Matched pair analysis of the effect of longer hypothermic machine perfusion time on kidney transplant outcomes

BACKGROUND Hypothermic machine perfusion(HMP)has demonstrated benefits in terms of early kidney transplant function compared to static cold storage.While longer preservation times have shown detrimental effects,a previous paired study indicated that longer pump times(the second kidney in a pair)might lead to improved outcomes.AIM To revisit the prior paired study's somewhat unexpected results by reviewing our program's experience.METHODS A total of 61 pairs of transplant recipients who received kidneys from the same donor(2012-2021)were analyzed.Patients were divided into two groups depending on whether they were transplanted first(K1)or second(K2).Therefore,the patients in each pair had identical donor characteristics,except for time on the pump.Statistical analyses included Kaplan-Meyer analysis and paired tests,including McNemar's test,student's paired t-test,or Wilcoxon's test,as appropriate.RESULTS The two groups of recipients had similar demographics(age,body mass index,diabetes,time on dialysis,sensit-ization and retransplants).Cold ischemic times for K1 and K2 were 8.9(95%CI:7.9,9.8)and 14.7 hours(13.7,15.8)(P<0.0001),respectively.Overall,K2 had a higher rate of freedom from biopsy-proven acute rejection at 1 year(P=0.015).Delayed graft function was less common in K2,12/61(20%)than in K1,20/61(33%)(P=0.046).Finally,K2 showed a higher graft survival than K1(P=0.023).CONCLUSION Our results agree with a previous study that suggested possible advantages to longer pump times.Both studies should encourage further research into HMP's potential anti-inflammatory effect.

Influence of perfusate on liver viability during hypothermic machine perfusion

AIM: To optimize the perfusates used for hypothermicmachine perfusion(HMP).METHODS: Sprague-Dawley rats were assigned randomly to three groups(n = 12 per group) that received either saline, University of Wisconsin coldstorage solution(UW) or histidine-tryptophan-ketoglutarate solution(HTK) as the perfusate. Each group was divided into two subgroups: static cold storage(SCS) and HMP(n = 6 per subgroup). The liver graft was retrieved according to the method described by Kamada. For the SCS group, the graft was directly placed into cold perfusate(0-4?℃) for 6 h after liver isolation while the portal vein of the graft was connected to the perfusion machine for the HMP group. Then the perfusates were collected at different time points for analysis of aspartate aminotransferase(AST), alanine transaminase(ALT) and lactate dehydrogenase(LDH) levels. Liver tissues were obtained for evaluation of histology, dry/wet weight(D/W) ratio, and malondialdehyde(MDA) and adenosine-triphosphate(ATP) levels. The portal vein pressure and velocity were monitored in real time in all HMP subgroups.RESULTS: Comparison of HMP and SCS: Regardless of the perfusate, HMP improved the architecture of donor graft in reducing the congestion around sinusoids and central vein and maintaining sinusoid lining in morphology; HMP improved liver function in terms of ALT, AST and LDH, especially during the 3-6 h period(SCS vs HMP using saline: ALT3, 225.00 ± 105.62 vs 49.50 ± 18.50, P = 0.047; LDH3, 1362.17 ± 563.30 vs 325.75 ± 147.43, P = 0.041; UW: LDH6, 2880.14 ± 948.46 vs 2135.00 ± 174.27, P = 0.049; HTK, AST6, 307.50 ± 52.95 vs 185.20 ± 20.46, P = 0.041); HMP decreased MDA level(saline, 2.79 ± 0.30 vs 1.09 ± 0.09, P = 0.008; UW, 3.01 ± 0.77 vs 1.23 ± 0.68, P = 0.005; HTK, 3.30 ± 0.52 vs 1.56 ± 0.22, P = 0.006). Comparison among HMP subgroups: HTK showed less portal vein resistance than UW and saline(vs saline, 3.41 ± 0.49 vs 5.00 ± 0.38, P < 0.001; vs UW, 3.41 ± 0.49 vs 4.52 ± 0.63, P = 0.007); UW reduced edema most efficiently(vs saline, 0.68 ± 0.02 vs 0.79 ± 0.05, P = 0.013), while HTK maintained ATP levels best(vs saline, 622.60 ± 29.11 vs 327.43 ± 44.66, P < 0.001; vs UW, 622.60 ± 29.11 vs 301.80 ± 37.68, P < 0.001).CONCLUSION: HMP is superior to SCS in maintaining both architecture and function of liver grafts. Further, HTK was found to be the optimal perfusate for HMP.

