Should we perform deceased donor liver transplantation after living donor liver transplantation has failed?

Should we perform DDLT after the failure of DDLT? Should we perform DDLT after the failure of LDLT in a patient without hepatocellular carcinoma (HCC)? Should we perform DDLT after the failure of LDLT in a patient with HCC who fulfills the local criteria for listing and increased priority on the wait list? Should we perform DDLT after the failure of LDLT in a patient with HCC who does not fulfill the local criteria for listing or increased priority on the wait list (ie, the patient failed to meet the criteria for DDLT originally)? With questions 1 to 3, we will consider the ethical foundation for the current practice of retransplantation for graft failure, and this discussion will serve as the basis for question 4, which is more controversial. DD, deceased donor; DDLT, deceased donor liver transplantation; HCC, hepatocellular carcinoma; LD, living donor; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; UCSF, University of California San Francisco. Electronic literature searches were performed with the Ovid MEDLINE, Embase, and Cochrane databases in English, German, and French. The following key words were used in various combinations: liver transplant, live donor liver transplant, retransplant, rejection, loss, failure, survival, primary nonfunction, hepatic artery thrombosis, mortality, UNOS (ie, the United Network for Organ Sharing), and Eurotransplant. The MEDLINE search yielded 49 publications, the Embase search yielded 68, and the Cochrane search yielded 46. These were reviewed; the relevant studies were supplemented with additional studies, and they are referenced in the literature review. Level 1a. Systematic review with homogeneity of randomized controlled trials. Level 1b. Individual randomized controlled trial with a narrow confidence interval. Level 1c. “All or none” series. Level 2a. Systematic review with homogeneity of cohort studies. Level 2b. Individual cohort study (or low-quality randomized controlled trial). Level 2c. Outcomes research. Level 3a. Systematic review with homogeneity of case-control studies. Level 3b. Individual case-control study. Level 4. Case series (and poor cohort or case-control studies). Level 5. Expert opinion. The analysis and discussion of the literature are supplemented with relevant ethical principles and considerations. The ethical framework is based on the 2 major principles used in the allocation of DD organs: justice and utility.2 Justice is the concept of moral rightness according to actions that are fair or equitable. There are 2 components of justice.3 Procedural justice refers to the fair process of distributing and accessing resources, and substantive justice refers to the subprinciples that inform notions of justice such as equity, liberty, and impartiality. The accountability for reasonableness framework ensures that the principles of procedural justice are met when priority-setting decisions are being made.4, 5 This framework contains 4 conditions to ensure that decisions are made fairly: relevance, publicity, revisions/appeals, and enforcement. Equality.6 This is the notion that every person should have access to the same quantity of resources [eg, everyone should undergo liver transplantation (LT) once]. Maximum opportunity for all. This principle emphasizes the importance of maximizing everyone's chances of reaching the top of the wait list. This is the case for restricting the number of organs that a person may receive so that others may have a better chance of undergoing transplantation (eg, a limit of 1 liver per lifetime or more than 1 organ in an ideal allocation system). Maximum opportunity for all aligns with the principle of equality insofar as it attempts to grant recipients an equal opportunity to receive an organ. Equity.3, 6 Resources ought to be allocated in proportion to the need of the patient; that is, sicker patients should receive priority. Every person should receive whatever quantity and quality of resources he or she needs. Liberty. This is the right of individuals to make choices regarding their health and to pursue goods without interference from others. This underlies the recipient's right to approach potential living donors (LDs) while he or she is on the DD wait list; this also supports the potential donor's right to accept a degree of risk with respect to the outcome of the donation. (This is similar to autonomy but considers the issues of justice and rights.) To what degree will the patient's health be improved and/or to what degree will illness be prevented (magnitude)? How long wil the patient's health be improved (duration)? How likely or unlikely is it that the patient's health will be improved (certainty)? How soon will the health benefit or prevention of pain or illness occur (propinquity)? What is the likelihood that this benefit will be followed by further benefits (fecundity)? What number of persons will be affected (positively and/or negatively) by an action (extent)? Grade A. Consistent level 1 studies. Grade B. Consistent level 2 or 3 studies or extrapolations from level 1 studies. Grade C. Level 4 studies or extrapolations from level 2 or 3 studies. Grade D. Level 5 evidence or troublingly inconsistent or inconclusive studies of any level. Because there are no randomized clinical trials or systematic reviews of retransplantation for graft failure after DDLT, the quality of the evidence is level 2b (ie, multiple cohort studies regarding the outcome of retransplantation after the failure of DDLT). For patients with initial liver allograft failure, retransplantation is the only option for survival. Although the outcomes of retransplantation are inferior to those of primary LT by nearly 15%,8-12 the results for retransplantation at 1 year have improved by 13%, whereas those for primary transplantation have improved by only 4.1%. The 1- and 5-year patient survival rates after primary transplantation, first retransplantation, and more than 2 transplants are 85%, 77%, and 72% and 73%, 63%, and 56%, respectively.13 From 1999 to 2008, the rate of retransplantation in the United States fell from 9.6% to 7.6%.12 