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Recommendations for Donor and Recipient Selection and Risk Prediction: Working Group Report From the ILTS Consensus Conference in DCD Liver Transplantation

Schlegel, Andrea MD1,2; Foley, David P. MD3; Savier, Eric MD4; Flores Carvalho, Mauricio BSc2; De Carlis, Luciano MD5,6; Heaton, Nigel MD7; Taner, C. Burcin MD8

Author Information
doi: 10.1097/TP.0000000000003825

Abstract

INTRODUCTION

Liver transplantation (LT) is the standard treatment for end-stage liver disease, acute liver failure (ALF), and selected patients with liver cancer today. As a result of the enormous technical and medical development in the last 2 decades, short- and long-term outcomes after LT have improved significantly. Parallel to improved results, the number of listed candidates has increased over time. The major limitation of LT is the dependence on donated organs. It is of utmost importance to increase the utilization of donated organs to save the lives of patients waiting for LT. Over the last 2 decades, several countries initiated donation after circulatory death (DCD) transplant programs, including Spain, the United Kingdom, France, The Netherlands, Belgium, Switzerland, Australia, and the United States with gradual increasing utilization.1 However, it became apparent that the success of DCD-LT depends on the strict selection of donor and recipient risk factors and the overall risk a surgeon, transplant center or country is willing to accept.2 This led to many controversies around the use of DCD liver grafts worldwide, including the acceptance criteria of specific DCD donor risk factors in combination with disease severity and medical fitness of the transplant candidate in context of standard cold storage (CS) liver preservation. The debate is ongoing as to predict outcomes of various donor-recipient risk combinations and which donor-recipient matching tools should be recommended to achieve comparable outcomes to that of standard donation after brain death (DBD).3,4 Regardless of the circumstances in different countries, the main goal of LT practice is to provide LT candidates with the best possible benefit from a limited and risky resource of donor organs, ideally in an ethically fair and cost-effective way. Multiple stakeholders are therefore found with significant impact on the allocation process and individual decision making.5

With the endorsement of the International Liver Transplantation Society (ILTS), an international consensus conference was organized, with the aim to reaching consensus regarding various aspects of DCD-LT in the context of currently available evidence. Herein, we present the recommendation for donor and recipient selection and assess the impact of currently available prediction models in DCD-LT.

MATERIALS AND METHODS

An international consensus conference on DCD-LT was held on January 31, 2020 in Venice, Italy, under the sponsorship of the ILTS. The aim was to establish a consensus regarding DCD-LT practice and to develop internationally accepted guidelines. For this purpose, the existing Danish model was adopted and modified.6 First, the organizing committee identified key topics and appointed 6 working groups, composed of up to 6 experts involved in LT and DCD donation (Figure 1). The selection was based on their scientific and clinical records to enable an efficient review preparation of the evidence from the literature and draft recommendations. The working groups were asked to follow the grading of recommendations assessment, development, and evaluation system (GRADE system) as guidance for the level of evidence.7 The material, prepared by panel 2, is available in Tables S1 and S2, SDC, http://links.lww.com/TP/C253. As a next step, the working group performed an English language search in the literature of the Cochrane register, Pubmed, Embase, and Scopus. Overall, 151 participants from 25 countries attended the meeting in Venice. Each of the 6 working groups prepared statements for each section considering the level of evidence based on their literature review. The 2 chairs of each working group reviewed the specific topic and suggested recommendations in a 20-min presentation, followed by questions from the audience. The prepared statements by the working group members were modified in real time in context with the debates during the meeting. Each working group met independently after the conference to finalize the recommendations, based on the expert reports and discussions with jury and attendees and confirmed the evidence level for each recommendation, according to the GRADE system.7

FIGURE 1.
FIGURE 1.:
Format of the ILTS consensus conference in DCD liver transplantation: the role of the organizing committee and expert groups describing each step of the consensus conference. DCD, donation after circulatory death; GRADE, grading of recommendations assessment, development, and evaluation; ILTS, International Liver Transplantation Society.

This recommendation article was prepared by the working group 2, which included the 2 group leaders (A.S. and C.B.T.) and 4 other members (D.F., L.D.C., E.S., and N.H.). The manuscript was circulated among the different working groups to support the accuracy of the data and to exclude and possibly modify any of the recommendations. The final manuscript version was approved by the members of the different working groups (Figure 1). The recommendations of working group 2 are summarized in Tables 1–3. Importantly, the ILTS statements are suggested in context of standard CS liver preservation and the individual risk a center is willing to accept on the background of the current waiting list dynamics and other local ethical and environmental factors and regulations.

Donor Risk Factors

This working group discussed conventional donor risk factors in the context of DCD-LT.44 In addition to technical developments, anesthetic and medical management of liver recipients have evolved with significantly improved outcomes after DCD-LT.8,45 In the context of an international expert review of outcomes, a greater awareness of risk factors and thresholds has further increased the number of organs accepted with differing risk profiles.3,4,22 National and center-specific rules regarding the risk strategy, which are based on clinical practice in a region, are the main contributing factors to accept or decline a specific donor liver.1,2,46 Such strategies also depend on the level of complications a center is willing to accept.2 Strict selection, optimal management of the donor and the transplant candidate, and minimization of cold ischemia times (CITs) have improved outcomes to a level comparable to DBD LT.1,2,47 Individual donor liver preselection during multidisciplinary listing meeting is routine practice to define the different grafts acceptable for a specific liver candidate.2 The following section will explain the recommendations regarding donor risk factors on the background of the current literature and clinical practice.