MicroRNA expression in the hippocampal CA1 region under deep hypothermic circulatory arrest

Using deep hypothermic circulatory arrest, thoracic aorta diseases and complex heart diseases can be subjected to corrective procedures. However, mechanisms underlying brain protection during deep hypothermic circulatory arrest are unclear. After piglet models underwent 60 minutes of deep hypothermic circulatory arrest at 14°C, expression of microRNAs(miRNAs) was analyzed in the hippocampus by microarray. Subsequently, TargetScan 6.2, RNA22 v2.0, miRWalk 2.0, and miRanda were used to predict potential targets, and gene ontology enrichment analysis was carried out to identify functional pathways involved. Quantitative reverse transcription-polymerase chain reaction was conducted to verify miRNA changes. Deep hypothermic circulatory arrest altered the expression of 35 miRNAs. Twenty-two miRNAs were significantly downregulated and thirteen miRNAs were significantly upregulated in the hippocampus after deep hypothermic circulatory arrest. Six out of eight targets among the differentially expressed miRNAs were enriched for neuronal projection(cyclin dependent kinase, CDK16 and SLC1 A2), central nervous system development(FOXO3, TYRO3, and SLC1 A2), ion transmembrane transporter activity(ATP2 B2 and SLC1 A2), and interleukin-6 receptor binding(IL6 R)– these are the key functional pathways involved in cerebral protection during deep hypothermic circulatory arrest. Quantitative reverse transcription-polymerase chain reaction confirmed the results of microarray analysis. Our experimental results illustrate a new role for transcriptional regulation in deep hypothermic circulatory arrest, and provide significant insight for the development of miRNAs to treat brain injuries. All procedures were approved by the Animal Care Committee of Xuanwu Hospital, Capital Medical University, China on March 1, 2017(approval No. XW-INI-AD2017-0112).

Hypothermic machine perfusion with metformin-University of Wisconsin solution for ex vivo preservation of standard and marginal liver grafts in a rat model

AIM To compare the effect of University of Wisconsin(UW) solution with or without metformin, an AMP-activated protein kinase(AMPK) activator, for preserving standard and marginal liver grafts of young and aged rats ex vivo by hypothermic machine perfusion(HMP).METHODS Eighteen young(4 mo old) and 18 aged(17 mo old)healthy male SD rats were selected and randomly divided into three groups: control group, UW solution perfusion group(UWP), and UW solution with metformin perfusion group(MUWP). Aspartate aminotransferase(AST), alanine aminotransferase(ALT), lactate dehydrogenase(LDH), interleukin-18(IL-18), and tumor necrosis factor-alpha(TNF-α) in the perfused liquid were tested. The expression levels of AMPK and endothelial nitric oxide synthase(e NOS) in liver sinusoidal endothelial cells were also examined.Additionally, microscopic evaluation of the harvested perfused liver tissue samples was done. RESULTS AST, ALT, LDH, IL-18 and TNF-α levels in the young and aged liver-perfused liquid were, respectively,significantly lower in the MUWP group than in the UWP group(P < 0.05), but no significant differences were found between the young and aged MUWP groups.Metformin increased the expression of AMPK and e NOS protein levels, and promoted the extracellular release of nitric oxide through activation of the AMPK-e NOS mediated pathway. Histological examination revealed that in the MUWP group, the extent of liver cells and tissue damage was significantly reduced compared with the UWP group.CONCLUSION The addition of metformin to the UW preservative solution for ex vivo HMP can reduce rat liver injury during cold ischemia, with significant protective effects on livers, especially of aged rats.