This question centers on whether it is fair to allocate a second organ to a person while others are awaiting their first transplant. We must examine whether there are morally relevant differences between a patient who has already received a transplant and one who has not. The principle of equity entails a moral duty to treat like cases alike. However, it is permissible to treat unequals differently in proportion to morally relevant inequalities. Accordingly, organs should be allocated to whoever needs them and is likely to benefit the most, whether or not the person is a first-time recipient. If a person has already received a transplant, he or she should be entitled to a subsequent transplant if transparent, objective criteria are met. If an HCC patient has an equal or greater need for transplantation in comparison with a patient with another indication, then the HCC patient may justifiably undergo retransplantation. To deny an HCC patient (or any patient) an opportunity for a second transplant because of a diagnosis per se could be viewed as an act of unjustified discrimination. Procedural justice is achieved when patients are evaluated for transplantation according to objective, transparent, and fair criteria that are applied to all potential recipients on an individual basis (no unjustified, prejudicial exclusions). Therefore, equity and procedural justice support retransplantation for patients, including those with HCC, whose grafts have failed after DDLT. Because the outcomes of subsequent transplants are poorer than those of first-time transplants (by approximately 15%), utility favors transplantation for first-time recipients. However, the survival rates of patients undergoing retransplantation are equal or superior to those of many first-time recipients with other conditions and are better than the minimum accepted standard (often quoted to be 50%). As for HCC patients, if there is a significant likelihood of a poorer retransplantation outcome for an HCC patient versus a patient without HCC, the organ can justifiably be allotted to the patient without HCC. However, because there is no reason to expect a poorer outcome from retransplantation for an HCC patient who meets the local criteria for transplantation, this patient should qualify equally for retransplantation according to the urgency and gravity of his or her acute need. If retransplantation were not an option, very few organs would be added to the pool (the incidence of rescue retransplantation is low). Not offering rescue transplantation would shorten the wait list only slightly and allow only a few more people on the DD wait list to receive organs sooner. In utilitarian terms, this would be marginally beneficial because the wait time for patients on the DD wait list would be only slightly reduced. However, the overall extent of the benefit would be reduced because those in need of retransplantation would not receive an organ; in other words, a policy of retransplantation increases the overall utility of the first transplant by 15%. Therefore, although utility argues against retransplantation because of the slightly lower survival rate, the survival rate after retransplantation compares favorably with the survival rates after transplantation for other indications. Moreover, the impact is mitigated by the low incidence of retransplantation and the overall improvement in the utility (ie, survival) of primary transplantation. Although there is a negative impact insofar as the maximum opportunity for all principle is contravened, we conclude that the practice of retransplantation is justifiable because it saves lives and has a minimal negative impact on the DD wait list. Moreover, a policy of liver retransplantation for graft failure after DDLT would be considered the current standard of practice by the vast majority of transplant programs. Retransplantation should be offered for transplant failure after DDLT. Because there are no randomized clinical trials or systematic reviews of retransplantation for graft failure after LDLT, the quality of the evidence is level 2b (ie, multiple cohort studies of outcomes of retransplantation after the failure of LDLT). In general, the 1-year graft survival rate after LDLT is approximately 90%; the graft failure rate within 90 days is as high as 13%.14 According to the largest available database from the United Network for Organ Sharing registry (which includes 2375 LDLT procedures), the graft survival rate at 7 years is still 61%.15 Retransplantation after LDLT is performed in 6% to 22% of patients according to larger patient series.14, 16-19 Retransplantation is more frequent after LDLT versus whole liver DDLT (16% versus 9%20 and 22% versus 11%19), and this reflects more frequent vascular complications with LDLT (5.7% versus 1%). Outcome data for retransplantation after LDLT are only rarely reported. According to Marsh et al.,16 6 of 7 patients are alive 1 year after retransplantation. This question rests on the moral relevance of the first liver graft coming from a DD or an LD. Some might argue that LDLT patients with graft failure unfairly “jump the queue” because patients can a DD liver than they would have with their DD priority. This can be evaluated with the following ethical Because recipients of have not resources the DD this is their first on an organ from the DD list. The of an liver benefits not only the but also on the DD list by the donor pool and the time for others to the top of the list. Some will to this option, and will not. Some will be in a LD, and will not. and and the number of available and and DD organs are not are allocated to a and organs are a This is by the morally relevant differences in the that and are to their people have more opportunity to undergo transplantation, and this may be as the Some of this is achieved by the allocation of organs to the DD list. The of LDLT an of outcomes because there is no that those who pursue this option will a who undergo LDLT receive an organ than they would have if they on the DD list. not a DD they other patients following them on the DD wait list to an organ more and their However, if the graft access to the DD grafts the queue” those them on