during NMPIn the study by Mergental et al., 23% of the livers did not appearto produce bile1. In our experience, we have always been able toexplain low or absent bile flow during NMP by a technical issuewith the biliary drain. Regularly, the tip of the biliary drain can bestuck against the bile duct wall, leading to obstruction of thelumen and limiting bile flow. We have tested biliary drainsextensively in preclinical experiments, and observed that bile flowinitiates more rapidly when a small diameter drain is used, as aresult of increased capillary force. As a result, we have been usinga small feeding tube catheter (8 French) with an open tip and sideholes as a biliary drain9.Combination of end-ischemic HMP and NMP versus NMPaloneIn the study by Mergental et al., it was chosen to perform end-ischemic NMP only1. Since the VITTAL study was initiated in2016, other centers shared similar experiences showing highhttps://doi.org/10.1038/s41467-021-21182-8 OPEN1 Department of Surgery, Section of Hepatobiliary Surgery & Liver Transplantation, University Medical Center Groningen, University of Groningen,Groningen, Netherlands. ✉email: r.j.porte@umcg.nlNATURE COMMUNICATIONS |         (2021) 12:1008 | https://doi.org/10.1038/s41467-021-21182-8 | www.nature.com/naturecommunications 11234567890():,;percentages of biliary complications after NMP for high-risk(DCD) donor livers3,5. End-ischemic NMP exposes a donororgan to ischemia-reperfusion injury, to which the bile ducts areextremely sensible. It has been shown before that a short period ofdual hypothermic oxygenated machine perfusion (DHOPE)reduces reperfusion injury of the liver and biliary tree10. Severalstudies have demonstrated a beneficial effect of performingDHOPE prior to either direct transplantation or NMP11–15. Aftercombined DHOPE and NMP, hepatic adenosine triphosphatecontent and biliary bicarbonate and bilirubin were higher incomparison to livers that underwent NMP only15. As a result, in2017, the DHOPE-COR-NMP trial was initiated with a combi-nation of one-hour DHOPE, followed by one-hour controlledoxygenated rewarming, and subsequent NMP, with the aim toreduce ischemia-reperfusion injury at the start of NMP6–8.Interestingly, all livers in the DHOPE-COR-NMP trial met thehepatocellular viability criteria used in the VITTAL study, despitethe fact that all livers were derived from high-risk DCD donorswith a substantially higher median age, compared to the VITTALstudy8. This could suggest that a short period of DHOPE prior toNMP is very effective in preventing additional reperfusion injuryof the liver parenchyma (hepatocytes) at the start of NMP. Onlylivers that have suffered too much (warm) ischemic injury of thebile ducts during and after the DCD procedure may no longer besalvageable with DHOPE and will not meet the biliary viabilitycriteria during the NMP phase.In conclusion, in a rapidly advancing field of liver machine per-fusion, we are all still learning and it is through sharing of ourexperiences that we can collective determine the most optimal use ofthe new technology in the benefit or our patients. From the emer-ging evidence, it becomes clear that end-ischemic NMP is animportant tool to assess and select donor livers that, based on tra-ditional criteria, were initially considered not suitable for trans-plantation. Yet, end-ischemic NMP alone, as applied in the VITTALstudy, does not protect the bile ducts against ischemia-reperfusioninjury. Therefore, a short period of HMP prior the NMP, as well asthe use of cholangiocellular viability criteria during machine perfu-sion, are important modifications that may help avoid post-transplant morbidity and graft loss due to cholangiopathy.Received: 18 June 2020; Accepted: 18 January 2021;References1. Mergental, H. et al. Transplantation of discarded livers following viabilitytesting with normothermic machine perfusion. Nat. Commun. 11, 2939 (2020).2. Op den Dries, S. et al. Ex vivo normothermic machine perfusion andviability testing of discarded human donor livers. Am. J. Transplant. 13,1327–1335 (2013).3. Watson, C. J. E. et al. Observations on the ex situ perfusion of livers fortransplantation. Am. J. Transplant. 18, 2005–2020 (2018).4. Matton, A. P. M. et al. Biliary bicarbonate, pH and glucose are suitablebiomarkers of biliary viability during ex situ normothermic machine perfusionof human donor livers. Transplantation 103, 1405–1413 (2019).5. Watson, C. J. E. et al. Normothermic perfusion in the assessment andpreservation of declined livers before transplantation: hyperoxia andvasoplegia—important lessons from the first 12 cases. Transplantation 101,1084–1098 (2017).6. De Vries, Y. et al. Transplantation of high-risk donor livers after resuscitationand viability assessment using a combined protocol of oxygenatedhypothermic, rewarming and normothermic machine perfusion: studyprotocol for a prospective, single-arm study (DHOPE-COR-NMP trial). BMJOpen. 9, e028596 (2019).7. De Vries, Y. et al. Pretransplant sequential hypo and normothermic machineperfusion of suboptimal livers donated after circulatory death using ahemoglobin-based oxygen carrier perfusion solution. Am. J. Transplant. 19,1202–1211 (2019).8. van Leeuwen, O. B. et al. Transplantation of high-risk donor livers after ex situresuscitation and assessment using combined hypo- and normothermicmachine perfusion: a prospective trial. Ann. Surg. 270, 906–914 (2019).9. Van Leeuwen, O. B., de Meijer, V. E. & Porte, R. J. Viability criteria forfunctional assessment of donor livers during normothermic machineperfusion. Liver Transpl. 24, 1333–1335 (2018).10. Van Rijn, R. et al. Hypothermic oxygenated machine perfusion reduces bileduct reperfusion injury after transplantation of donation after circulatorydeath livers. Liver Transpl. 24, 655–664 (2018).11. Guarrera, J. V. et al. Hypothermic machine preservation in human livertransplantation: the first clinical series. Am. J. Transplant. 10, 372–381 (2010).12. Dutkowski, P. et al. HOPE for human liver grafts obtained from donors aftercardiac death. J. Hepatol. 60, 765–772 (2014).13. van Rijn, R. et al. Dual hypothermic oxygenated machine perfusion inliver transplants donated after circulatory death. Br. J. Surg. 104, 907–917(2017).14. Burlage, L. C. et al. Oxygenated hypothermic machine perfusion after staticcold storage improves endothelial function of extended criteria donor livers.HPB (Oxford) 19, 538–546 (2017).15. Westerkamp, A. C. et al. Oxygenated hypothermic machine perfusion afterstatic cold storage improves hepatobiliary function of extended criteria donorlivers. Transplantation 100, 825–835 (2016).Author contributionsO.B.v.L., Y.d.V., V.E.d.M., and R.J.P. wrote and critically revised the manuscript.Competing interestsThe authors declare no competing interests.Additional informationCorrespondence and requests for materials should be addressed to R.J.P.Peer review information Nature Communications thanks Renato Romagnoli and StefanSchneeberger for their contribution to the peer review of this work.Reprints and permission information is available at http://www.nature.com/reprintsPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2021Table 1 Hepatocellular and cholangiocellular viability criteriafor human donor livers during NMPa.VITTAL criteria Groningen criteriaHepatocellular criteria HepatocellularcriteriaCholangiocellularcriteriaLactate clearance Lactate clearance Delta bile pHAt least two of the followingcriteriaPerfusate pHstabilizationDelta bile bicarbonateBile production Delta bile glucose- Bile production- Perfusate pH stabilization- Metabolism of glucose- Stable flows- Homogenous perfusionaThe VITTAL criteria had to be met within 4 h of NMP, the Groningen criteria within 2.5 h ofNMP1,8.MATTERS ARISING NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21182-82 NATURE COMMUNICATIONS |         (2021) 12:1008 | https://doi.org/10.1038/s41467-021-21182-8 | www.nature.com/naturecommunications

