Background:The use of grafts from donation after circulatory death(DCD)overcomes the inadequate donor organ supply.Our team developed a transportable dual hypothermic oxygenated machine perfusion(DHOPE)device,which in...Background:The use of grafts from donation after circulatory death(DCD)overcomes the inadequate donor organ supply.Our team developed a transportable dual hypothermic oxygenated machine perfusion(DHOPE)device,which initiates DHOPE at a recipient center to reduce static cold storage(SCS)time and the risk of graft failure in DCD liver transplantation.Methods:Six porcine livers per group with 30 min of warm ischemia exposure were preserved via SCS or DHOPE for 6 h and then reperfused for 12 h with whole blood to mimic transplantation.Hepatocellular and biliary function and injury were assessed in perfusate and bile samples.Molecular biomarkers and histology were compared between groups.Results:Reperfusion portal vein pressure,in a flow-constant manner,and alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP)and gamma-glutamyltransferase(γ-GGT)release were significantly lower in the DHOPE group than in the SCS group at all time points.Higher bile production paralleled the lower levels of ALP andγ-GGT in the DHOPE group.The DHOPE group secreted more total bilirubin(TBIL)in bile,resulting in decreased TBIL in the perfusate,and livers preserved with DHOPE exhibited better cholangiocellular function.Furthermore,improvements in hypoxia,the inflammatory response,cell-free microRNAs and energy metabolism were observed in the DHOPE group.There were fewer apoptotic cells and TGF-β1-positive cells in the liver parenchyma and extrahepatic bile duct in the DHOPE group than in the SCS group.Conclusions:This study demonstrates the efficacy of local 4℃DHOPE to protect porcine liver grafts from30-min warm ischemia damage.展开更多
Acute-on-chronic liver failure(ACLF)is a syndrome that occurs in patients with chronic liver disease and is characterized by acute decompensation,organ failure and high short-term mortality.Partially due to the lack o...Acute-on-chronic liver failure(ACLF)is a syndrome that occurs in patients with chronic liver disease and is characterized by acute decompensation,organ failure and high short-term mortality.Partially due to the lack of universal diagnostic criteria,the actual ACLF prevalence remains unclear;nevertheless,it is expected to be a highly prevalent condition worldwide.Earlier transplantation is an effective protective measure for selected ACLF patients.Besides liver transplantation,diagnosing and treating precipitant events and providing supportive treatment for organ failures are currently the cornerstone of ACLF therapy.Although new clinical specific therapies have been researched,more studies are necessary to assess safety and efficacy.Therefore,future ACLF management strategies must consider measures to improve access to liver transplantation because the time window for this life-saving therapy is frequently narrow.Thus,an urgent and global discussion about allocation and prioritization for transplantation in critically ill ACLF patients is needed because there is evidence suggesting that the current model may not portray their waitlist mortality.In addition,while donor organ quality is meant to be a prognostic factor in the ACLF setting,recent evidence suggests that machine perfusion of the liver may be a safe tool to improve the donor organ pool and expedite liver transplantation in this scenario.展开更多
The widespread uptake of different machine perfusion(MP)strategies for liver transplant has been driven by an effort to minimize graft injury.Damage to the cholangiocytes during the liver donation,preservation,or earl...The widespread uptake of different machine perfusion(MP)strategies for liver transplant has been driven by an effort to minimize graft injury.Damage to the cholangiocytes during the liver donation,preservation,or early posttransplant period may result in stricturing of the biliary tree and inadequate biliary drainage.This problem continues to trouble clinicians,and may have catastrophic consequences for the graft and patient.Ischemic injury,as a result of compromised hepatic artery flow,is a well-known cause of biliary strictures,sepsis,and graft failure.However,very similar lesions can appear with a patent hepatic artery and these are known as ischemic type biliary lesions(ITBL)that are attributed to microcirculatory