the DD wait list. In the literature a retransplantation of 6% to 22% after LDLT with but Although retransplantation after LDLT those for their first transplant, because of this low incidence of graft failure after LDLT and the benefit of LDLT to many on the DD wait the utility principle the allocation of DD to patients who received grafts that have Moreover, retransplantation with a DD organ for graft failure after LDLT is by the vast majority and is considered the current standard of Because of the survival data for LDLT and the outcomes of retransplantation after LDLT as as the overall of LDLT to all on the DD wait retransplantation with DD organs after graft failure following LDLT is With the literature we could no to the of retransplantation for transplant failure after LDLT for HCC. The literature on retransplantation after the failure of LDLT does not the incidence or outcomes for patients who LDLT for HCC. Therefore, there are no data to so the quality of the evidence is level 5. the survival of patients with HCC who meet the local criteria for listing and increased priority the is with 1-year survival rates from to The survival rates are lower for patients the criteria survival, versus survival, versus but they equal for those the University of California San criteria and those the criteria survival, versus LDLT, HCC rates at 3 years to outcomes have at 5 years rate of Because we not any differences between those undergoing LDLT for HCC and it is likely that the incidence and outcomes of retransplantation after LDLT for patients undergoing transplantation for or with HCC will be similar to those for patients without HCC. This question whether the diagnosis of HCC for patients whose fulfill the local criteria for listing and increased priority on the wait list is morally relevant to listing for In with procedural justice the same ethical principles still and should be considered in all has in the discussion for questions 1 and 2 that organ transplants and the of the liver transplant DD or an should not further Because the listing policy for listing with increased the criteria for should be applied to all patients, including HCC patients whose transplants have like those patients without HCC, the HCC patients for DDLT and the right to be considered for DDLT. Therefore, not retransplantation with a DD liver for HCC patients who have LDLT would be discrimination. as for question LDLT an overall benefit to others on the list by them to on the list. These HCC patients were that they could pursue an and that if they a the would be This within the and transplant to perform Therefore, the of patients from DDLT after the failure of LDLT would discrimination. at likely outcomes according to the for a for transplantation. the local criteria for listing with increased HCC patients are to have outcomes with DDLT by with Therefore, like the outcomes of patients without HCC, their outcomes after retransplantation must be considered This their access to DDLT. In because there are no differences between those undergoing transplantation for HCC who fulfill the local criteria for listing and increased priority on the wait list and those with other for transplantation, this should have the same access to DDLT for transplant failure that others undergoing LDLT The practice of DD for retransplantation for graft failure after LDLT in patients with HCC who fulfill the local criteria for listing and increased priority on the wait list is This question considers that first-time LDLT may be offered to patients with HCC who not fulfill (ie, the local criteria for listing and increased priority on the wait list. Because patients not meet the criteria for DDLT, their only chance for LT is LDLT (or the of a DD organ whose quality is so poor and whose are so high that it has for all recipients on the DD wait or for liver listing and allocation are based on equity, that is, the patient's degree of urgency (the likelihood of on the This is by the Model for End-Stage Liver or a such as the level of Because patients whose for transplantation is HCC are not as as those for liver failure (ie, they have a low or allocation increased priority for those with HCC versus those without HCC. This is an to DDLT by a fair and For to patients whose fulfill a of is in the United in a of is and this patients a between those of patients and patients at Because of the poor overall transplant outcomes for patients with HCC rates of and to the HCC that a person can have while still for listing and increased priority. criteria that fulfill the criteria for and (often without evidence of Because in this increased priority is for HCC patients, those who not fulfill criteria are not if they are are unlikely to be offered DDLT because they are not for priority they are to accept a organ that has for all others on the list. For many of patients with more transplantation still the the outcome may be than that accepted by the DDLT allocation is also that many patients who criteria may have survival because data that the outcomes of transplantation for patients with criteria (eg, the or the those for patients within the In there is a that the accepted criteria are and better of that are more than and number are this many transplant centers transplantation to patients who the criteria the of LDLT or DD organs that have for all patients on the wait list. In this should patients who were not for DDLT retransplantation after the failure of as for question 3, the literature on retransplantation after the failure of LDLT does not the incidence or outcomes for patients who LDLT for HCC within or the local listing and priority The quality of the evidence is, level 5. as for question 3, it is likely that the incidence and outcomes of retransplantation after LDLT for patients who transplantation for or with HCC and and not fulfill the local criteria are similar to those of patients without HCC. Therefore, the question one of ethical considerations. The question is patient should be evaluated according to criteria from those for all other The morally relevant from question 3 is that the patients retransplantation not fulfill the local criteria for listing with increased priority