Proceedings - University of Groningen

   University of GroningenHypothermic machine perfusion before viability testing of previously discarded human liversvan Leeuwen, Otto B; de Vries, Yvonne; de Meijer, Vincent E; Porte, Robert JPublished in:Nature CommunicationsDOI:10.1038/s41467-021-21182-8IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):van Leeuwen, O. B., de Vries, Y., de Meijer, V. E., & Porte, R. J. (2021). Hypothermic machine perfusionbefore viability testing of previously discarded human livers. Nature Communications, 12(1), [1008].https://doi.org/10.1038/s41467-021-21182-8CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-10-2022MATTERS ARISINGHypothermic machine perfusion before viabilitytesting of previously discarded human liversOtto B. van Leeuwen 1, Yvonne de Vries1, Vincent E. de Meijer 1 & Robert J. Porte1✉ARISING FROM H. Mergental et al. Nature Communications https://doi.org/10.1038/s41467-020-16251-3 (2020)The results from the VITTAL study, with back-to-base end-ischemic normothermic machine perfusion (NMP) forviability testing of high-risk donor livers, were eagerlyawaited as in this field different techniques are currently beingused1. Of 31 initially discarded livers, 22 (71%) met the viabilitycriteria during NMP and were transplanted with a 100% 90-daygraft survival; however, three out of ten livers donated after cir-culatory death (DCD) developed biliary complications (30%) andrequired retransplantation. Because the trial was already initiatedin 2016, more recent insights in viability testing should be con-sidered when discussing the design and results of this clinicaltrial. Therefore, there are three issues that needs commenting tointerpret the high rate of biliary complications reported: (1) theviability criteria used in this trial, (2) production of bile duringNMP and (3) the use of end-ischemic NMP alone.Cholangiocyte viability assessment and liver functionbiomarkers for clinical decision making during NMPIn contrast to hypothermic (<12 °C) machine perfusion (HMP),livers are metabolically fully active during NMP. This leads torestoration of hepatobiliary metabolism, such as clearance oflactate, production of (coagulation) proteins, and, importantly,bile production. Two types of viability criteria for donor liversduring NMP have been distinguished: hepatocellular (‘liver par-enchyma’) and cholangiocellular (‘bile duct’) viability criteria(Table 1). In the current study by Mergental et al., only hepato-cellular viability criteria were used to assess ‘transplantability’ ofliver grafts during NMP1. The first reports on the value of bilecomposition as a tool to determine bile duct viability were pub-lished after the initiation of this study2,3. In our experience, asubstantial number of especially high-risk DCD grafts do notmeet the cholangiocellular viability criteria during NMP(Table 1). We therefore do not transplant these livers, as bilecomposition during NMP has been shown to correlate withbiliary injury and thereby the risk of post-transplant cholangio-pathy4. Transplanting high-risk (DCD) donor livers withoutmonitoring bile composition during NMP poses a risk to therecipient, as other investigators have previously shown a high rateof post-transplant cholangiopathy after end-ischemic NMP ofhigh-risk DCD livers3,5. Therefore, with the current knowledge itis not a complete surprise that Mergental et al. have noted a highincidence of post-transplant cholangiopathy (30% after DCDtransplantation) and need for retransplantation in their series1.In another clinical trial on NMP and transplantation of initiallydiscarded human donor livers (DHOPE-COR-NMP trial), wehave monitored bile composition point of care6–8. Following anearly case of post-transplant cholangiopathy, we have learned thatabsolute values of bile pH, bicarbonate, and glucose during NMPare not the most suitable markers for cholangiocellular viabilitytesting. We have learned that the difference between the bile andperfusate levels of pH, bicarbonate, and glucose should be used toidentify alkalization of the bile and reabsorption of glucose by thebiliary epithelium (biomarkers of bile duct viability; Table 1)8.Currently, we have performed over 50 DHOPE-COR-NMPprocedures of initially nation-wide discarded, high-risk DCDlivers and after using the delta pH, bicarbonate, and glucose ascholangiocellular viability criteria during NMP, we have notobserved any case of post-transplant cholangiopathy.Bile production during NMPIn the study by Mergental et al., 23% of the livers did not appearto produce bile1. In our experience, we have always been able toexplain low or absent bile flow during NMP by a technical issuewith the biliary drain. Regularly, the tip of the biliary drain can bestuck against the bile duct wall, leading to obstruction of thelumen and limiting bile flow. We have tested biliary drainsextensively in preclinical experiments, and observed that bile flowinitiates more rapidly when a small diameter drain is used, as aresult of increased capillary force. As a result, we have been usinga small feeding tube catheter (8 French) with an open tip and sideholes as a biliary drain9.Combination of end-ischemic HMP and NMP versus NMPaloneIn the study by Mergental et al., it was chosen to perform end-ischemic NMP only1. Since the VITTAL study was initiated in2016, other centers shared similar experiences showing highhttps://doi.org/10.1038/s41467-021-21182-8 OPEN1 Department of Surgery, Section of Hepatobiliary Surgery & Liver Transplantation, University Medical Center Groningen, University of Groningen,Groningen, Netherlands. ✉email: r.j.porte@umcg.nlNATURE COMMUNICATIONS |         (2021) 12:1008 | https://doi.org/10.1038/s41467-021-21182-8 | www.nature.com/naturecommunications 11234567890():,;percentages of biliary complications after NMP for high-risk(DCD) donor livers3,5. End-ischemic NMP exposes a donororgan to ischemia-reperfusion injury, to which the bile ducts areextremely sensible. It has been shown before that a short period ofdual hypothermic oxygenated machine perfusion (DHOPE)reduces reperfusion injury of the liver and biliary tree10. Severalstudies have demonstrated a beneficial effect of performingDHOPE prior to either direct transplantation or NMP11–15. Aftercombined DHOPE and NMP, hepatic adenosine triphosphatecontent and biliary bicarbonate and bilirubin were higher incomparison to livers that underwent NMP only15. As a result, in2017, the DHOPE-COR-NMP trial was initiated