dysfunction rather than main hepatic arterial compromise.Both the warm and cold ischemic period duration appear to influence the onset of ITBL.All of the commonly used MP techniques deliver oxygen to the graft cells,and therefore may minimize the cholangiocyte injury and subsequently reduce the incidence of ITBL.As clinical experience and published evidence grows for these modalities,the impact they have on ITBL rates is important to consider.In this review,the evidence for the three commonly used MP strategies(abdominal normothermic regional perfusion[A-NRP],hypothermic oxygenated perfusion[HOPE],and normothermic machine perfusion[NMP])for ITBL prevention has been critically reviewed.Inconsistencies with ITBL definitions used in trials,coupled with variations in techniques of MP,make interpretation challenging.Overall,the evidence suggests that both HOPE and A-NRP prevent ITBL in donated after circulatory death grafts compared to cold storage.The evidence for ITBL prevention in donor after brain death grafts with any MP technique is weak.展开更多
Background:Liver transplantation(LT)is a crucial treatment for end-stage liver disease,but the limited organ supply has led to the use of extended criteria donors(ECD).The implementation of dynamic preservation techni...Background:Liver transplantation(LT)is a crucial treatment for end-stage liver disease,but the limited organ supply has led to the use of extended criteria donors(ECD).The implementation of dynamic preservation techniques like hypothermic oxygenated machine perfusion(HOPE)is crucial in improving outcomes for ECD grafts.However,graft contamination and infection are a concern.This study aimed to evaluate the risk of infections within 10 days from LT between HOPE and static cold storage(SCS)groups and postoperative complications.Methods:A retrospective cohort study was conducted,including LT recipients transplanted at a single-center from March 2016 to June 2023.Patients were divided into HOPE and SCS groups,and propensity score matching was used to select comparable cohorts.Data on patient and donor characteristics were analyzed.Results:After propensity score matching,a cohort of 370(HOPE,n=185;SCS,n=185)patients was selected for analysis.The study found no significant differences in the rate of clinically relevant infections,microbiological positive samples,or donor-derived infections within 10 days between HOPE and SCS groups.Postoperative outcomes,as well as patient and graft survival,were also similar between the two groups.The study showed that HOPE is a feasible and safe approach,with a comparable risk of infection.Conclusions:The study results indicate that HOPE use in LT does not increase the risk of infection and is associated with similar patient and graft survival outcomes compared to SCS.These findings confirm the safety and efficacy of HOPE in LT and its potential to expand the donor pool without compromising recipient outcomes.展开更多
Background:Ischemia reperfusion injury(IRI)is a major contributing factor to organ damage in liver transplantation(LT)impacting donor organ quality and patient survival.IRI-inflicted graft injury can be reduced by usi...Background:Ischemia reperfusion injury(IRI)is a major contributing factor to organ damage in liver transplantation(LT)impacting donor organ quality and patient survival.IRI-inflicted graft injury can be reduced by using hypothermic oxygenated machine perfusion(HOPE)as a preservation strategy instead of static cold storage(SCS).The endothelial glycocalyx is highly sensitive to IRI and its degradation during graft preservation and reperfusion was previously associated with inferior postoperative outcome after LT.Here,we aimed to measure glycocalyx degradation during and after HOPE in order to evaluate its potential for viability-assessment during machine perfusion and outcome prediction in patients undergoing LT.Methods:Glycocalyx degradation was quantified via enzyme-linked immunoassay(ELISA)for its main component syndecan-1(Sdc-1)in serum of 40 patients undergoing LT after HOPE.In addition,Sdc-1 was evaluated at multiple time points during HOPE.Patients were followed up for 3.5 years to assess postoperative complications including morbidity,the development of early allograft dysfunction(EAD)and graft survival.Results:Liver grafts which later developed EAD showed significantly higher Sdc-1 concentrations after 60 min of HOPE compared to grafts exhibiting normal postoperative function(P=0.02).Receiver operating characteristic analysis revealed a strong predictive potential with an area under the curve of 0.73.A cut-off at 808 ng/mL Sdc-1 at 60 min of HOPE allowed identification of a high-risk group with an incidence of EAD of 66.7%.Sdc-1 concentrations increased during all types of HOPE but were significantly higher in HOPE versus dual HOPE(D-HOPE)after 120 min of perfusion(P=0.02).Conclusions:Sdc-1 evaluated at 60 min during HOPE allows prediction of EAD after LT.Accordingly,Sdc-1 should be considered a potential additional biomarker for viability assessment during HOPE.展开更多