Donor Age

Donor age is a well-recognized donor risk factor in solid organ transplantation.9,48,49 The greater utilization of older donors has been observed in the last 2 decades and has made a major contribution to organ availability.9 The cellular cytochrome P450 content decreases during liver aging and may explain the greater vulnerability to ischemia/reperfusion injury seen in elderly livers with a limited regenerative capacity.44,48 Based on the difficulties of capturing the overall donor risk, lower outcomes for grafts and patients were reported with different donor age cutoffs.48 An early experience demonstrated a higher risk of biliary complications in donors above an age of 40 y.10 Subsequent, a retrospective cohort study demonstrated that the utilization of DCD livers from selected donors above 60 and 70 y led to comparable outcomes, provided that other risk factors are limited.8,11,19 The Birmingham team demonstrated equal graft survival rates, utilizing 93 DCD livers from donors above an age of 60 y.11 Donor age at a threshold of 60 y failed to stratify posttransplant complications and graft and recipient survival. However, authors described diminished outcomes when advanced donor age was combined with an elevated donor body mass index (BMI) above 25 kg/m2.12,30,50,51 Such findings support the concept of a cumulative donor risk profile, which remains difficult to capture, despite defining cutoff values available for many single risk parameters.3,9,52 Comparing the literature provided from Europe and the United States, a cluster of countries has categorically limited the donor age to a threshold of ≤40–50, ≤60, ≤65, ≤70, or ≤80 y, whereas countries with significant waiting list mortality, for example, Switzerland, accept DCD livers from donors at any age.8,10,11,13-16,23,53-56 Of note, such grafts undergo obligatory end-ischemic hypothermic-oxygenated machine perfusion and viability assessment.56,57 The panel has figured the suggestions listed below regarding donor age (Table 1).

TABLE 1. - Donor risk factors
Donor risk factors Panel recommendation (in context of standard super rapid retrieval and cold storage, if not stated differently. In context of controlled DCD liver donation) Literature (references) Quality of evidence Grade of recommendation
General statement (1) The consensus was built on the expert opinion and reviewing the current literature.
(2) The thinking process was to provide general guidelines for centers with interest to start a DCD program.
(3) The recommendations should be considered in the context of the waiting list mortality and outcome acceptable in each country.
Donor age (1) The ILTS recommends the routine use of DCD livers from donors up to an age of ≤60 y, respecting other risk factors. 8-18 A-B I (strong)
(2) The ILTS recommends the selective utilization of livers from controlled DCD donors older than 60 y with consideration of other potential risk factors:
•Functional donor warm ischemia time
•Donor BMI
•Macrovesicular steatosis
•Donor in hospital stay
•Trends in donor liver function tests
•Donor hepatectomy time
•Expected cold ischemia time
A-B I-IIa (strong to moderate)
Donor BMI (1) The ILTS recommends to routinely use livers from controlled DCD donors with a BMI of ≤30 kg/m2. 10,11,16,19 B I-IIa (strong to moderate)
(2) The ILTS recommends further to selectively use liver grafts from controlled DCD donors with a BMI of >30 kg/m2 with consideration of the following risk factors:
•Donor age
•Functional donor warm ischemia time
•Macrovesicular steatosis
•Donor in hospital stay
•Trends donor liver function tests
•Donor hepatectomy time
•Expected cold ischemia time
B I-IIa (strong to moderate)
Steatosis The ILTS recommends to avoid the utilization of DCD liver grafts with macrovesicular steatosis >30%, in the absence of machine perfusion technology. 20,21 B IIa (moderate)
Cold ischemia (1) The ILTS recommends the implantation of controlled DCD donor livers ideally within 8 h of cold ischemia time 3,4,8,9,11,13,14,17,18,22-27 A-B I (strong)
(2) The ILTS suggests the selective use of controlled DCD donor livers with an expected cold ischemia time of >8 h, with consideration of the following risk factors:
•Donor age
•Donor BMI
•Functional donor warm ischemia time
•Macrovesicular steatosis
•Donor in hospital stay
•Trends donor liver function tests
•Donor hepatectomy time
A-B I-IIa (strong to moderate)
(3) The ILTS recommends not to use DCD donor livers with an expected cold ischemia time of >12 h. B I-IIa (strong to moderate)
BMI, body mass index; DCD, circulatory death donor; ILTS, International Liver Transplantation Society.

Recommendations are as follows (Table 1):

  • (1) The ILTS recommends the routine use of DCD livers from donors up to an age of ≤60 y, respecting other risk factors (Quality of evidence: High to moderate; Grade of Recommendation: Strong).
  • (2) The ILTS recommends the selective utilization of livers from controlled DCD donors older than 60 y with consideration of other risk factors including functional donor warm ischemia time, donor BMI, macrovesicular steatosis, duration of donor in hospital stay, trends in donor liver function tests, donor hepatectomy time and expected CIT (Quality of evidence: High to moderate; Grade of Recommendation: Strong to moderate).