with a combi-nation of one-hour DHOPE, followed by one-hour controlledoxygenated rewarming, and subsequent NMP, with the aim toreduce ischemia-reperfusion injury at the start of NMP6–8.Interestingly, all livers in the DHOPE-COR-NMP trial met thehepatocellular viability criteria used in the VITTAL study, despitethe fact that all livers were derived from high-risk DCD donorswith a substantially higher median age, compared to the VITTALstudy8. This could suggest that a short period of DHOPE prior toNMP is very effective in preventing additional reperfusion injuryof the liver parenchyma (hepatocytes) at the start of NMP. Onlylivers that have suffered too much (warm) ischemic injury of thebile ducts during and after the DCD procedure may no longer besalvageable with DHOPE and will not meet the biliary viabilitycriteria during the NMP phase.In conclusion, in a rapidly advancing field of liver machine per-fusion, we are all still learning and it is through sharing of ourexperiences that we can collective determine the most optimal use ofthe new technology in the benefit or our patients. From the emer-ging evidence, it becomes clear that end-ischemic NMP is animportant tool to assess and select donor livers that, based on tra-ditional criteria, were initially considered not suitable for trans-plantation. Yet, end-ischemic NMP alone, as applied in the VITTALstudy, does not protect the bile ducts against ischemia-reperfusioninjury. Therefore, a short period of HMP prior the NMP, as well asthe use of cholangiocellular viability criteria during machine perfu-sion, are important modifications that may help avoid post-transplant morbidity and graft loss due to cholangiopathy.Received: 18 June 2020; Accepted: 18 January 2021;References1. Mergental, H. et al. Transplantation of discarded livers following viabilitytesting with normothermic machine perfusion. Nat. Commun. 11, 2939 (2020).2. Op den Dries, S. et al. Ex vivo normothermic machine perfusion andviability testing of discarded human donor livers. Am. J. Transplant. 13,1327–1335 (2013).3. Watson, C. J. E. et al. Observations on the ex situ perfusion of livers fortransplantation. Am. J. Transplant. 18, 2005–2020 (2018).4. Matton, A. P. M. et al. Biliary bicarbonate, pH and glucose are suitablebiomarkers of biliary viability during ex situ normothermic machine perfusionof human donor livers. Transplantation 103, 1405–1413 (2019).5. Watson, C. J. E. et al. Normothermic perfusion in the assessment andpreservation of declined livers before transplantation: hyperoxia andvasoplegia—important lessons from the first 12 cases. Transplantation 101,1084–1098 (2017).6. De Vries, Y. et al. Transplantation of high-risk donor livers after resuscitationand viability assessment using a combined protocol of oxygenatedhypothermic, rewarming and normothermic machine perfusion: studyprotocol for a prospective, single-arm study (DHOPE-COR-NMP trial). BMJOpen. 9, e028596 (2019).7. De Vries, Y. et al. Pretransplant sequential hypo and normothermic machineperfusion of suboptimal livers donated after circulatory death using ahemoglobin-based oxygen carrier perfusion solution. Am. J. Transplant. 19,1202–1211 (2019).8. van Leeuwen, O. B. et al. Transplantation of high-risk donor livers after ex situresuscitation and assessment using combined hypo- and normothermicmachine perfusion: a prospective trial. Ann. Surg. 270, 906–914 (2019).9. Van Leeuwen, O. B., de Meijer, V. E. & Porte, R. J. Viability criteria forfunctional assessment of donor livers during normothermic machineperfusion. Liver Transpl. 24, 1333–1335 (2018).10. Van Rijn, R. et al. Hypothermic oxygenated machine perfusion reduces bileduct reperfusion injury after transplantation of donation after circulatorydeath livers. Liver Transpl. 24, 655–664 (2018).11. Guarrera, J. V. et al. Hypothermic machine preservation in human livertransplantation: the first clinical series. Am. J. Transplant. 10, 372–381 (2010).12. Dutkowski, P. et al. HOPE for human liver grafts obtained from donors aftercardiac death. J. Hepatol. 60, 765–772 (2014).13. van Rijn, R. et al. Dual hypothermic oxygenated machine perfusion inliver transplants donated after circulatory death. Br. J. Surg. 104, 907–917(2017).14. Burlage, L. C. et al. Oxygenated hypothermic machine perfusion after staticcold storage improves endothelial function of extended criteria donor livers.HPB (Oxford) 19, 538–546 (2017).15. Westerkamp, A. C. et al. Oxygenated hypothermic machine perfusion afterstatic cold storage improves hepatobiliary function of extended criteria donorlivers. Transplantation 100, 825–835 (2016).Author contributionsO.B.v.L., Y.d.V., V.E.d.M., and R.J.P. wrote and critically revised the manuscript.Competing interestsThe authors declare no competing interests.Additional informationCorrespondence and requests for materials should be addressed to R.J.P.Peer review information Nature Communications thanks Renato Romagnoli and StefanSchneeberger for their contribution to the peer review of this work.Reprints and permission information is available at http://www.nature.com/reprintsPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2021Table 1 Hepatocellular and cholangiocellular viability criteriafor human donor livers during NMPa.VITTAL criteria Groningen criteriaHepatocellular criteria HepatocellularcriteriaCholangiocellularcriteriaLactate clearance Lactate clearance Delta bile pHAt least two of the followingcriteriaPerfusate pHstabilizationDelta bile bicarbonateBile production Delta bile glucose- Bile production- Perfusate pH stabilization- Metabolism of glucose- Stable flows- Homogenous perfusionaThe VITTAL criteria had to be met within 4 h of NMP, the Groningen criteria within 2.5 h ofNMP1,8.MATTERS ARISING NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21182-82 NATURE COMMUNICATIONS |         (2021) 12:1008 | https://doi.org/10.1038/s41467-021-21182-8 | www.nature.com/naturecommunications

University of Groningen

   University of GroningenHypothermic machine perfusion before viability testing of previously discarded human liversvan Leeuwen, Otto B; de Vries, Yvonne; de Meijer, Vincent E; Porte, Robert JPublished in:Nature CommunicationsDOI:10.1038/s41467-021-21182-8IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):van Leeuwen, O. B., de Vries, Y., de Meijer, V. E., & Porte, R. J. (2021). Hypothermic machine perfusionbefore viability testing of previously discarded human livers. Nature Communications, 12(1), [1008].https://doi.org/10.1038/s41467-021-21182-8CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 29-04-2023MATTERS ARISINGHypothermic machine perfusion before viabilitytesting of previously discarded human liversOtto B. van Leeuwen 1, Yvonne de Vries1, Vincent E. de Meijer 1 & Robert J. Porte1✉ARISING FROM H. Mergental et al. Nature Communications https://doi.org/10.1038/s41467-020-16251-3 (2020)The results from the VITTAL study, with back-to-base end-ischemic normothermic machine perfusion (NMP) forviability testing of high-risk donor livers, were eagerlyawaited as in this field different techniques are currently beingused1. Of 31 initially discarded livers, 22 (71%) met the viabilitycriteria during NMP and were transplanted with a 100% 