Liver transplantation(LT),an ultimate and vital method for treating end-stage liver disease,is often accompanied by ischemiareperfusion injury(IRI)resulting from warm or cold ischemia of the donor liver.Organ protecti...Liver transplantation(LT),an ultimate and vital method for treating end-stage liver disease,is often accompanied by ischemiareperfusion injury(IRI)resulting from warm or cold ischemia of the donor liver.Organ protection techniques are used to improve the quality of liver grafts(from retrieval to implantation).Reactive oxygen species(ROS)cause oxidative stress,which is considered a crucial factor in IRI after LT.Nano antioxidants capable of scavenging ROS alleviate IRI in multiple types of organs and tissues.In this study,we synthesized ceria nanoparticles(NPs)with antioxidant properties using a pyrolysis method and covered them with phospholipid-polyethylene glycol to improve their biocompatibility in vivo.We investigated the potential organprotective effect of ceria NPs and the underlying mechanisms.Ceria NPs promoted liver function recovery after LT by attenuating IRI in liver grafts in vivo.The protective effect of ceria NPs on liver grafts was investigated by applying hypothermic oxygenated machine perfusion ex vivo.Ceria NPs attenuated hypoxia reoxygenation-or H_(2)O_(2)-induced hepatocyte injury by enhancing mitochondrial activity and ROS scavenging in vitro.These effects may be associated with the activation of the nuclear factor erythroid-derived 2-related factor 2(Nrf2)/Kelch-like ECH-associated protein 1(Keap1)/heme oxygenase 1(HO-1)signaling pathway.In conclusion,ceria NPs may serve as a promising antioxidant agent for the treatment of hepatic IRI after LT.展开更多
基金supported by grants from 2020 Guangdong Provincial and Municipal Joint Fund For Basic and Applied Basic Research Project(2020B1515120031)2020 Foshan Municipal Deng Fang Distinguished Research Program(2020A007)+2 种基金Key Scientific Research Program for the development of Ex vivo Liver Perfusion System of Foshan City,China[(2019)No.42]Science and Technol-ogy Program of Guangzhou(202002030201)Guangzhou Sci-ence and Technology Plan(2025A04J3674)。
文摘Background:The use of grafts from donation after circulatory death(DCD)overcomes the inadequate donor organ supply.Our team developed a transportable dual hypothermic oxygenated machine perfusion(DHOPE)device,which initiates DHOPE at a recipient center to reduce static cold storage(SCS)time and the risk of graft failure in DCD liver transplantation.Methods:Six porcine livers per group with 30 min of warm ischemia exposure were preserved via SCS or DHOPE for 6 h and then reperfused for 12 h with whole blood to mimic transplantation.Hepatocellular and biliary function and injury were assessed in perfusate and bile samples.Molecular biomarkers and histology were compared between groups.Results:Reperfusion portal vein pressure,in a flow-constant manner,and alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP)and gamma-glutamyltransferase(γ-GGT)release were significantly lower in the DHOPE group than in the SCS group at all time points.Higher bile production paralleled the lower levels of ALP andγ-GGT in the DHOPE group.The DHOPE group secreted more total bilirubin(TBIL)in bile,resulting in decreased TBIL in the perfusate,and livers preserved with DHOPE exhibited better cholangiocellular function.Furthermore,improvements in hypoxia,the inflammatory response,cell-free microRNAs and energy metabolism were observed in the DHOPE group.There were fewer apoptotic cells and TGF-β1-positive cells in the liver parenchyma and extrahepatic bile duct in the DHOPE group than in the SCS group.Conclusions:This study demonstrates the efficacy of local 4℃DHOPE to protect porcine liver grafts from30-min warm ischemia damage.