THE TECHNIQUE OF THE NORMOTHERMIC AND HYPOTHERMIC TOTAL HEPATIC VASCULAR EXCLUSION FOR RESECTION OF THE LIVER TUMORS

The technique for bloodless hepatic resection using the total hepatic vascular isolation under the normothermic or hypothermic perfusion was reported to deal with the large liver tumor involving in the liver hilum,the main hepatic veins or the retrohepatic vena cava.The original Heaney's and Fortner's methods were modified so that the technique could be simpler and more practicable to perform otherwise hazardous liver resection.During the past 4 year,major hepatic resection with the normothermic or hypothermic total vascular exclusion technique was successfully performed on 19 patients with liver tumors in our department.Among the 19 cases,16 underwent hepatic resection with the normothermic selective total vascular exclusion(extended right lobectomy in 5 cases,extended left lobectomy in 3 cases;right lobectomy in 5 cases;central segmentectomy in 3 cases)and 3 with the total vascular isolation and in situ cold perfusion(extended left lobectomy in 2 case,extended right lobectong in 1case).We believe that the technique of normothermic vascular exclusion may be indicated to deal with the lesion close to the hepatic veins and the retrohepatic vena cava.However,for more complicated hepatic resection,the hypothermic perfusion technique should be considered to prolong the safety of ischemic tune of the liver.The preliminary experience in the clinical application using the above technique is reported.

Persistent left superior vena cava in right hemiarch replacement under deep hypothermic circulatory arrest:A case report

BACKGROUND Persistent left superior vena cava(PLSVC),a relatively rare thoracic vascular malformation,can inconvenience perfusionists and operators when encountered during deep hypothermic circulatory arrest(DHCA).CASE SUMMARY Herein,we describe the case of a patient with concurrent giant aortic arch aneurysm,aortic stenosis,and PLSVC.To treat these conditions,we performed right hemiarch and aortic valve replacements under DHCA.Notably,we applied“bilateral superior vena cava retrograde cerebral perfusion(RCP)”for cerebral protection,which significantly optimized the surgical procedure and reduced the risk of postoperative complications.The patient was discharged 14 d after surgery with no complications.CONCLUSION Surgical intervention for PLSVC under DHCA can be performed using the bilateral superior vena cava RCP approach.

Prevascularized spongy-like hydrogels maintain their angiogenic potential after prolonged hypothermic storage

The chronic shortage of organs and tissues for transplantation represents a dramatic burden on healthcare systems worldwide.Tissue engineering offers a potential solution to address these shortages,but several challenges remain,with prevascularization being a critical factor for in vivo survival and integration of tissue engineering products.Concurrently,a different challenge hindering the clinical implementation of such products,regards their efficient preservation from the fabrication site to the bedside.Hypothermia has emerged as a potential solution for this issue due to its milder effects on biologic systems in comparison with other cold preservation methodologies.Its impact on prevascularization,however,has not been well studied.In this work,3D prevascularized constructs were fabricated using adipose-derived stromal vascular fraction cells and preserved at 4◦C using Hypothermosol or basal culture media(α-MEM).Hypothermosol efficiently preserved the structural and cellular integrity of prevascular networks as compared to constructs before preservation.In contrast,the use ofα-MEM led to a clear reduction in prevascular structures,with concurrent induction of high levels of apoptosis and autophagy at the cellular level.In vivo evaluation using a chorioallantoic membrane model demonstrated that,in opposition toα-MEM,Hypothermosol preservation retained the angiogenic potential of constructs before preservation by recruiting a similar number of blood vessels from the host and presenting similar integration with host tissue.These results emphasize the need of studying the impact of preservation techniques on key properties of tissue engineering constructs such as prevascularization,in order to validate and streamline their clinical application.

Biliary tract viability assessment and sequential hypothermic-normothermic perfusion in liver transplantation

We read with great interest the study of Mergental et al.(1)reporting the 5-year outcomes of the VITTAL trial(2,3).VITTAL was a prospective,non-randomized,single-arm trial that tested end-ischemic oxygenated normothermic machine perfusion(NMP)with a“back-to-base”strategy to evaluate,and potentially transplant,liver grafts declined by all liver transplantation(LT)centers in the United Kingdom.For a liver to be considered viable,it had to metabolize perfusate lactate to a concentration of≤2.5 mmol/L within four hours from the start of perfusion,and meet at least two of the following criteria:bile production without a defined quantity;maintenance of perfusate pH above 7.3;glucose consumption in the perfusate;maintenance of stable arterial and portal flow above 150 and 500 mL/min,respectively;maintenance of graft suppleness and homogeneous perfusion(4).Thirty-one discarded human donor livers underwent viability testing by using end-ischemic NMP,of which 22(71%)livers were subsequently transplanted.The primary outcome of the trial was graft survival rate at 90 days and it was 100%.