90-daygraft survival; however, three out of ten livers donated after cir-culatory death (DCD) developed biliary complications (30%) andrequired retransplantation. Because the trial was already initiatedin 2016, more recent insights in viability testing should be con-sidered when discussing the design and results of this clinicaltrial. Therefore, there are three issues that needs commenting tointerpret the high rate of biliary complications reported: (1) theviability criteria used in this trial, (2) production of bile duringNMP and (3) the use of end-ischemic NMP alone.Cholangiocyte viability assessment and liver functionbiomarkers for clinical decision making during NMPIn contrast to hypothermic (<12 °C) machine perfusion (HMP),livers are metabolically fully active during NMP. This leads torestoration of hepatobiliary metabolism, such as clearance oflactate, production of (coagulation) proteins, and, importantly,bile production. Two types of viability criteria for donor liversduring NMP have been distinguished: hepatocellular (‘liver par-enchyma’) and cholangiocellular (‘bile duct’) viability criteria(Table 1). In the current study by Mergental et al., only hepato-cellular viability criteria were used to assess ‘transplantability’ ofliver grafts during NMP1. The first reports on the value of bilecomposition as a tool to determine bile duct viability were pub-lished after the initiation of this study2,3. In our experience, asubstantial number of especially high-risk DCD grafts do notmeet the cholangiocellular viability criteria during NMP(Table 1). We therefore do not transplant these livers, as bilecomposition during NMP has been shown to correlate withbiliary injury and thereby the risk of post-transplant cholangio-pathy4. Transplanting high-risk (DCD) donor livers withoutmonitoring bile composition during NMP poses a risk to therecipient, as other investigators have previously shown a high rateof post-transplant cholangiopathy after end-ischemic NMP ofhigh-risk DCD livers3,5. Therefore, with the current knowledge itis not a complete surprise that Mergental et al. have noted a highincidence of post-transplant cholangiopathy (30% after DCDtransplantation) and need for retransplantation in their series1.In another clinical trial on NMP and transplantation of initiallydiscarded human donor livers (DHOPE-COR-NMP trial), wehave monitored bile composition point of care6–8. Following anearly case of post-transplant cholangiopathy, we have learned thatabsolute values of bile pH, bicarbonate, and glucose during NMPare not the most suitable markers for cholangiocellular viabilitytesting. We have learned that the difference between the bile andperfusate levels of pH, bicarbonate, and glucose should be used toidentify alkalization of the bile and reabsorption of glucose by thebiliary epithelium (biomarkers of bile duct viability; Table 1)8.Currently, we have performed over 50 DHOPE-COR-NMPprocedures of initially nation-wide discarded, high-risk DCDlivers and after using the delta pH, bicarbonate, and glucose ascholangiocellular viability criteria during NMP, we have notobserved any case of post-transplant cholangiopathy.Bile production during NMPIn the study by Mergental et al., 23% of the livers did not appearto produce bile1. In our experience, we have always been able toexplain low or absent bile flow during NMP by a technical issuewith the biliary drain. Regularly, the tip of the biliary drain can bestuck against the bile duct wall, leading to obstruction of thelumen and limiting bile flow. We have tested biliary drainsextensively in preclinical experiments, and observed that bile flowinitiates more rapidly when a small diameter drain is used, as aresult of increased capillary force. As a result, we have been usinga small feeding tube catheter (8 French) with an open tip and sideholes as a biliary drain9.Combination of end-ischemic HMP and NMP versus NMPaloneIn the study by Mergental et al., it was chosen to perform end-ischemic NMP only1. Since the VITTAL study was initiated in2016, other centers shared similar experiences showing highhttps://doi.org/10.1038/s41467-021-21182-8 OPEN1 Department of Surgery, Section of Hepatobiliary Surgery & Liver Transplantation, University Medical Center Groningen, University of Groningen,Groningen, Netherlands. ✉email: r.j.porte@umcg.nlNATURE COMMUNICATIONS |         (2021) 12:1008 | https://doi.org/10.1038/s41467-021-21182-8 | www.nature.com/naturecommunications 11234567890():,;percentages of biliary complications after NMP for high-risk(DCD) donor livers3,5. End-ischemic NMP exposes a donororgan to ischemia-reperfusion injury, to which the bile ducts areextremely sensible. It has been shown before that a short period ofdual hypothermic oxygenated machine perfusion (DHOPE)reduces reperfusion injury of the liver and biliary tree10. Severalstudies have demonstrated a beneficial effect of performingDHOPE prior to either direct transplantation or NMP11–15. Aftercombined DHOPE and NMP, hepatic adenosine triphosphatecontent and biliary bicarbonate and bilirubin were higher incomparison to livers that underwent NMP only15. As a result, in2017, the DHOPE-COR-NMP trial was initiated with a combi-nation of one-hour DHOPE, followed by one-hour controlledoxygenated rewarming, and subsequent NMP, with the aim toreduce ischemia-reperfusion injury at the start of NMP6–8.Interestingly, all livers in the DHOPE-COR-NMP trial met thehepatocellular viability criteria used in the VITTAL study, despitethe fact that all livers were derived from high-risk DCD donorswith a substantially higher median age, compared to the VITTALstudy8. This could suggest that a short period of DHOPE prior toNMP is very effective in preventing additional reperfusion injuryof the liver parenchyma (hepatocytes) at the start of NMP. Onlylivers that have suffered too much (warm) ischemic injury of thebile ducts during and after the DCD procedure may no longer besalvageable with DHOPE and will not meet the biliary viabilitycriteria during the NMP phase.In conclusion, in a rapidly advancing field of liver machine per-fusion, we are all still learning and it is through sharing of ourexperiences that we can collective determine the most optimal use ofthe new technology in the benefit or our patients. From the emer-ging evidence, it becomes clear that end-ischemic NMP is animportant tool to assess and select donor livers that, based on tra-ditional criteria, were initially considered not suitable for trans-plantation. Yet, end-ischemic NMP alone, as applied in the VITTALstudy, does not protect the bile ducts against ischemia-reperfusioninjury. Therefore, a short period of HMP prior the NMP, as well asthe use of cholangiocellular viability criteria during machine perfu-sion, are important modifications that may help avoid post-transplant morbidity and graft loss due to cholangiopathy.Received: 18 June 2020; Accepted: 18 January 2021;References1. Mergental, H. et al. Transplantation of discarded livers following viabilitytesting with normothermic machine perfusion. Nat. Commun. 11, 2939 (2020).2. Op den Dries, S. et al. Ex vivo normothermic machine perfusion andviability testing of discarded human donor livers. Am. J. Transplant. 