Donor Body Mass Index

Donor size or BMI is considered as surrogate marker of liver steatosis and therefore frequently assessed in retrospective studies.11,17,54,58,59 Most data are available from experience using DBD donors for LT. Liver grafts from donors with a high BMI > 40 kg/m2 are frequently declined before procurement surgery because of the expected increased steatosis, which is, however, based on a very limited number of anecdotal reports and the overall low evidence for a reliable link between donor BMI and liver steatosis.11,60 This is further paralleled by Mathurin et al,61 who demonstrated that obese patients undergoing bariatric surgery have only limited features of macrosteatosis, despite very high BMI. DCD livers from donors with a high BMI are, however, still frequently declined without macroscopic evaluation. The majority of retrospective transplant studies suggested either a donor BMI of ≤25 kg/m2, ≤30 kg/m2, or ≤35 kg/m2 for DCD liver graft acceptance.10,11,54 A strict policy is frequently lacking in most centers.62 Foley et al10 have described more biliary complications with a donor BMI of >25 kg/m2 and donor body weight >180 lbs. These findings were supported by Schlegel et al, who demonstrated an impaired graft survival in recipients of DCD liver grafts from older donors (>60 y) with elevated donor BMI (>25 kg/m2).11 Higher rates of acute kidney injury (AKI) after DCD-LT were also associated with the same donor BMI cutoff.63

An elevated donor, BMI, and body weight can also have an impact on the donor procurement surgery. The time required for cannulation and donor hepatectomy was shown to impact significantly on outcomes after DCD-LT. The Kings College team has demonstrated that a prolonged hepatectomy time of >40 and >60 min increases the risk for graft loss.64-66 High-donor BMI may lead to an additional period of warm ischemia time after cold liver flush, because of the prolonged time required to perform the incision, cannulation, and hepatectomy in the donor, particularly in less experienced surgeons. Based on the insulation principle, steatotic livers were also found to cool down more slowly.1,4,67 Farid et al65 demonstrated a higher risk for graft loss when the donor hepatectomy time was found to be >60 min. The poorer visualization during procurement surgery with the time pressure may also lead to a higher rate of procurement injuries, tears of the liver capsule, or damage to blood vessels. A certain level of surgical experience in DCD liver procurement is required.65-67

Based on the current literature, the panel has summarized the following suggestions regarding the DCD donor BMI.

Recommendations are as follows (Table 1):

  • (1) The ILTS recommends to routinely use livers from controlled DCD donors with a BMI of ≤30 kg/m2 (Quality of evidence: Moderate; Grade of Recommendation: Strong to moderate).
  • (2) The ILTS recommends further to selectively use liver grafts from controlled DCD donors with a BMI of >30 kg/m2 with consideration of the following risk factors: donor age, functional donor warm ischemia time, macrovesicular steatosis, duration of donor in hospital stay, trends in donor liver function tests, donor hepatectomy time and expected CIT (Quality of evidence: Moderate; Grade of Recommendation: Strong to moderate).

Donor Liver Steatosis

Microvesicular steatosis of liver graft has been shown to minimally impact on outcomes after LT. Macrovesicular steatosis of liver graft affects outcome of LT.20 Based on the known hesitancy regarding the combination of DCD donation and advanced macrovesicular steatosis, currently data on the acceptable donor liver steatosis are scarce. An additional contributor is the inconsistent pathological quantification of macrovesicular steatosis.68 The utilization of such donor livers is generally avoided to restrict the additional risk for the development of a primary nonfunction or other complications leading to graft loss or recipient death.21 The available number of LTs with moderately or severely macrosteatotic liver grafts (DBD and DCD) is therefore limited. Previous studies have described an increased risk for the development of ischemic cholangiopathy (IC) in DBD livers with advanced macrovesicular steatosis.69,70 Of note, the majority of risk analyses in DCD-LT lacks the additional information on donor liver graft steatosis or provides a very limited number of cases with moderate macrovesicular steatosis to be able to reach a conclusion at this time.11,24,71-73 The first in-depth analysis of long-term outcomes utilizing DCD livers with different levels of macrovesicular steatosis (≤30% versus >30%) was recently provided by Croome et al.21 Recipients of DCD liver grafts with moderate macrovesicular steatosis (>30%) presented with higher rate of postreperfusion syndrome (53.9% versus 26.2%; P = 0.002), postreperfusion cardiac arrest (7.7% versus 0.3%; P < 0.001), primary nonfunction (7.7% versus 1.0%; P = 0.003), early allograft dysfunction (70.8% versus 45.6% and 8.3%; P = 0.02), and AKI (39.1% versus 19.4%; P = 0.02) when compared with candidates, who received DCD liver grafts with lower levels of macrovesicular steatosis.21 Although the data are limited, higher percentages of macrosteatosis appear to have a negative impact on patient outcomes. Therefore, the panel provides the following recommendation below.

Recommendations are as follows (Table 1):

  • (1) The ILTS recommends to avoid the utilization of DCD liver grafts with macrovesicular steatosis >30% in the absence of machine perfusion technology (Quality of evidence: Moderate; Grade of Recommendation: Moderate).