Beneficial Effect of Moderately Increasing Hypothermic Machine Perfusion Pressure on Donor after Cardiac Death Renal Transplantation

Background:Vascular resistance and flow rate during hypotherrnic machine perfusion (HMP)of kidneys is correlated with graft function. We aimed to determine the effects of increasing HMP pressure versus maintaining the initial pressure on kidney transplantation outcomes. Methods:We retrospectively reviewed the data of 76 primary transplantation patients who received HMP-preserved kidneys from 48 donors after cardiac death between September 1,2013,and August 31,2015.HMP pressure was increased from 30 to 40mmHg (1mmHg =0.133kPa)in kidneys with poor flow and/or vascular resistance (increased pressure [IP]group;36 patients);otherwise,the initial pressure was maintained (constant pressure group;40 patients).Finally,the clinical characteristics and transplantation outcomes in both groups were assessed. Results:Delayed graft function (DGF)incidence,1-year allograft,patient survival,kidney function recovery time,and serum creatinine level on day 30 were similar in both groups,with improved flow and resistance in the IP group.Among patients with DGF,kidney function recovery time and DGF duration were ameliorated in the IP group.Multivariate logistic regression analysis revealed that donor hypertension (odds ratio [OR]:1.43,95%confidence interval [CI]:1.02-2.06,P =0.035),donor terminal serum creatinine (OR:1.27,95%C7:1.06-1.62,P =0.023),warm ischemic time (OR:3.45,95%CI:1.97-6.37,P =0.002),and terminal resistance (OR:3.12,95%CI:1.76-6.09,P =0.012)were independent predictors of DGF.Cox proportional hazards analysis showed that terminal resistance (hazard ratio:2.06,95%C1:1.32-5.16,P =0.032)significantly affected graft survival. Conclusion:Increased HMP pressure improves graft perfusion but does not affect DGF incidence or 1-year graft survival.

Predictive Score Model for Delayed Graft Function Based on Hypothermic Machine Perfusion Variables in Kidney Transplantation

Background: Hypothermic machine perfusion(HMP) is being used more often in cardiac death kidney transplantation; however, the significance of assessing organ quality and predicting delayed graft function(DGF) by HMP parameters is still controversial. Therefore,we used a readily available HMP variable to design a scoring model that can identify the highest risk of DGF and provide the guidance and advice for organ allocation and DCD kidney assessment.Methods: From September 1, 2012 to August 31, 2016, 366 qualified kidneys were randomly assigned to the development and validation cohorts in a 2:1 distribution. The HMP variables of the development cohort served as candidate univariate predictors for DGF. The independent predictors of DGF were identified by multivariate logistic regression analysis with a P < 0.05. According to the odds ratios(ORs) value, each HMP variable was assigned a weighted integer, and the sum of the integers indicated the total risk score for each kidney. The validation cohort was used to verify the accuracy and reliability of the scoring model.Results: HMP duration(OR = 1.165, 95% confidence interval [CI ]: 1.008–1.360, P = 0.043), resistance(OR = 2.190, 95%CI: 1.032–10.20, P < 0.001), and flow rate(OR = 0.931, 95% CI: 0.894–0.967, P = 0.011) were the independent predictors of identified DGF. The HMP predictive score ranged from 0 to 14, and there was a clear increase in the incidence of DGF, from the low predictive score group to the very high predictive score group. We formed four increasingly serious risk categories(scores 0–3, 4–7, 8–11, and 12–14)according to the frequency associated with the different risk scores of DGF. The HMP predictive score indicates good discriminative power with a c?statistic of 0.706 in the validation cohort, and it had significantly better prediction value for DGF compared to both terminal flow(P = 0.012) and resistance(P = 0.006).Conclusion: The HMP predictive score is a good noninvasive tool for assessing the quality of DCD kidneys, and it is potentially useful for physicians in making optimal decisions about the organs donated.