13,1327–1335 (2013).3. Watson, C. J. E. et al. Observations on the ex situ perfusion of livers fortransplantation. Am. J. Transplant. 18, 2005–2020 (2018).4. Matton, A. P. M. et al. Biliary bicarbonate, pH and glucose are suitablebiomarkers of biliary viability during ex situ normothermic machine perfusionof human donor livers. Transplantation 103, 1405–1413 (2019).5. Watson, C. J. E. et al. Normothermic perfusion in the assessment andpreservation of declined livers before transplantation: hyperoxia andvasoplegia—important lessons from the first 12 cases. Transplantation 101,1084–1098 (2017).6. De Vries, Y. et al. Transplantation of high-risk donor livers after resuscitationand viability assessment using a combined protocol of oxygenatedhypothermic, rewarming and normothermic machine perfusion: studyprotocol for a prospective, single-arm study (DHOPE-COR-NMP trial). BMJOpen. 9, e028596 (2019).7. De Vries, Y. et al. Pretransplant sequential hypo and normothermic machineperfusion of suboptimal livers donated after circulatory death using ahemoglobin-based oxygen carrier perfusion solution. Am. J. Transplant. 19,1202–1211 (2019).8. van Leeuwen, O. B. et al. Transplantation of high-risk donor livers after ex situresuscitation and assessment using combined hypo- and normothermicmachine perfusion: a prospective trial. Ann. Surg. 270, 906–914 (2019).9. Van Leeuwen, O. B., de Meijer, V. E. & Porte, R. J. Viability criteria forfunctional assessment of donor livers during normothermic machineperfusion. Liver Transpl. 24, 1333–1335 (2018).10. Van Rijn, R. et al. Hypothermic oxygenated machine perfusion reduces bileduct reperfusion injury after transplantation of donation after circulatorydeath livers. Liver Transpl. 24, 655–664 (2018).11. Guarrera, J. V. et al. Hypothermic machine preservation in human livertransplantation: the first clinical series. Am. J. Transplant. 10, 372–381 (2010).12. Dutkowski, P. et al. HOPE for human liver grafts obtained from donors aftercardiac death. J. Hepatol. 60, 765–772 (2014).13. van Rijn, R. et al. Dual hypothermic oxygenated machine perfusion inliver transplants donated after circulatory death. Br. J. Surg. 104, 907–917(2017).14. Burlage, L. C. et al. Oxygenated hypothermic machine perfusion after staticcold storage improves endothelial function of extended criteria donor livers.HPB (Oxford) 19, 538–546 (2017).15. Westerkamp, A. C. et al. Oxygenated hypothermic machine perfusion afterstatic cold storage improves hepatobiliary function of extended criteria donorlivers. Transplantation 100, 825–835 (2016).Author contributionsO.B.v.L., Y.d.V., V.E.d.M., and R.J.P. wrote and critically revised the manuscript.Competing interestsThe authors declare no competing interests.Additional informationCorrespondence and requests for materials should be addressed to R.J.P.Peer review information Nature Communications thanks Renato Romagnoli and StefanSchneeberger for their contribution to the peer review of this work.Reprints and permission information is available at http://www.nature.com/reprintsPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2021Table 1 Hepatocellular and cholangiocellular viability criteriafor human donor livers during NMPa.VITTAL criteria Groningen criteriaHepatocellular criteria HepatocellularcriteriaCholangiocellularcriteriaLactate clearance Lactate clearance Delta bile pHAt least two of the followingcriteriaPerfusate pHstabilizationDelta bile bicarbonateBile production Delta bile glucose- Bile production- Perfusate pH stabilization- Metabolism of glucose- Stable flows- Homogenous perfusionaThe VITTAL criteria had to be met within 4 h of NMP, the Groningen criteria within 2.5 h ofNMP1,8.MATTERS ARISING NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21182-82 NATURE COMMUNICATIONS |         (2021) 12:1008 | https://doi.org/10.1038/s41467-021-21182-8 | www.nature.com/naturecommunications

   University of GroningenHypothermic machine perfusion before viability testing of previously discarded human liversvan Leeuwen, Otto B; de Vries, Yvonne; de Meijer, Vincent E; Porte, Robert JPublished in:Nature CommunicationsDOI:10.1038/s41467-021-21182-8IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):van Leeuwen, O. B., de Vries, Y., de Meijer, V. E., & Porte, R. J. (2021). Hypothermic machine perfusionbefore viability testing of previously discarded human livers. Nature Communications, 12(1), [1008].https://doi.org/10.1038/s41467-021-21182-8CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 08-06-2022MATTERS ARISINGHypothermic machine perfusion before viabilitytesting of previously discarded human liversOtto B. van Leeuwen 1, Yvonne de Vries1, Vincent E. de Meijer 1 & Robert J. Porte1✉ARISING FROM H. Mergental et al. Nature Communications https://doi.org/10.1038/s41467-020-16251-3 (2020)The results from the VITTAL study, with back-to-base end-ischemic normothermic machine perfusion (NMP) forviability testing of high-risk donor livers, were eagerlyawaited as in this field different techniques are currently beingused1. Of 31 initially discarded livers, 22 (71%) met the viabilitycriteria during NMP and were transplanted with a 100% 90-daygraft survival; however, three out of ten livers donated after cir-culatory death (DCD) developed biliary complications (30%) andrequired retransplantation. Because the trial was already initiatedin 2016, more recent insights in viability testing should be con-sidered when discussing the design and results of this clinicaltrial. Therefore, there are three issues that needs commenting tointerpret the high rate of biliary complications reported: (1) theviability criteria used in this trial, (2) production of bile duringNMP and (3) the use of end-ischemic NMP alone.Cholangiocyte viability assessment and liver functionbiomarkers for clinical decision making during NMPIn contrast to hypothermic (<12 °C) machine perfusion (HMP),livers are metabolically fully active during NMP. This leads torestoration of hepatobiliary metabolism, such as clearance oflactate, production of (coagulation) proteins, and, importantly,bile production. Two types of viability criteria for donor liversduring NMP have been distinguished: hepatocellular (‘liver par-enchyma’) and cholangiocellular (‘bile duct’) viability criteria(Table 1). In the current study by Mergental et al., only hepato-cellular viability criteria were used to assess ‘transplantability’ ofliver grafts during NMP1. The first reports on the value of bilecomposition as a tool to determine bile duct viability were pub-lished after the initiation of this study2,3. In our experience, asubstantial number of especially high-risk DCD grafts do notmeet the cholangiocellular viability criteria during NMP(Table 1). We therefore do not transplant these livers, as bilecomposition during NMP has been shown to correlate withbiliary injury and thereby the risk of post-transplant cholangio-pathy4. Transplanting high-risk (DCD) donor livers withoutmonitoring bile composition during NMP poses a risk to therecipient, as other investigators have previously shown a high rateof post-transplant cholangiopathy after end-ischemic NMP ofhigh-risk DCD livers3,5. Therefore, with the current knowledge itis