文摘Acute-on-chronic liver failure(ACLF)is a syndrome that occurs in patients with chronic liver disease and is characterized by acute decompensation,organ failure and high short-term mortality.Partially due to the lack of universal diagnostic criteria,the actual ACLF prevalence remains unclear;nevertheless,it is expected to be a highly prevalent condition worldwide.Earlier transplantation is an effective protective measure for selected ACLF patients.Besides liver transplantation,diagnosing and treating precipitant events and providing supportive treatment for organ failures are currently the cornerstone of ACLF therapy.Although new clinical specific therapies have been researched,more studies are necessary to assess safety and efficacy.Therefore,future ACLF management strategies must consider measures to improve access to liver transplantation because the time window for this life-saving therapy is frequently narrow.Thus,an urgent and global discussion about allocation and prioritization for transplantation in critically ill ACLF patients is needed because there is evidence suggesting that the current model may not portray their waitlist mortality.In addition,while donor organ quality is meant to be a prognostic factor in the ACLF setting,recent evidence suggests that machine perfusion of the liver may be a safe tool to improve the donor organ pool and expedite liver transplantation in this scenario.
基金funding received in the form of the Catherine Marie Enright research scholarship from the Royal Australasian College of Surgeons to support his program of research
文摘The widespread uptake of different machine perfusion(MP)strategies for liver transplant has been driven by an effort to minimize graft injury.Damage to the cholangiocytes during the liver donation,preservation,or early posttransplant period may result in stricturing of the biliary tree and inadequate biliary drainage.This problem continues to trouble clinicians,and may have catastrophic consequences for the graft and patient.Ischemic injury,as a result of compromised hepatic artery flow,is a well-known cause of biliary strictures,sepsis,and graft failure.However,very similar lesions can appear with a patent hepatic artery and these are known as ischemic type biliary lesions(ITBL)that are attributed to microcirculatory dysfunction rather than main hepatic arterial compromise.Both the warm and cold ischemic period duration appear to influence the onset of ITBL.All of the commonly used MP techniques deliver oxygen to the graft cells,and therefore may minimize the cholangiocyte injury and subsequently reduce the incidence of ITBL.As clinical experience and published evidence grows for these modalities,the impact they have on ITBL rates is important to consider.In this review,the evidence for the three commonly used MP strategies(abdominal normothermic regional perfusion[A-NRP],hypothermic oxygenated perfusion[HOPE],and normothermic machine perfusion[NMP])for ITBL prevention has been critically reviewed.Inconsistencies with ITBL definitions used in trials,coupled with variations in techniques of MP,make interpretation challenging.Overall,the evidence suggests that both HOPE and A-NRP prevent ITBL in donated after circulatory death grafts compared to cold storage.The evidence for ITBL prevention in donor after brain death grafts with any MP technique is weak.
文摘Background:Liver transplantation(LT)is a crucial treatment for end-stage liver disease,but the limited organ supply has led to the use of extended criteria donors(ECD).The implementation of dynamic preservation techniques like hypothermic oxygenated machine perfusion(HOPE)is crucial in improving outcomes for ECD grafts.However,graft contamination and infection are a concern.This study aimed to evaluate the risk of infections within 10 days from LT between HOPE and static cold storage(SCS)groups and postoperative complications.Methods:A retrospective cohort study was conducted,including LT recipients transplanted at a single-center from March 2016 to June 2023.Patients were divided into HOPE and SCS groups,and propensity score matching was used to select comparable cohorts.Data on patient and donor characteristics were analyzed.Results:After propensity score matching,a cohort of 370(HOPE,n=185;SCS,n=185)patients was selected for analysis.The study found no significant differences in the rate of clinically relevant infections,microbiological positive samples,or donor-derived infections within 10 days between HOPE and SCS groups.Postoperative outcomes,as well as patient and graft survival,were also similar between the two groups.The study showed that HOPE is a feasible and safe approach,with a comparable risk of infection.Conclusions:The study results indicate that HOPE use in LT does not increase the risk of infection and is associated with similar patient and graft survival outcomes compared to SCS.These findings confirm the safety and efficacy of HOPE in LT and its potential to expand the donor pool without compromising recipient outcomes.