on the DD wait list. the person has received a transplant. any transplant from a DD or an LD. The for transplantation insofar as it is not to poor In with a fair one could argue that because of an poorer outcome outcome the by the allocation patients in this should not be considered for retransplantation with DDLT. If the allograft and the needs DDLT, it is that retransplantation is because the person not meet the criteria for the DD list only the of an is the in a in which he or she may for a DD The process that the followed to the DD organ might to those still on the DD This of may from of opportunity and outcome question 2 and allocation However, patients were by their health that if they a LD, the would be have their and an in with allocation In questions 2 and 3, the recipients met the criteria for DD to the DD list for retransplantation for graft failure is by the low incidence of graft failure after LDLT and the outcomes of retransplantation. is also by the that by and not DD patients others to access organs more because LDLT the outcomes for others on the list However, for patients whose local criteria for listing and this be used because they were not on the DD wait list or not have any priority at the time of Therefore, not others the list more and not outcomes for others on the list. the against patients with HCC access to DDLT after the failure of LDLT is based on a of justice and the outcome is inferior to that by the DD allocation and LDLT not an opportunity for other potential recipients to the wait list. The potential the and their as as all the of the health need to that DDLT will not be available if the graft The may to not and the may to not The of the LDLT must that the patient may from primary or hepatic artery when retransplantation could be The may be to LDLT by the of a If the patient and potential donor accept the increased risk of without the of DDLT for a failed this will deny the patient a The in of access to the DD list for retransplantation is based on is a of justice that to treat like cases and cases differently according to their morally relevant For ethical the policy for this of LDLT patients should be with the policy for recipients of DDLT whose HCC also the local criteria for increased priority. The practice of listing patients without priority and a liver that has for all other patients on the wait list is more than the LDLT These recipients have a risk of graft failure because they have received that were considered to be for any others on the wait list and that would have retransplantation for graft failure in this is accepted in many patients qualify for with a high priority for DDLT for the diagnosis of liver failure, they not qualify for DDLT priority. This current practice the that retransplantation for graft failure in patients whose were not for listing and priority is is the relevant ethical in this the LDLT and DDLT recipients are similar because the criteria and need retransplantation. The current practice of offering retransplantation to recipients who received low-quality DDLT that were for other recipients an of If it is to perform retransplantation for recipients who received low-quality according to the equity it should be to perform retransplantation for LDLT recipients who the Moreover, it is to that after retransplantation, patients for LDLT failed will at as as those who received low-quality DD grafts that were for other recipients (ie, have similar retransplantation for failed LDLT meets the of benefits that retransplantation. Therefore, equity this a for DD organs to recipients for LDLT failed and who not meet local listing or priority The of the low of LDLT in patients with HCC and the low incidence of graft failure after LDLT the of this very Therefore, the impact of this policy on the DD wait list would be is the moral that to and is, it is to if the utility may be offering a any of utility is morally to must be to all patients on the wait list for LT will be and it is the for allocation that have to while patients are (ie, the patients undergo transplantation The urgency with graft failure of the for the that retransplantation for patients should priority because others on the wait list will undergo In the of graft failure after LDLT, the for the need of the and the donor an must be against the for the others on the wait list. must not be it must have utility to a Although the outcome of transplantation for patients whose the criteria has to be poor for DD the outcome for an individual undergoing LDLT is and may be (ie, transplantation for many may not be For the patient may fulfill other criteria (eg, the or that have with for this the transplant considered the likelihood of survival with LDLT to be to the risk to the LD. and retransplantation for graft failure in patients whose local criteria for listing with priority. of the of a policy that retransplantation after the failure of LDLT might be a to In in which multiple transplant centers organs and not all centers LDLT to patients whose the local access to the DD organs after the failure of LDLT may the patients by another policy of retransplantation to the of by the LDLT accessing DD grafts for patients whose LDLT has in which the LDLT a DD graft in would the of this practice to the patients by the LDLT and the of the policy on the LDLT and In the of DDLT after transplant failure following LDLT in a patient with HCC who does not fulfill the local criteria for listing and/or increased priority on the wait list from all the other the would have achieved priority for DDLT and the LDLT not those on the DD wait list. the ethical for and against retransplantation for graft failure, we retransplantation by DDLT. We are that this may not be accepted in every organ allocation This a or between the in the of DD and this may between or Because of the of graft failure after LDLT, the for retransplantation for graft failure after DDLT with a graft that has for all others on the and the of survival, the of DDLT after the failure of LDLT for a patient with HCC who does not fulfill the local criteria for listing and/or increased priority on the wait list is

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