not a complete surprise that Mergental et al. have noted a highincidence of post-transplant cholangiopathy (30% after DCDtransplantation) and need for retransplantation in their series1.In another clinical trial on NMP and transplantation of initiallydiscarded human donor livers (DHOPE-COR-NMP trial), wehave monitored bile composition point of care6–8. Following anearly case of post-transplant cholangiopathy, we have learned thatabsolute values of bile pH, bicarbonate, and glucose during NMPare not the most suitable markers for cholangiocellular viabilitytesting. We have learned that the difference between the bile andperfusate levels of pH, bicarbonate, and glucose should be used toidentify alkalization of the bile and reabsorption of glucose by thebiliary epithelium (biomarkers of bile duct viability; Table 1)8.Currently, we have performed over 50 DHOPE-COR-NMPprocedures of initially nation-wide discarded, high-risk DCDlivers and after using the delta pH, bicarbonate, and glucose ascholangiocellular viability criteria during NMP, we have notobserved any case of post-transplant cholangiopathy.Bile production during NMPIn the study by Mergental et al., 23% of the livers did not appearto produce bile1. In our experience, we have always been able toexplain low or absent bile flow during NMP by a technical issuewith the biliary drain. Regularly, the tip of the biliary drain can bestuck against the bile duct wall, leading to obstruction of thelumen and limiting bile flow. We have tested biliary drainsextensively in preclinical experiments, and observed that bile flowinitiates more rapidly when a small diameter drain is used, as aresult of increased capillary force. As a result, we have been usinga small feeding tube catheter (8 French) with an open tip and sideholes as a biliary drain9.Combination of end-ischemic HMP and NMP versus NMPaloneIn the study by Mergental et al., it was chosen to perform end-ischemic NMP only1. Since the VITTAL study was initiated in2016, other centers shared similar experiences showing highhttps://doi.org/10.1038/s41467-021-21182-8 OPEN1 Department of Surgery, Section of Hepatobiliary Surgery & Liver Transplantation, University Medical Center Groningen, University of Groningen,Groningen, Netherlands. ✉email: r.j.porte@umcg.nlNATURE COMMUNICATIONS |         (2021) 12:1008 | https://doi.org/10.1038/s41467-021-21182-8 | www.nature.com/naturecommunications 11234567890():,;percentages of biliary complications after NMP for high-risk(DCD) donor livers3,5. End-ischemic NMP exposes a donororgan to ischemia-reperfusion injury, to which the bile ducts areextremely sensible. It has been shown before that a short period ofdual hypothermic oxygenated machine perfusion (DHOPE)reduces reperfusion injury of the liver and biliary tree10. Severalstudies have demonstrated a beneficial effect of performingDHOPE prior to either direct transplantation or NMP11–15. Aftercombined DHOPE and NMP, hepatic adenosine triphosphatecontent and biliary bicarbonate and bilirubin were higher incomparison to livers that underwent NMP only15. As a result, in2017, the DHOPE-COR-NMP trial was initiated with a combi-nation of one-hour DHOPE, followed by one-hour controlledoxygenated rewarming, and subsequent NMP, with the aim toreduce ischemia-reperfusion injury at the start of NMP6–8.Interestingly, all livers in the DHOPE-COR-NMP trial met thehepatocellular viability criteria used in the VITTAL study, despitethe fact that all livers were derived from high-risk DCD donorswith a substantially higher median age, compared to the VITTALstudy8. This could suggest that a short period of DHOPE prior toNMP is very effective in preventing additional reperfusion injuryof the liver parenchyma (hepatocytes) at the start of NMP. Onlylivers that have suffered too much (warm) ischemic injury of thebile ducts during and after the DCD procedure may no longer besalvageable with DHOPE and will not meet the biliary viabilitycriteria during the NMP phase.In conclusion, in a rapidly advancing field of liver machine per-fusion, we are all still learning and it is through sharing of ourexperiences that we can collective determine the most optimal use ofthe new technology in the benefit or our patients. From the emer-ging evidence, it becomes clear that end-ischemic NMP is animportant tool to assess and select donor livers that, based on tra-ditional criteria, were initially considered not suitable for trans-plantation. Yet, end-ischemic NMP alone, as applied in the VITTALstudy, does not protect the bile ducts against ischemia-reperfusioninjury. Therefore, a short period of HMP prior the NMP, as well asthe use of cholangiocellular viability criteria during machine perfu-sion, are important modifications that may help avoid post-transplant morbidity and graft loss due to cholangiopathy.Received: 18 June 2020; Accepted: 18 January 2021;References1. Mergental, H. et al. Transplantation of discarded livers following viabilitytesting with normothermic machine perfusion. Nat. Commun. 11, 2939 (2020).2. Op den Dries, S. et al. Ex vivo normothermic machine perfusion andviability testing of discarded human donor livers. Am. J. Transplant. 13,1327–1335 (2013).3. Watson, C. J. E. et al. Observations on the ex situ perfusion of livers fortransplantation. Am. J. Transplant. 18, 2005–2020 (2018).4. Matton, A. P. M. et al. Biliary bicarbonate, pH and glucose are suitablebiomarkers of biliary viability during ex situ normothermic machine perfusionof human donor livers. Transplantation 103, 1405–1413 (2019).5. Watson, C. J. E. et al. Normothermic perfusion in the assessment andpreservation of declined livers before transplantation: hyperoxia andvasoplegia—important lessons from the first 12 cases. Transplantation 101,1084–1098 (2017).6. De Vries, Y. et al. Transplantation of high-risk donor livers after resuscitationand viability assessment using a combined protocol of oxygenatedhypothermic, rewarming and normothermic machine perfusion: studyprotocol for a prospective, single-arm study (DHOPE-COR-NMP trial). BMJOpen. 9, e028596 (2019).7. De Vries, Y. et al. Pretransplant sequential hypo and normothermic machineperfusion of suboptimal livers donated after circulatory death using ahemoglobin-based oxygen carrier perfusion solution. Am. J. Transplant. 19,1202–1211 (2019).8. van Leeuwen, O. B. et al. Transplantation of high-risk donor livers after ex situresuscitation and assessment using combined hypo- and normothermicmachine perfusion: a prospective trial. Ann. Surg. 270, 906–914 (2019).9. Van Leeuwen, O. B., de Meijer, V. E. & Porte, R. J. Viability criteria forfunctional assessment of donor livers during normothermic machineperfusion. Liver Transpl. 24, 1333–1335 (2018).10. Van Rijn, R. et al. Hypothermic oxygenated machine perfusion reduces bileduct reperfusion injury after transplantation of donation after circulatorydeath livers. Liver Transpl. 24, 655–664 (2018).11. Guarrera, J. V. et al. Hypothermic machine preservation in human livertransplantation: the first clinical series. Am. J. Transplant. 10, 372–381 (2010).12. Dutkowski, P. et al. HOPE for human liver grafts obtained from donors aftercardiac death. J. Hepatol. 