Assessing Donor Liver Quality and Restoring Graft Function in the Era of Extended Criteria Donors

Liver transplantation(LT)is the final treatment option for patients with end-stage liver disease.The increasing donor shortage results in the wide usage of grafts from extended criteria donors across the world.Using such grafts is associated with the elevated incidences of post-transplant complications including initial nonfunction and ischemic biliary tract diseases,which significantly reduce recipient survival.Although several clinical factors have been demonstrated to impact donor liver quality,accurate,comprehensive,and effective assessment systems to guide decision-making for organ usage,restoration or discard are lacking.In addition,the development of biochemical technologies and bioinformatic analysis in recent years helps us better understand graft injury during the perioperative period and find potential ways to restore graft function.Moreover,such advances reveal the molecular profiles of grafts or perfusate that are susceptible to poor graft function and provide insight into finding novel biomarkers for graft quality assessment.Focusing on donors and grafts,we updated potential biomarkers in donor blood,liver tissue,or perfusates that predict graft quality following LT,and summarized strategies for restoring graft function in the era of extended criteria donors.In this review,we also discuss the advantages and drawbacks of these potential biomarkers and offer suggestions for future research.

Extended criteria brain-dead organ donors:Prevalence and impact on the utilisation of livers for transplantation in Brazil

BACKGROUND Despite its association with higher postoperative morbidity and mortality,the use of extended criteria donor(ECD)livers for transplantation has increased globally due to the high demand for the procedure.AIM To investigate the prevalence of ECD in donation after brain death(DBD)and its impact on organ acceptance for transplantation.METHODS Retrospective analysis of DBD organ offers for liver transplantation between 2017 and 2020 in a high-volume transplant centre.The incidence of the Eurotransplant risk factors to define an ECD(ET-ECD)among DBD donors and the likelihood of organ acceptance over the years were analysed.The relationship between organ refusal for transplantation,the occurrence,and the number of ET-ECD was assessed by simple and multiple logistic regression adjustment.RESULTS A total of 1619 organ donors were evaluated.Of these,78.31%(n=1268)had at least one ET-ECD criterion.There was an increase in the acceptance of ECD DBD organs for transplantation(1 criterion:from 23.40%to 31.60%;2 criteria:from 13.10%to 27.70%;3 criteria:From 6.30%to 13.60%).For each addition of one ETECD variable,the estimated chance of organ refusal was 64.4%higher(OR 1.644,95%CI 1.469-1.839,P<0.001).Except for the donor serum sodium>165 mmol/L(P=0.310),all ET-ECD criteria increased the estimated chance of organ refusal for transplantation.CONCLUSION A high prevalence of ECD DBD was observed.Despite the increase in their utilisation,the presence and the number of extended donor criteria were associated with an increased likelihood of their refusal for transplantation.

The potential use of extended criteria donors and eligible recipients in liver transplantation for unresectable colorectal liver metastases in Central Sweden

Background:Unresectable colorectal liver metastases(CRLM)is a condition with poor prognosis.A recent treatment alternative improving survival in patients with unresectable CRLM,has emerged with the introduction of liver transplantation(LT),yet not uncontroversial with the current organ shortage.This study aimed to retrospectively investigate the potential of declined donors with acceptable risk as liver graft donors and patients with unresectable CRLM as potential recipients.Methods:All declined donors in central Sweden and all patients with CRLM discussed at multidisciplinary team conference at Karolinska University Hospital,January 2013-October 2018,were identified.Donors were classified according to the European Committee Guide to the quality and safety of organs for transplantation and potential recipients were evaluated by selection criteria,based on studies on the Norwegian Secondary Cancer study database.Results:Out of 1,462 evaluated potential donors,62(2.7 pmp)donors were identified,corresponding to 6-18%of the utilized donor pool.Out of 1,008 included patients with CRLM,25(2.1 pmp)potential recipients were recognized.Eligibility for LT and left-sided colon cancer were favorable prognostic factors.Conclusions:Today’s donor pool could increase with the use of extended criteria donors,which is sufficient and display an acceptable risk-benefit ratio for patients with unresectable CRLM.With current selection criteria a small subset of patients with unresectable CRLM are eligible recipients.This subset of patients has a better survival compared to patients ineligible for LT.

Application of extended criteria donor grafts in liver transplantation for acute-on-chronic liver failure:A retrospective cohort study

BACKGROUND There is no consensus on the usage of extended criteria donor(ECD)grafts in liver transplantation(LT)for acute-on-chronic liver failure(ACLF)patients.AIM To summarize the experience of using ECD livers in ACLF-LT.METHODS A retrospective cohort study was conducted,enrolling patients who underwent LT at the First Affiliated Hospital of Sun Yat-Sen University from January 2015 to November 2021.The patients were divided into ECD and non-ECD groups for analysis.RESULTS A total of 145 recipients were enrolled in this study,of which ECD and non-ECD recipients accounted for 53.8%and 46.2%,respectively.Donation after cardiac death(DCD)recipients accounted for the minority compared with donation after brain death(DBD)recipients(16.6%vs 83.4%).Neither overall survival nor graft survival significantly differed between ECD and non-ECD and DCD and DBD recipients.ECD grafts were associated with a significantly higher incidence of early allograft dysfunction(EAD)than non-ECD grafts(67.9%vs 41.8%,P=0.002).Postoperative outcomes between DCD and DBD recipients were comparable(P>0.05).ECD graft(P=0.009),anhepatic phase(P=0.034)and recipient gamma glutamyltransferase(P=0.016)were independent risk factors for EAD.Recipient preoperative number of extrahepatic organ failures>2(P=0.015)and intraoperative blood loss(P=0.000)were independent predictors of poor post-LT survival.CONCLUSION Although related to a higher risk of EAD,ECD grafts can be safely used in ACLF-LT.The main factors affecting post-LT survival in ACLF patients are their own severe preoperative disease and intraoperative blood loss.