文摘Background:Ischemia reperfusion injury(IRI)is a major contributing factor to organ damage in liver transplantation(LT)impacting donor organ quality and patient survival.IRI-inflicted graft injury can be reduced by using hypothermic oxygenated machine perfusion(HOPE)as a preservation strategy instead of static cold storage(SCS).The endothelial glycocalyx is highly sensitive to IRI and its degradation during graft preservation and reperfusion was previously associated with inferior postoperative outcome after LT.Here,we aimed to measure glycocalyx degradation during and after HOPE in order to evaluate its potential for viability-assessment during machine perfusion and outcome prediction in patients undergoing LT.Methods:Glycocalyx degradation was quantified via enzyme-linked immunoassay(ELISA)for its main component syndecan-1(Sdc-1)in serum of 40 patients undergoing LT after HOPE.In addition,Sdc-1 was evaluated at multiple time points during HOPE.Patients were followed up for 3.5 years to assess postoperative complications including morbidity,the development of early allograft dysfunction(EAD)and graft survival.Results:Liver grafts which later developed EAD showed significantly higher Sdc-1 concentrations after 60 min of HOPE compared to grafts exhibiting normal postoperative function(P=0.02).Receiver operating characteristic analysis revealed a strong predictive potential with an area under the curve of 0.73.A cut-off at 808 ng/mL Sdc-1 at 60 min of HOPE allowed identification of a high-risk group with an incidence of EAD of 66.7%.Sdc-1 concentrations increased during all types of HOPE but were significantly higher in HOPE versus dual HOPE(D-HOPE)after 120 min of perfusion(P=0.02).Conclusions:Sdc-1 evaluated at 60 min during HOPE allows prediction of EAD after LT.Accordingly,Sdc-1 should be considered a potential additional biomarker for viability assessment during HOPE.
基金supported by Public Projects of Zhejiang Province(No.LGF21H030006)Major Science and Technology Projects of Hainan Province(No.ZDKJ2019009)+2 种基金the Zhejiang Provincial Natural Science Foundation of China(No.LZ21H180001)a Research Project of Jinan Microecological Biomedicine Shandong Laboratory(Nos.JNL-2022002A,JNL-2022007B,and JNL-2022023C)the National Natural Science Foundation of China(No.82000618).
文摘Liver transplantation(LT),an ultimate and vital method for treating end-stage liver disease,is often accompanied by ischemiareperfusion injury(IRI)resulting from warm or cold ischemia of the donor liver.Organ protection techniques are used to improve the quality of liver grafts(from retrieval to implantation).Reactive oxygen species(ROS)cause oxidative stress,which is considered a crucial factor in IRI after LT.Nano antioxidants capable of scavenging ROS alleviate IRI in multiple types of organs and tissues.In this study,we synthesized ceria nanoparticles(NPs)with antioxidant properties using a pyrolysis method and covered them with phospholipid-polyethylene glycol to improve their biocompatibility in vivo.We investigated the potential organprotective effect of ceria NPs and the underlying mechanisms.Ceria NPs promoted liver function recovery after LT by attenuating IRI in liver grafts in vivo.The protective effect of ceria NPs on liver grafts was investigated by applying hypothermic oxygenated machine perfusion ex vivo.Ceria NPs attenuated hypoxia reoxygenation-or H_(2)O_(2)-induced hepatocyte injury by enhancing mitochondrial activity and ROS scavenging in vitro.These effects may be associated with the activation of the nuclear factor erythroid-derived 2-related factor 2(Nrf2)/Kelch-like ECH-associated protein 1(Keap1)/heme oxygenase 1(HO-1)signaling pathway.In conclusion,ceria NPs may serve as a promising antioxidant agent for the treatment of hepatic IRI after LT.