60, 765–772 (2014).13. van Rijn, R. et al. Dual hypothermic oxygenated machine perfusion inliver transplants donated after circulatory death. Br. J. Surg. 104, 907–917(2017).14. Burlage, L. C. et al. Oxygenated hypothermic machine perfusion after staticcold storage improves endothelial function of extended criteria donor livers.HPB (Oxford) 19, 538–546 (2017).15. Westerkamp, A. C. et al. Oxygenated hypothermic machine perfusion afterstatic cold storage improves hepatobiliary function of extended criteria donorlivers. Transplantation 100, 825–835 (2016).Author contributionsO.B.v.L., Y.d.V., V.E.d.M., and R.J.P. wrote and critically revised the manuscript.Competing interestsThe authors declare no competing interests.Additional informationCorrespondence and requests for materials should be addressed to R.J.P.Peer review information Nature Communications thanks Renato Romagnoli and StefanSchneeberger for their contribution to the peer review of this work.Reprints and permission information is available at http://www.nature.com/reprintsPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2021Table 1 Hepatocellular and cholangiocellular viability criteriafor human donor livers during NMPa.VITTAL criteria Groningen criteriaHepatocellular criteria HepatocellularcriteriaCholangiocellularcriteriaLactate clearance Lactate clearance Delta bile pHAt least two of the followingcriteriaPerfusate pHstabilizationDelta bile bicarbonateBile production Delta bile glucose- Bile production- Perfusate pH stabilization- Metabolism of glucose- Stable flows- Homogenous perfusionaThe VITTAL criteria had to be met within 4 h of NMP, the Groningen criteria within 2.5 h ofNMP1,8.MATTERS ARISING NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21182-82 NATURE COMMUNICATIONS |         (2021) 12:1008 | https://doi.org/10.1038/s41467-021-21182-8 | www.nature.com/naturecommunications

   University of GroningenHypothermic machine perfusion before viability testing of previously discarded human liversvan Leeuwen, Otto B; de Vries, Yvonne; de Meijer, Vincent E; Porte, Robert JPublished in:Nature CommunicationsDOI:10.1038/s41467-021-21182-8IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):van Leeuwen, O. B., de Vries, Y., de Meijer, V. E., & Porte, R. J. (2021). Hypothermic machine perfusionbefore viability testing of previously discarded human livers. Nature Communications, 12(1), [1008].https://doi.org/10.1038/s41467-021-21182-8CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 20-11-2022MATTERS ARISINGHypothermic machine perfusion before viabilitytesting of previously discarded human liversOtto B. van Leeuwen 1, Yvonne de Vries1, Vincent E. de Meijer 1 & Robert J. Porte1✉ARISING FROM H. Mergental et al. Nature Communications https://doi.org/10.1038/s41467-020-16251-3 (2020)The results from the VITTAL study, with back-to-base end-ischemic normothermic machine perfusion (NMP) forviability testing of high-risk donor livers, were eagerlyawaited as in this field different techniques are currently beingused1. Of 31 initially discarded livers, 22 (71%) met the viabilitycriteria during NMP and were transplanted with a 100% 90-daygraft survival; however, three out of ten livers donated after cir-culatory death (DCD) developed biliary complications (30%) andrequired retransplantation. Because the trial was already initiatedin 2016, more recent insights in viability testing should be con-sidered when discussing the design and results of this clinicaltrial. Therefore, there are three issues that needs commenting tointerpret the high rate of biliary complications reported: (1) theviability criteria used in this trial, (2) production of bile duringNMP and (3) the use of end-ischemic NMP alone.Cholangiocyte viability assessment and liver functionbiomarkers for clinical decision making during NMPIn contrast to hypothermic (<12 °C) machine perfusion (HMP),livers are metabolically fully active during NMP. This leads torestoration of hepatobiliary metabolism, such as clearance oflactate, production of (coagulation) proteins, and, importantly,bile production. Two types of viability criteria for donor liversduring NMP have been distinguished: hepatocellular (‘liver par-enchyma’) and cholangiocellular (‘bile duct’) viability criteria(Table 1). In the current study by Mergental et al., only hepato-cellular viability criteria were used to assess ‘transplantability’ ofliver grafts during NMP1. The first reports on the value of bilecomposition as a tool to determine bile duct viability were pub-lished after the initiation of this study2,3. In our experience, asubstantial number of especially high-risk DCD grafts do notmeet the cholangiocellular viability criteria during NMP(Table 1). We therefore do not transplant these livers, as bilecomposition during NMP has been shown to correlate withbiliary injury and thereby the risk of post-transplant cholangio-pathy4. Transplanting high-risk (DCD) donor livers withoutmonitoring bile composition during NMP poses a risk to therecipient, as other investigators have previously shown a high rateof post-transplant cholangiopathy after end-ischemic NMP ofhigh-risk DCD livers3,5. Therefore, with the current knowledge itis not a complete surprise that Mergental et al. have noted a highincidence of post-transplant cholangiopathy (30% after DCDtransplantation) and need for retransplantation in their series1.In another clinical trial on NMP and transplantation of initiallydiscarded human donor livers (DHOPE-COR-NMP trial), wehave monitored bile composition point of care6–8. Following anearly case of post-transplant cholangiopathy, we have learned thatabsolute values of bile pH, bicarbonate, and glucose during NMPare not the most suitable markers for cholangiocellular viabilitytesting. We have learned that the difference between the bile andperfusate levels of pH, bicarbonate, and glucose should be used toidentify alkalization of the bile and reabsorption of glucose by thebiliary epithelium (biomarkers of bile duct viability; Table 1)8.Currently, we have performed over 50 DHOPE-COR-NMPprocedures of initially nation-wide discarded, high-risk DCDlivers and after using the delta pH, bicarbonate, and glucose ascholangiocellular viability criteria during NMP, we have notobserved any case of post-transplant cholangiopathy.Bile production during NMPIn the study by Mergental et al., 23% of the livers did not appearto produce bile1. In our experience, we have always been able toexplain low or absent bile flow during NMP by a technical issuewith the biliary drain. Regularly, the tip of the biliary drain can bestuck against the bile duct wall, leading to obstruction of thelumen and limiting bile flow. We have tested biliary drainsextensively in preclinical experiments, and observed that bile flowinitiates more rapidly when a small diameter drain is used, as aresult of increased capillary force. As a result, we have been usinga small feeding tube catheter (8 French) with an open tip and sideholes as a biliary drain9.Combination of end-ischemic HMP and NMP versus NMPaloneIn the study by Mergental et al., it was chosen to perform end-ischemic NMP only1. Since the VITTAL study was initiated in2016, other centers shared similar experiences showing