Cold Ischemia Time

The minimization of CIT has always been considered crucial to reduce posttransplant complications.4,22,28,62 In combination with donor warm ischemia, each additional hour CIT is generally considered to significantly increase the graft failure rate.18 Mathur et al18 and Abt et al17 have described an increasing graft loss with each additional hour of CIT (HR 1.06, P < 0.001, HR 1.17, respectively) in DCD-LT. The impact of CIT on outcomes has been assessed in many further retrospective studies with various suggested thresholds (≤4, ≤6, ≤8, or ≤10 h).3,4,10,23,25 Although Paterno et al have suggested to avoid any prolonged CIT above 4 h to prevent higher graft loss, the majority of retrospective studies accepted a CIT cutoff between 6 and 8 h.3,10,23,25 Based on the optimized organ transport by expert donor coordinators combined with modern communication systems, the duration of CIT is routinely limited and can also be accurately estimated at the time of organ donation in centers with experience in DCD-LT. The duration of CIT is therefore seen in context of the overall donor and recipient risk, and the recent literature and prediction models have suggested to limit the CIT to ≤8 h or ideally ≤6 h.3,16,22,74,75 Shortening of CIT can balance for other risk factors to keep the overall donor risk within an acceptable limit to achieve good outcomes.3,4,22 Although a fairly low-risk DCD liver graft with <60 y of donor age, and a limited functional donor warm ischemia time of ≤20 min and no relevant steatosis might be capable of sustaining an 8 h period of CIT,3 the remaining uncertainty of the cellular metabolic situation leads to the reluctance to accept such a specific DCD donor in some centers with limited experience in DCD-LT.57 The consensus regarding the CIT was described as follows by the panel:

Recommendations are as follows (Table 1):

  • (1) The ILTS recommends the implantation of controlled DCD donor livers ideally within 8 h of CIT (Quality of evidence: High to moderate; Grade of Recommendation: Strong).
  • (2) The ILTS suggests the selective use of controlled DCD donor livers with an expected CIT of >8 h, with consideration of the following risk factors: donor age, donor BMI, functional donor warm ischemia time, macrovesicular steatosis, duration of donor hospital stay, trends in donor liver function tests and donor hepatectomy time (Quality of evidence: High to moderate; Grade of Recommendation: Strong to moderate).
  • (3) The ILTS recommends not to use DCD donor livers with an expected CIT of >12 h (Quality of evidence: moderate; Grade of Recommendation: Strong to moderate).

Recipient Risk Factors

Although the majority of recipient risk factors are less well explored, they might be of equal importance for posttransplant outcomes compared with donor risk parameters. One reason for this is the wide range of medical risk factors and the influence of individual decision making at the multidisciplinary team listing meeting regarding the applicability of a DCD liver graft for a specific recipient. In addition to recipient age, BMI, and model of end-stage liver disease (MELD) score, the underlying disease, and the presence of technically challenging procedures, including retransplantation status or presence of portal vein thrombosis impact the decision of accepting a DCD liver graft. The following section discusses the most relevant recipient risk factors and provides suggestions in context of DCD liver graft utilization.

Recipient Age

The increasing age of the world population has triggered a higher number of elderly recipients in solid organ transplantation. With careful selection both older and younger recipients are expected to perform equally well.9 The overall number of LT candidates >65 y of age has increased in the Eurotransplant region.9,76 Similar figures were reported from the United States with an increase in the mean recipient age from 51 to 56 y between 2002 and 2014.76 One quarter of liver recipients in the United States was >65 y of age.9 Due to decreasing number of patients with hepatitis C–related cirrhosis requiring LT and the new leading indication of nonalcoholic steatohepatitis (NASH) in the western world, it is likely, that there will be a continuing increase in age at registration for LT.77,78 In addition, recipients with NASH-related liver tumors (hepatocellular carcinoma [HCC]) were found to be older than other candidates with different underlying liver diseases.9,79

Older LT candidates drop out from the waiting list more frequently due to comorbidities (medically unfit), and this group is also associated with a higher waiting list mortality, despite lower laboratory MELD scores at death.76 Within the first year after LT elderly recipients achieve similar outcomes.9 However, most retrospective case series have demonstrated a 10%–20% inferior 5-y recipient survival in the group older than 60–70 y, when compared with younger LT recipients.80-83 One reason for the reluctance to list elderly candidates for LT appears to be higher risk of developing cardiac events during and after LT with coronary artery disease as predisposing factor.84,85

In addition, research has shown that the posttransplant mortality of elderly recipients is affected by donor age and the cumulative donor risk in all transplantations from deceased donors.86 This becomes most evident when liver grafts from donors >60 y of age are utilized for candidates aged >60 y.87

Although there is a large body of literature on the impact of recipient age in overall deceased donor LT, the number of specific recommendations regarding recipient age in DCD-LT is very limited. With the known occurrence of potassium release with subsequent postreperfusion syndrome after implantation of DCD liver grafts, older recipients are exposed to a particularly higher risk to develop cardiac complications during transplantation.9 To define an absolute upper recipient age limit, centers will follow their standard practice in context of the medical fitness of the LT candidate. Mathur et al18 described a higher risk for posttransplant complications more than a recipient age of 55 y.

To provide a recommendation for young LT candidates, the panel has also assessed the impact of DCD liver grafts in pediatric recipients. The safe utilization of pediatric DCD donors for LT has been shown recently with similar long-term outcomes as seen in the comparator DBD cohort.29,88 Bartlett et al89 presented the largest cohort from Kings College Hospital in London. In context of the potential donor and recipient age mismatch, there is a general reluctance to use DCD liver grafts for pediatric recipients.90,91 Hwang et al91 showed equal graft survival rates in pediatric DCD and DBD recipients in the UNOS cohort from very young donors with an age of 11 and 12 y, respectively. DCD liver grafts are also more frequently transplanted into older children. The mean recipient age in the UNOS cohort was 7.7 y, as described in 2019.91 In the context of the available literature and clinical experience, the panel has made the following recommendations below.