RGFP966 inactivation of the YAP pathway attenuates cardiac dysfunction induced by prolonged hypothermic preservation

Oxidative stress and apoptosis are the key factors that limit the hypothermic preservation time of donor hearts to within 4–6 h.The aim of this study was to investigate whether the histone deacetylase 3(HDAC3)inhibitor RmGodFyPn9 a6 m6 i cc opualrda mpreotteercst daugrianing srt ecpaerrdfiuasci oinn juwreyr ei nedvuacleuda tebyd.pTrholeo nexgperde shsyipoont haenrdm pich opsrpehsoerryvlaattiioonn.leRvaet lsh eoaf rtms awmemrea lihayn-??STE20-like kinase-1(Mst1)and Yes-associated protein(YAP)were determined by western blotting.Cell apoptosis was measured by the terminal deoxynucleotidyl-transferase(TdT)-mediated dUTP nick-end labeling(TUNEL)method.Addition of RGFP966 in Celsior solution significantly inhibited cardiac dysfunction induced by hypothermic preservation.RGFP966 inhibited the hypothermic preservation-induced increase of the phosphorylated(p)-Mst1/Mst1 and p-YAP/YAP ratios,prevented a reduction in total YAP protein expression,and increased the nuclear YAP protein level.Verteporfin(VP),a small molecular inhibitor of YAP–transcriptional enhanced associate domain(TEAD)interaction,partially abolished the protective effect of RGFP966 on cardiac function,and reduced lactate dehydrogenase activity and malondialdehyde content.RGFP966 increased superoxide dismutase,catalase,and glutathione peroxidase gene and protein expression,which was abolished by VP.RGFP966 inhibited hypothermic preservation-induced overexpression of B-cell lymphoma protein 2(Bcl-2)-associated X(Bax)and cleaved caspase-3,increased Bcl-2 mRNA and protein expression,and reduced cardiomyocyte apoptosis.The antioxidant and anti-apoptotic effects of RGFP966 were cancelled by VP.The results suggest that supplementation of Celsior solution with RGFP966 attenuated prolonged hypothermic preservation-induced cardiac dysfunction.The mechanism may involve inhibition of oxidative stress and apoptosis via inactivation of the YAP pathway.

Predictive value of hypothermic machine perfusion parameters combined perfusate biomarkers in deceased donor kidney transplantation

Background:Delayed graft function(DGF)is the main cause of renal function failure after kidney transplantation.This study aims at investigating the value of hypothermic machine perfusion(HMP)parameters combined with perfusate biomarkers on predicting DGF and the time of renal function recovery after deceased donor(DD)kidney transplantation.Methods:HMP parameters,perfusate biomarkers and baseline characteristics of 113 DD kidney transplantations from January 1,2019 to August 31,2019 in the First Affiliated Hospital of Xi’an Jiaotong University were retrospectively analyzed using univariate and multivariate logistic regression analysis.Results:In this study,the DGF incidence was 17.7%(20/113);The multivariate logistic regression results showed that terminal resistance(OR:1.879,95%CI 1.145-3.56)and glutathione S-transferase(GST)(OR=1.62,95%CI 1.23-2.46)were risk factors for DGF;The Cox model analysis indicated that terminal resistance was an independent hazard factor for renal function recovery time(HR=0.823,95%CI 0.735-0.981).The model combining terminal resistance and GST(AUC=0.888,95%CI:0.842-0.933)significantly improved the DGF predictability compared with the use of terminal resistance(AUC=0.756,95%CI 0.693-0.818)or GST alone(AUC=0.729,95%CI 0.591-0.806).Conclusion:According to the factors analyzed in this study,the combination of HMP parameters and perfusate biomarkers displays a potent DGF predictive value.

A novel rat model of cardiopulmonary bypass for deep hypothermic circulatory arrest without blood priming

Background Large animal cardiopulmonary bypass （CPB） models are expensive,and prevent assessment of neurocognitive function,and difficulties with long-term recovery.The purpose of this study was to establish a novel rat model of cardiopulmonary bypass for deep hypothermic circulatory arrest without blood priming.Methods Twenty adult male Sprague-Dawley rats weighing 450-560 g were randomized to CPB with deep hypothermic circulatory arrest （DHCA） and control groups,with 10 rats each.The experimental protocols,including blood and crystalloid fluid administration,anesthesia,orotracheal intubation,ventilation,cannulation,and heparinization were identical in both groups.After inducing cardiac arrest,the circuit was turned off and rats were left in a DHCA state for 15 minutes.Rats were rewarmed to 34℃ to 35℃ over a period of 36 to 42 minutes using CPB-assisted rewarming,a heating blanket,and a heating lamp along with administration of 0.1 mEq of sodium bicarbonate and 0.14 mEq of calcium chloride.The remaining priming volume was reinfused and animals were weaned from CPB.Results All CPB with DHCA processes were successfully achieved.Blood gas analysis and hemodynamic parameters were in the normal range.The vital signs of all rats were stable.Conclusions Our CPB circuit has several novel features,including a small priming volume,active cooling/rewarming processes,vacuum-assisted venous drainage,peripheral cannulation without thoracotomy or stemotomy,and an accurate means of monitoring peripheral tissue oxygenation.