highhttps://doi.org/10.1038/s41467-021-21182-8 OPEN1 Department of Surgery, Section of Hepatobiliary Surgery & Liver Transplantation, University Medical Center Groningen, University of Groningen,Groningen, Netherlands. ✉email: r.j.porte@umcg.nlNATURE COMMUNICATIONS |         (2021) 12:1008 | https://doi.org/10.1038/s41467-021-21182-8 | www.nature.com/naturecommunications 11234567890():,;percentages of biliary complications after NMP for high-risk(DCD) donor livers3,5. End-ischemic NMP exposes a donororgan to ischemia-reperfusion injury, to which the bile ducts areextremely sensible. It has been shown before that a short period ofdual hypothermic oxygenated machine perfusion (DHOPE)reduces reperfusion injury of the liver and biliary tree10. Severalstudies have demonstrated a beneficial effect of performingDHOPE prior to either direct transplantation or NMP11–15. Aftercombined DHOPE and NMP, hepatic adenosine triphosphatecontent and biliary bicarbonate and bilirubin were higher incomparison to livers that underwent NMP only15. As a result, in2017, the DHOPE-COR-NMP trial was initiated with a combi-nation of one-hour DHOPE, followed by one-hour controlledoxygenated rewarming, and subsequent NMP, with the aim toreduce ischemia-reperfusion injury at the start of NMP6–8.Interestingly, all livers in the DHOPE-COR-NMP trial met thehepatocellular viability criteria used in the VITTAL study, despitethe fact that all livers were derived from high-risk DCD donorswith a substantially higher median age, compared to the VITTALstudy8. This could suggest that a short period of DHOPE prior toNMP is very effective in preventing additional reperfusion injuryof the liver parenchyma (hepatocytes) at the start of NMP. Onlylivers that have suffered too much (warm) ischemic injury of thebile ducts during and after the DCD procedure may no longer besalvageable with DHOPE and will not meet the biliary viabilitycriteria during the NMP phase.In conclusion, in a rapidly advancing field of liver machine per-fusion, we are all still learning and it is through sharing of ourexperiences that we can collective determine the most optimal use ofthe new technology in the benefit or our patients. From the emer-ging evidence, it becomes clear that end-ischemic NMP is animportant tool to assess and select donor livers that, based on tra-ditional criteria, were initially considered not suitable for trans-plantation. Yet, end-ischemic NMP alone, as applied in the VITTALstudy, does not protect the bile ducts against ischemia-reperfusioninjury. Therefore, a short period of HMP prior the NMP, as well asthe use of cholangiocellular viability criteria during machine perfu-sion, are important modifications that may help avoid post-transplant morbidity and graft loss due to cholangiopathy.Received: 18 June 2020; Accepted: 18 January 2021;References1. Mergental, H. et al. Transplantation of discarded livers following viabilitytesting with normothermic machine perfusion. Nat. Commun. 11, 2939 (2020).2. Op den Dries, S. et al. Ex vivo normothermic machine perfusion andviability testing of discarded human donor livers. Am. J. Transplant. 13,1327–1335 (2013).3. Watson, C. J. E. et al. Observations on the ex situ perfusion of livers fortransplantation. Am. J. Transplant. 18, 2005–2020 (2018).4. Matton, A. P. M. et al. Biliary bicarbonate, pH and glucose are suitablebiomarkers of biliary viability during ex situ normothermic machine perfusionof human donor livers. Transplantation 103, 1405–1413 (2019).5. Watson, C. J. E. et al. Normothermic perfusion in the assessment andpreservation of declined livers before transplantation: hyperoxia andvasoplegia—important lessons from the first 12 cases. Transplantation 101,1084–1098 (2017).6. De Vries, Y. et al. Transplantation of high-risk donor livers after resuscitationand viability assessment using a combined protocol of oxygenatedhypothermic, rewarming and normothermic machine perfusion: studyprotocol for a prospective, single-arm study (DHOPE-COR-NMP trial). BMJOpen. 9, e028596 (2019).7. De Vries, Y. et al. Pretransplant sequential hypo and normothermic machineperfusion of suboptimal livers donated after circulatory death using ahemoglobin-based oxygen carrier perfusion solution. Am. J. Transplant. 19,1202–1211 (2019).8. van Leeuwen, O. B. et al. Transplantation of high-risk donor livers after ex situresuscitation and assessment using combined hypo- and normothermicmachine perfusion: a prospective trial. Ann. Surg. 270, 906–914 (2019).9. Van Leeuwen, O. B., de Meijer, V. E. & Porte, R. J. Viability criteria forfunctional assessment of donor livers during normothermic machineperfusion. Liver Transpl. 24, 1333–1335 (2018).10. Van Rijn, R. et al. Hypothermic oxygenated machine perfusion reduces bileduct reperfusion injury after transplantation of donation after circulatorydeath livers. Liver Transpl. 24, 655–664 (2018).11. Guarrera, J. V. et al. Hypothermic machine preservation in human livertransplantation: the first clinical series. Am. J. Transplant. 10, 372–381 (2010).12. Dutkowski, P. et al. HOPE for human liver grafts obtained from donors aftercardiac death. J. Hepatol. 60, 765–772 (2014).13. van Rijn, R. et al. Dual hypothermic oxygenated machine perfusion inliver transplants donated after circulatory death. Br. J. Surg. 104, 907–917(2017).14. Burlage, L. C. et al. Oxygenated hypothermic machine perfusion after staticcold storage improves endothelial function of extended criteria donor livers.HPB (Oxford) 19, 538–546 (2017).15. Westerkamp, A. C. et al. Oxygenated hypothermic machine perfusion afterstatic cold storage improves hepatobiliary function of extended criteria donorlivers. Transplantation 100, 825–835 (2016).Author contributionsO.B.v.L., Y.d.V., V.E.d.M., and R.J.P. wrote and critically revised the manuscript.Competing interestsThe authors declare no competing interests.Additional informationCorrespondence and requests for materials should be addressed to R.J.P.Peer review information Nature Communications thanks Renato Romagnoli and StefanSchneeberger for their contribution to the peer review of this work.Reprints and permission information is available at http://www.nature.com/reprintsPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2021Table 1 Hepatocellular and cholangiocellular viability criteriafor human donor livers during NMPa.VITTAL criteria Groningen criteriaHepatocellular criteria HepatocellularcriteriaCholangiocellularcriteriaLactate clearance Lactate clearance Delta bile pHAt least two of the followingcriteriaPerfusate pHstabilizationDelta bile bicarbonateBile production Delta bile glucose- Bile production- Perfusate pH stabilization- Metabolism of glucose- Stable flows- Homogenous perfusionaThe VITTAL criteria had to be met within 4 h of NMP, the Groningen criteria within 2.5 h ofNMP1,8.MATTERS ARISING NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21182-82 NATURE COMMUNICATIONS |         (2021) 12:1008 | https://doi.org/10.1038/s41467-021-21182-8 | www.nature.com/naturecommunications

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Hypothermic machine perfusion before viability testing of previously discarded human livers

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