Recommendations are as follows (Table 2):

TABLE 2. - Recipient risk factors
Recipient risk factors Panel recommendation (in context of standard super rapid retrieval and cold storage, if not stated differently. In context of controlled DCD liver donation) Literature (references) Quality of evidence Grade of recommendation
General statement regarding recipient selection The ILTS recommends to allocate DCD livers to recipients in consideration with the overall medical risk, disease cause, risk of mortality on the waiting list, and the probability to survive a redo liver transplantation. All A-B I (strong)
Recipient age (1) The ILTS does not recommend a specific recipient age cutoff (high or low) for the use of DCD livers. 15,26-29 B IIb (weak)
(2) The ILTS suggests the selective use of Livers from young DCD donors with a very limited overall risk for pediatric recipients. B IIb (weak)
Recipient BMI The ILTS does not recommend a specific recipient BMI cutoff for the use of DCD livers. 24 B-C IIb (weak)
Recipient laboratory MELD (1) The ILTS recommends the routine use of DCD livers for candidates with a laboratory MELD of ≤25 points. 4,8,10,11,15,27,28 A-B I (strong)
(2) The ILTS recommends to carefully select DCD donors with limited risk for candidates with advanced liver disease and a laboratory MELD of >25 points. B IIa (moderate)
Underlying diseases:
PSC, PBC, and HCC The use of DCD liver grafts for candidates with primary transplantation for PSC, PBC, or HCC is not contraindicated, as recommended by the ILTS. 4,30-34 B I-IIa (strong to moderate)
NASH The ILTS suggests to use livers from DCD donors for candidates with NASH selectively and in context of the overall medical risk, including cardiovascular disease. 4 B-C IIa-b (moderate to weak)
Regrafting The ILTS suggests to use DCD livers selectively for recipients requiring retransplantation or with previous complex upper abdominal surgery. 3,4,11,22,24,35 B I-IIa (strong to moderate)
Portal vein thrombosis The ILTS does not recommend the routine use of DCD livers for recipients with known complex portal vein thrombosis. 36 B III (recommendation not to do)
Acute liver failure (SU status) The ILTS recommends to selectively use DCD liver grafts for recipients listed for acute liver failures or super urgent status, considering the specific recipient situation. 37 B IIa (moderate)
Combined liver-kidney transplants The ILTS recommends the selective use of DCD donors for recipients listed for combined liver-kidney transplantation. 38-40 B-C IIa (moderate)
BMI, body mass index; DCD, circulatory death donor; HCC, hepatocellular carcinoma; ILTS, International Liver Transplantation Society; MELD, model of end-stage liver disease; NASH, nonalcoholic steatohepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.

  • (1) The ILTS does not recommend a specific recipient age cutoff (high or low) for the use of DCD livers (Quality of evidence: Moderate to Low; Grade of Recommendation: Weak).
  • (2) The ILTS suggests the selective use of livers from young DCD donors with a very limited overall risk for pediatric recipients (Quality of evidence: Moderate to Low; Grade of Recommendation: Weak).

Recipient Body Mass Index

In context of the increasingly obese population worldwide, recipient body weight and BMI is more frequently assessed and listed as well-explored risk factor for a higher posttransplant morbidity.92 The recipient BMI may contribute to the time required to remove the recipient native liver, which in turn may extend the CIT. In addition, very high-recipient BMIs may also prolong the graft implantation time, which extends the recipient warm ischemia time of the graft and may therefore lead to more reperfusion injury, impaired function and further complications.93 Although the impact of recipient, BMI is a known contributor to outcomes, there is no general cutoff when not to accept a candidate for LT and comparable outcomes can be achieved provided other risk factors are limited.92,94 The recipient BMI has been more frequently assessed in LT from DBD donors with multiple single center studies, while the data from the DCD cohort remains limited. Garcia-Fernandez et al95 demonstrated a decreased 5-y survival of 71% in obese recipients. The team from St. James University Hospital in Leeds, United Kingdom, has also linked a higher recipient BMI of >29.9 kg/m2 with significantly more complications, including infections and prolonged hospital stay, compared with candidates with a normal body weight.31 The rate of posttransplant complications started to increase in the overweight group with a BMI of >24.9 kg/m2 and became more pronounced in the obese and morbidly obese subcohorts.31 During the development of a prediction model of DCD-LT, the team from the University of California at Los Angeles (UCLA) has found more complications and more graft loss in recipients with a BMI of >30 kg/m2.22 This was further supported by Kalisvaart et al, who developed a score model to assess risk factors predicting AKI after liver utilization: recipients with BMI of >30 kg/m2 contributed with 4 risk points in the model.63 In general, the recipient BMI is also affected by various cofounders and frequently not corrected for the amount of ascites, which leads to a higher morbidity also in the context of the impaired kidney function in those recipients.92

Based on this, the group has defined the following recommendation below.

Recommendations are as follows (Table 2):

  • (1) The ILTS does not recommend a specific recipient BMI cutoff for the use of DCD livers. (Quality of evidence: Moderate to Very Low; Grade of Recommendation: Weak).