Effect of continuous hypothermic machine perfusion transport system（AirdriveTM） on canine kidney preservation

Background Organ preservation keeps the quality of the organs under prolonged ischemia. Continuous machineperfusions are gaining an important position in clinical research and practice. The aim of this study was to evaluate theprotective effect of continuous hypothermic machine perfusion transport system （AirdriveTM） on cold ischemic injury ofcanine kidney.

Routine utilization of machine perfusion in liver transplantation:Ready for prime time?

The last decade has been notable for increasing high-quality research and dramatic improvement in outcomes with dynamic liver preservation.Robust evidence from numerous randomized controlled trials has been pooled by meta-analyses,providing the highest available evidence on the protective effect of machine perfusion(MP)over static cold storage in liver transplantation(LT).Based on a protective effect with less complications and improved graft survival,the field has seen a paradigm shift in organ preservation.This editorial focuses on the role of MP in LT and how it could become the new“gold standard”.Strong collaborative efforts are needed to explore its effects on long-term outcomes.

Effect of resuscitation after selective cerebral ultraprofound hypothermia on expressions of nerve growth factor and glial cell line-derived neurotrophic factor in the brain of monkey

Objective To investigate the expression of nerve growth factor （NGF） and glial cell line-derived neurotrophic factor （GDNF） in monkeys of resuscitation after selective cerebral ultraprofound hypothermia and blood flow occlusion. Methods The monkeys were immediately removed brain after death in operation of group A （identical temperature perfusion group） and group B （ultraprofound hypothermia perfusion group）. Immunohistochemical technique was used to determine frontal cellular expression of NGF and GDNF. Statistics were analyzed by ANOVA analyses with significance level at P 〈 0.05. Results The expressions of NGF and GDNF in the group B were significantly higher than those in the group A （P 〈 0.05）. Conclusion NGF and GDNF increased significantly in the monkeys of resuscitation after selective cerebral ultraprofound hypothermia and blood flow occlusion. It may be a protective mechanism for neuron survival and neural function recovery.

Liver graft preservation methods during cold ischemia phase and normothermic machine perfusion

The growing demand for donor organs requires measures to expand donor pool.Those include extended criteria donors, such as elderly people, steatotic livers,donation after cardiac death, etc. Static cold storage to reduce metabolic requirements developed by Collins in late 1960 s is the mainstay and the golden standard for donated organ protection. Hypothermic machine perfusion provides dynamic organ preservation at 4°C with protracted infusion of metabolic substrates to the graft during the ex vivo period. It has been used instead of static cold storage or after it as short perfusion in transplant center. Normothermic machine perfusion(NMP) delivers oxygen, and nutrition at physiological temperature mimicking regular environment in order to support cellular function. This would minimize effects of ischemia/reperfusion injury.Potentially, NMP may help to estimate graft functionality before implantation into a recipient. Clinical studies demonstrated at least its non-inferiority or better outcomes vs static cold storage. Regular grafts donated after brain death could be safely preserved with convenient static cold storage. Except for prolonged ischemia time where hypothermic machine perfusion started in transplant center could be estimated to provide possible positive reconditioning effect. Use of hypothermic machine perfusion in regular donation instead of static cold storage or in extended criteria donors requires further investigation. Multicenter randomized clinical trial supposed to be completed in December 2021. Extended criteria donors need additional measures for graft storage and assessment until its implantation. NMP is actively evaluating promising method for this purpose.Future studies are necessary for precise estimation and confirmation to issue clinical practice recommendations.

Current and future perspectives on acute-on-chronic liver failure: Challenges of transplantation, machine perfusion, and beyond

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.

Machine perfusion and the prevention of ischemic type biliary lesions following liver transplant:What is the evidence?

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.