“机械灌注+”应用于扩大标准供肝移植--肝尽其用

Transplantation represents the most effective treatment for end-stage liver diseases but is limited by the shortage of healthy donor organs.Extended criteria donor(ECD)liver grafts are increasingly utilized in clinical practice to mitigate this challenge.However,impaired ischemic tolerance of these grafts jeopardizes organ viability during cold storage.Machine perfusion(MP)was designed to improve organ preservation and reduce posttransplant complications.Nevertheless,it is increasingly evident that MP alone may not preserve ECD grafts optimally.Increasing emphasis has thus been placed on modified MP strategies,including the use of different perfusates,modified perfusion modalities,and different therapeutic interventions.Here,we introduce a novel term,"MP Plus,"denoting these additional strategies that are designed to restore organ function and potentially enable regeneration of ECD grafts.In this review,we summarize the existing and potential modified MP strategies and discuss their advantages in reconditioning different ECD grafts in clinical settings.

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.

Therapeutics administered during ex vivo liver machine perfusion:An overview

Although the use of extended criteria donors has increased the pool of available livers for transplant,it has also introduced the need to develop improved methods of protection against ischemia-reperfusion injury(IRI),as these"marginal"organs are particularly vulnerable to IRI during the process of procurement,preservation,surgery,and post-transplantation.In this review,we explore the current basic science research investigating therapeutics administered during ex vivo liver machine perfusion aimed at mitigating the effects of IRI in the liver transplantation process.These various categories of therapeutics are utilized during the perfusion process and include invoking the RNA interference pathway,utilizing defatting cocktails,and administering classes of agents such as vasodilators,anti-inflammatory drugs,human liver stem cell-derived extracellular vesicles,and δ-opioid agonists in order to reduce the damage of IRI.Ex vivo machine perfusion is an attractive alternative to static cold storage due to its ability to continuously perfuse the organ,effectively deliver substrates and oxygen required for cellular metabolism,therapeutically administer pharmacological or cytoprotective agents,and continuously monitor organ viability during perfusion.The use of administered therapeutics during machine liver perfusion has demonstrated promising results in basic science studies.While novel therapeutic approaches to combat IRI are being developed through basic science research,their use in clinical medicine and treatment in patients for liver transplantation has yet to be explored.

Machine perfusion of the liver:Putting the puzzle pieces together

The realm of extended criteria liver transplantation created the'adjacent possible'for dynamic organ preservation.Machine perfusion of the liver greatly expanded donor organ preservation possibilities,reaching before unattainable goals,including the mitigation of ischemia-reperfusion injury,viability assessment,and organ reconditioning prior to transplantation.However,current scientific evidence lacks uniformity between studies,perfusion protocols,and acceptance criteria.Construction of collaborative research networks for sharing knowledge should,therefore,enable the development of high-level evidence and guidelines for machine perfusion utilization,including donor acceptance criteria.Finally,this approach shall guarantee conditions for further progress to occur.

Kidney donation after cardiac death

There is continuing disparity between demand for and supply of kidneys for transplantation. This review describes the current state of kidney donation after cardiac death （DCD） and provides recommendations for a way forward. The conversion rate for potential DCD donors varies from 40%-80%. Compared to con-trolled DCD, uncontrolled DCD is more labour intensive, has a lower conversion rate and a higher discard rate. The super-rapid laparotomy technique involving direct aortic cannulation is preferred over in situ perfusion in controlled DCD donation and is associated with lower kidney discard rates, shorter warm ischaemia times and higher graft survival rates. DCD kidneys showed a 5.73-fold increase in the incidence of delayed graft function （DGF） and a higher primary non function rate compared to donation after brain death kidneys, but the long term graft function is equivalent between the two. The cold ischaemia time is a controllable factor that signifcantly infuences the outcome of allografts, for example, limiting it to 〈 12 h markedly reduces DGF. DCD kidneys from donors 〈 50 function like stan-dard criteria kidneys and should be viewed as such. As the majority of DCD kidneys are from controlled dona-tion, incorporation of uncontrolled donation will expand the donor pool. Efforts to maximise the supply of kid-neys from DCD include： implementing organ recovery from emergency department setting; improving family consent rate; utilising technological developments to optimise organs either prior to recovery from donors or during storage; improving organ allocation to ensure best utility; and improving viability testing to reduce primary non function.

Liver transplantation for unresectable colorectal liver metastases (CRLM) using extended criteria donor (ECD) grafts: proceed with caution

Liver transplantation(LT)for colorectal liver metastases(CRLM)seems to be nowadays an established treatment,not only of unresectable CRLM(uCRLM)(1)but also for borderline resectable ones(2,3).For these patients,the benefit of LT vs standard modern advanced palliative therapies ranges between 40-80%(1).Notwithstanding the high rates of recurrence,LT can definitely be considered as a curative option,in particular considering the excellent long-term results recently published by the Oslo group(4).