Recipient MELD Score

Although the MELD score has well-known weaknesses in predicting outcomes after LT, the score is routinely used to describe the status of the liver disease in transplant candidates.96 The logarithmic nature of this model contributes to the steadily increasing risk with higher score points. Recipients with a MELD > 30 points are prone to higher risk for intraoperative complications and reperfusion injury as well as early postoperative complications and longer intensive care and hospital stays.96,97 Of note, higher early mortality rates after deceased donor LT were typically observed in older candidates with a MELD score above 25 points.9

Specific data in the setting of DCD liver grafts and acceptable laboratory MELD score are lacking, and the majority of centers instinctively allocate DCD liver grafts to recipients with low laboratory MELD scores, frequently listed in context of hepatocellular carcinoma.3,30,62,98,99 Previously, 2 prediction models showed impaired outcomes with increase in laboratory MELD above 25 points in the combination of a DCD liver graft utilization.3,4 In context of standard CS preservation, the panel has suggested the following guidelines for recipient laboratory MELD when DCD liver graft is utilized.

Recommendations are as follows (Table 2):

  • (1) The ILTS recommends the routine use of DCD liver graft for candidates with a laboratory MELD of ≤25 points (Quality of evidence: High to Moderate; Grade of Recommendation: Strong).
  • (2) The ILTS recommends to carefully select DCD donors with limited risk for candidates with advanced liver disease and a laboratory MELD of >25 points (Quality of evidence: Moderate; Grade of Recommendation: Moderate).

Recipient Underlying Disease

The overall success story of LT with a steadily improved outcome has led to a broadening of recipient indications with subsequent higher need for donor livers, although the number of acceptable grafts remained stable.9,100 Based on the known impact of the medical fitness of the candidate to overcome the reperfusion syndrome and the potential perioperative complications in the immediate posttransplant phase, the majority of DCD liver grafts are allocated to candidates listed with low laboratory MELD scores.32,33,101 Although a few studies have assessed outcomes in recipients with HCC transplanted with DCD liver grafts, the data on the recurrence rate remain fairly limited and are reported with a range between 10% and 15%.30,98,102 The recurrence rate generally depends on the tumor status (load, activity, vascular invasion) and the majority of studies included LT with candidates inside Milan or University of California San Francisco criteria.5,98,103,104 The overall results of DCD-LT on outcomes in recipients with HCC appear comparable to results of DCD-LT for other recipient diseases.

An initial report from the UNOS database was provided by Croome et al,102 which reported inferior survival rates and more recurrence in DCD liver recipients transplanted for an HCC. Two years later, the team from the Mayo Clinic, Florida, using a larger cohort, found that HCC recurrence rate in DCD-LT to be similar to that in DBD-LT.98,102 Khorsandi et al30 have then analyzed the cohort from Kings College, London, and presented similar survivals in LT candidates with HCC transplanted with any deceased donor graft. Further studies assessing the impact of CIT on HCC recurrence support the recently presented mechanistical link between ischemia-reperfusion injury and later HCC recurrence, which point to a possible higher risk for HCC recurrence when livers from extended criteria donors (ECDs), including DCDs, are used.32,34,99,105 Nagai et al demonstrated higher HCC recurrence rates in LT with prolonged CIT.106,107 The perfect environment needed for cancer cells to invade and regrow includes most features of ischemia-reperfusion injury with a general inflammation in the new graft and recipient body.34 The majority of available studies have included DCD liver grafts with limited overall risk and have demonstrated good outcomes. Based on this, the panel currently recommends the use of DCD liver grafts for LT candidates with HCC. Further studies are needed in the future to assess the impact of DCD grafts with different risk profiles transplanted into recipients with various tumor stages and also in context of new organ preservation technology.99

Specific studies assessing the outcome of DCD-LT in context of other underlying diseases are very limited. LT candidates with primary sclerosing cholangitis (PSC) and primary biliary cholangitis frequently receive DCD liver grafts with acceptable outcomes.108 Khorsandi et al have demonstrated that cholestatic liver disease contributed with minimal risk points and therefore suggest allocation of DCD liver grafts to those candidates unless there is a precluding medical risk.4 In contrast, a multicenter study has found a higher risk to develop IC in context of a Roux-en-Y biliary reconstruction, frequently needed in recipients transplanted for PSC.23 This might be based on the higher sensitivity of ischemic bile ducts toward the exposure to enteric bacteria and toxins, particularly in donor livers with prolonged DWIT. A recent metanalysis has however demonstrated similar outcomes in PSC recipients with duct-to-duct anastomosis and authors have therefore suggested to individually decide if a Roux-en-Y reconstruction is really needed.109 The better access to the anastomosis and the entire biliary tree is an additional advantage.108,109

Another important and fast-growing indication for LT worldwide is the nonalcoholic fatty liver disease or NASH. This high-risk recipient cohort is particularly known for their unique comorbidities with a potentially high risk for posttransplant cardiovascular complications and mortality.110 Based on this, strict selection criteria are applied to enable listing of NASH recipients with the option to utilize DCD liver grafts in this cohort.4 The panel recommends to selectively transplant NASH recipients with DCD liver grafts, provided the overall medical and cardiovascular risk is low, and their liver frailty index appears acceptable.111 The panel provides the following recommendations below.

Recommendations are as follows (Table 2):

  • (1) The use of DCD liver grafts for candidates with primary transplantation for PSC, primary biliary cholangitis, or HCC is not contraindicated, as recommended by the ILTS (Quality of evidence: Moderate; Grade of Recommendation: Strong to moderate).
  • (2) The ILTS suggests to use liver grafts from DCD donors for candidates with NASH selectively and in context of the overall medical risk, including cardiovascular disease (Quality of evidence: Moderate to very low; Grade of Recommendation: Moderate to weak).

Retransplantation

Candidates listed for re-LT are known to develop more complications, and outcomes are generally inferior compared with primary LT.112 Of note, outcomes depend on the indication for re-LT and also the time interval between LTs. Experienced, high-volume transplant centers allocate good-quality DCD liver grafts with short donor warm ischemia times to such candidates. According to the currently available prediction models, only a very good, young DCD donor liver with short donor warm and CIT would be eligible for this recipient cohort.3 Based on this, the small number of available studies many centers do generally avoid the combination of DCD liver graft and high-risk re-LT candidate.3,4 The prolonged recipient hepatectomy time with the potential need for an arterial conduit or venous interposition graft with subsequently longer CIT and the candidates’ medical situation and frailty contribute to the risk of this approach.112 Van Reeven et al have recently explored a Dutch cohort and found comparable 3-y survival rates in 21 re-LT with the selected use of DCD and DBD liver grafts with an equally good early outcome, although 38.1% of recipients developed a nonanastomotic biliary stricture.35

Recommendations are as follows (Table 2):

  • (1) The ILTS suggests to selective use of DCD liver grafts for recipients requiring re-LT or recipients with previous complex upper abdominal surgery (Quality of evidence: Moderate; Grade of Recommendation: Strong to moderate).

Portal Vein Thrombosis

Candidates with known advanced portal vein thrombosis are at high risk for prolonged LT surgery with longer CIT and the risk of unsuccessful graft revascularization. The majority of centers perform abdominal computer tomography to exclude recipient portal vein thrombosis at the time of listing. Although candidates with Yerdel Grade I/II thrombosis may be successfully treated with thrombectomy also in combination with a DCD liver, recipients with complete portal vein thrombosis may require jump grafts or other time-consuming vascular reconstructions.36 Based on the elevated donor risk transferred with DCD liver grafts, additional technical or medical recipient risk factors should generally be limited. The number of reports of DCD liver grafts utilized for candidates with portal vein thrombosis is scarce.

Recommendations are as follows (Table 2):

  • (1) The ILTS does not recommend the routine use of DCD livers for recipients with known complex portal vein thrombosis (Quality of evidence: Moderate; Grade of Recommendation: recommended not to do).

Acute Liver Failure

Although critical care and graft selection have evolved significantly, graft and patient survival after LT for ALF remain inferior compared with other etiologies.37 The scarcity of available donor organs for this cohort of prioritized high-risk candidates with ALF and the narrow window of opportunity has prompted the consideration of ECD and DCD liver graft utilization.37 In the United States, over the past 20 y, an increased number of DCD liver grafts have been used for candidates listed for ALF. Kumar et al37 performed a recent analysis of a UNOS cohort looking at outcomes from the utilization of DCD livers in ALF. One-year graft survival in ALF recipients was comparable to candidates with other underlying diseases, and long-term graft and patient survival were similar when compared with recipients of DBD liver grafts.37

Recommendations are as follows (Table 2):

  • (1) The ILTS recommends to selectively use DCD liver grafts for recipients listed for ALF or super urgent status (Quality of evidence: Moderate; Grade of Recommendation: Moderate).

Combined Liver-kidney Transplantation

The known prolongation of CIT for the kidney with subsequent delayed graft function and impaired survivals in the setting of a combined liver and kidney transplantation may be a reason for the reluctance to use DCD organs. Three retrospective cohort studies focused on combined liver and kidney transplants with the use of DCD organs. Although in 2014, outcomes from combined liver-kidney DCD transplantations were found to be inferior when compared with DBD organs, recent improvements in DCD organ selection and overall patient management have led to better results.38,39 Nunez-Nateras et al39 have compared outcomes of 30 combined liver-kidney transplantations from DCD donors with 131 DBD organs. Authors describe similar delayed graft function rates in both cohorts with a longer time required to recover the kidney function in the DCD group. Although graft and recipient survival rates were comparable between the recipients of DCD and DBD grafts, a higher incidence of IC (10%) was observed in DCD recipients.39 Recently, Croome et al40 have explored outcomes in the large national dataset from the United States. Candidates transplanted with DCD organs achieved comparable good outcomes as matched DBD recipients of combined liver and kidney transplants in the most recent era between 2011 and 2018.40 Additional information on delayed kidney function was not provided because of the lack of available data in this registry-based analysis. Donor and recipient selection in experienced centers may achieve comparable outcomes in combined liver-kidney transplants from DCD donors. Further larger volume studies are required to establish risk factor thresholds and combinations for centers starting a combined liver-kidney DCD program.

Recommendations are as follows (Table 2):

  • (1) The ILTS recommends the selective use of DCD donors for recipients listed for combined liver-kidney transplantation (Quality of evidence: Moderate to very low; Grade of Recommendation: Moderate).

Prediction Models in DCD Liver Transplantation

With the general higher awareness of donor and recipient risk, the decision has shifted from the acceptance of a single risk factor, “yes or no” or a threshold, to the combination of a specific donor with a certain recipient risk profile.3,9 Simultaneously, new tools, considering donor and recipient factors, have been developed.1,4,22,26,41 The majority of models are based on a limited number of key parameters identified from large databases in accordance with specific regression coefficients for each factor.97 Although most scores were established to match DBD liver grafts to limit recipient mortality or graft loss only a few models involve DCD organs. Two concepts for risk analysis are currently available. Scores, which include DCD as cumulative risk factor, follow the concept of the donor risk index (DRI), introduced in 2006 by Feng et al. The DRI is a continuous system of risk measurement and includes other parameters, such as donor age, split graft, African-American race, cardiovascular accident as donor cause of death and donor height.41,96,113 To enhance applicability in other transplant centers and to validate this American model in Europe, the DRI was modified with the introduction of the Eurotransplant (ET)-DRI in 2012.26 Both, the included risk factors and outcome prediction, were comparable with 61% 5-y graft survival in a combined DBD and DCD transplant cohort.26,41 Of note, such models, base their prediction solitarily on donor risk factors and are not clinically useful for outcome prediction and are rather used to describe the donor liver quality. The threshold of ≤1.8 DRI points as an acceptance criterion was suggested by many because liver grafts with a higher DRI demonstrated already lower survival rates when combined with low MELD recipients (≤15 points). The general risk for a DCD liver graft in the DRI was measured with a hazard ratio of 1.71 (CI 1.27-2.29, P < 0.001) and independently of the type and duration of the donor warm ischemia.41 Another model, the donor liver index, was derived from the national liver transplant database in the United Kingdom and has similar features to those found in the DRI concept with additional donor parameters: smoking, donor gender, and plasma bilirubin.42 The donor-type DCD is included with an HR of 1.89. Expectedly, the donor liver index correlated well with the other 2 models, DRI and ET-DRI (Table S3, SDC, http://links.lww.com/TP/C253).42

Although such models may contribute with an additional donor liver risk categorization, for the donor variable DCD (yes; no), those scenarios cover a large number of donors with very different risk profiles, including rapid deterioration to prolonged hypoxia and hypotension.42 The other concept, a combined donor-recipient balance system, involves various parameters and builds a sum of risk factors.3,4,22 The first model, described by Hong et al in 2011, the UCLA-DCD-Score, a hazard-derived model, combines CIT with 2 donors and 3 recipient risk factors.3,22 Authors recommend declining donor-recipient combinations with an overall risk above the suggested threshold.22 Importantly, outcome predictors in DCD donation, for example, functional donor warm ischemia time, contributed only a limited number of score points.22 The next important model, developed by the team at Kings College, London, is the DCD-risk index.4 Similarly to the UCLA score, the DCD-risk index defines the risk based on comparable hazard calculations. Two donor and 3 recipient risk factors, with an overall range between 0 and 14 points, are considered.4 Of note, the underlying recipient disease is included as 1 dominant risk factor in combination with the duration of donor hepatectomy time.4 Interestingly, the strict selection policy of the center, which the database is derived from, has led to a narrow range of donor warm ischemia times with a subsequent contribution of only 1 score point to the overall risk, provided the donor warm ischemia is longer than 25 min. A prolonged CIT of >10 h contributed with only 1 score point, which decreases the applicability of the system because only a few DCD grafts worldwide would be used with such prolonged CS times.15,27,114

The last model to be discussed is the UK-DCD-Risk score, combining 3 donor and 3 recipient factors plus CIT to an overall number of 0 to 27 points (Table S3, SDC, http://links.lww.com/TP/C253).3,115 Three risk classes were defined, and D-R combinations with >10 points were classified as “futile” because of the limited 5 y patient and graft survival of <40% and <20%, respectively.3 Low-risk combinations (maximum 5 score points) achieved an excellent graft survival of 80% in 5 y.3,74 Despite the practicability of such models with the score point system, all tools have shortcomings.3,96 A few parameters, for example, donor warm ischemia time, are not present at donor offer, and the CIT can only be estimated. In context of the new preservation approaches currently developed, we may well expect a general risk reduction, in which “futile donor-recipient combinations” may become downgraded to high risk with subsequent transplantation. The lack of graft steatosis as variable in all models is another disadvantage.20,43,56,116 Finally, all tools have a selection bias due to the limited number of parameters available in retrospective national datasets with missing values and variations in the donor and recipient protocols.

Recommendations are as follows (Table 3):

TABLE 3. - Prediction models
Prediction models Panel recommendation (in context of standard super rapid retrieval for controlled DCD liver donation and cold storage, if not stated differently) Literature (references)
3,4,22,41-43
Quality of evidence Grade of recommendation
The ILTS suggests use prediction models in DCD liver transplantation because they may help to evaluate the overall donor and recipient risk. B IIa (moderate)
The ILTS recommends the use of DCD-risk scores, which might be useful tools to define thresholds for declining certain donor-recipient risk combinations. B IIa (moderate)
DCD, circulatory death donor; ILTS, International Liver Transplantation Society.

  • (1) The ILTS suggests the use of prediction models in DCD-LT because they may help evaluate the overall donor and recipient risk (Quality of evidence: Moderate; Grade of Recommendation: Moderate).
  • (2) The ILTS recommends the use of DCD-risk scores, which might be useful tools to define thresholds for declining certain donor-recipient risk combinations (Quality of evidence: Moderate; Grade of Recommendation: Moderate).

ACKNOWLEDGMENTS

This consensus conference was endorsed and sponsored by the International Liver Transplantation Society (ILTS). We acknowledge the generous financial support from the industry, including Avionord, Bridge to Life, Organ Assist, and OrganOx.

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