Due to the continued donor organ shortage, liver transplantation from DCD donors has been increasing in recent years. Although more centers are transplanting DCD livers, there is a lack of enthusiasm in the transplant community due to inferior outcomes with DCD livers. Reported one-year and three-year graft survival rates for DCD liver transplantation range between 67%–73% and 56%–63% respectively. Most studies comparing DBD and DCD liver transplantation demonstrate significantly worse one- and three-year graft survival rates for DCD compared to DBD liver transplantation.3,2,16
However, other single-center studies have demonstrated similar graft survival rates between the two groups.13,20,21
A recent single-center analysis of 19 DCD and 234 DBD liver transplants demonstrated no difference in graft survival in recipients without hepatitis C (HCV). However, graft survival rates were significantly worse in HCV recipients of DCD and expanded criteria donor (ECD) livers when compared to standard criteria donor (SCD) livers.8
This updated analysis of 87 DCD liver transplants reveals significantly lower graft survival compared to that seen in DBD liver transplants. Our 10-year graft survival of 43% is similar to that reported by deVera et al. from the University of Pittsburgh.3
With longer follow-up we are able to report a 15-year graft survival rate of 43% compared to 51% for DBD liver transplants. It is clear that the differences in graft survival between DCD and DBD liver transplants are greatest within the first year of transplantation and that gap narrows over time. Despite its inferiority to DBD liver transplants, long-term DCD liver graft survival appears acceptable and comparable to DBD liver transplantation.
Reported long-term patient survival rates after DCD liver transplantation are lower than after DBD liver transplantation, but in multiple studies the differences are not statistically significant.21,2,3,20,22
One-year and three-year patient survival rates for DCD liver transplantation range between 79%–89% and 68%–81%, respectively. Both our previous analysis1
and this updated analysis demonstrate significantly lower patient survival in the DCD vs. DBD liver recipients. One factor contributing to this difference may be the higher patient survival rates in our DBD recipients compared to other single center studies.3,21, 20
The data also suggests the influence of a learning curve in our earlier experiences. An additional analysis of liver transplants performed after 2005 at our institution showed similar patient survival rates between DCD and DBD transplant recipients (data not shown).
Our retransplant rate within the first year for DCD recipients (19%) was significantly higher than that for DBD recipients (4.8%). One must be cautious in interpreting retransplantation rates because those data underestimate true graft failure, as some patients may have died prior to being retransplanted. Nonetheless, a significantly higher retransplant rate was seen in the DCD group. This observation is similar to other analyses describing higher DCD liver retransplant rates.23, 24
In our analysis we did not see any differences in the rates of PNF or HAT between DCD and DBD liver recipients, and 81% of the DCD retransplants were for complications of ischemic cholangiopathy. DCD recipients have a low rate of technical failures and usually maintain adequate hepatocellular function despite severe biliary tract damage. Based on other analyses, this unique pattern of graft failure leads to significantly longer times prior to listing for retransplantation, lower MELD scores at retransplantation, and limits access to retransplantation for these patients. In addition, these patients have been shown to receive higher-risk livers at retransplantation compared to DBD recipients.24,23
We agree with these authors that a modification of the allocation system with MELD score exceptions is necessary to truly reflect the severity of disease in these DCD recipients so that they are not disadvantaged at the time of retransplantation.
In our previous analysis of 36 DCD liver transplants, we found a significantly higher rate of hepatic artery stenosis (HAS) in the DCD group.1
These stenoses were all distal to the anastomosis. Since our procurement techniques did not change over time, we hypothesized that the artery may have sustained some ischemic injury secondary to the DCD recovery and implantation process. A recent single-center analysis of 39 DCD liver transplants demonstrated a significantly higher rate of HAS (12.8%) compared to that in DBD transplants. However, two of the five strictures were at the arterial anastomosis, so it is difficult to ascertain whether the cause was technical vs. issues related to the DCD allograft itself. With this expanded analysis of 87 DCD liver transplants, we did not find a significant increase in HAS. It remains unclear whether the incidence of HAS is significantly elevated in DCD liver transplants. We are still aggressive in ordering CT angiograms on any DCD recipient with an abnormal hepatic arterial Doppler signal to rule out concomitant HAS.
The development of biliary complications after liver transplantation has been described as the true Achilles heel of the operation. While most complications can be treated with endoscopic or percutaneous techniques, some require reoperation and retransplantation. Although many cases of IC lead to retransplantation, not all patients with IC require retransplantation. Lee et al. studied 44 patients who developed intrahepatic biliary strictures after DCD liver transplantation and classified the strictures into four groups on the basis of cholangiographic appearance: unilateral focal, confluence, bilateral multifocal, and diffuse necrosis. They found patients who developed unilateral focal, defined as stricture only in the segmental branch of the unilateral hemiliver, or confluence, defined as several strictures at the confluence level, had 100 % survival and good outcome with or without additional interventions. Patients with bilateral multifocal strictures, or diffuse necrosis of the bile ducts had poor prognosis resulting in either death or retransplantation despite aggressive therapeutic interventions.6
In our analysis 65% of patients who developed IC either died or underwent retransplantation, and 35% of patients are alive without requiring retransplantation. Those who died without retransplantation developed comorbidities that excluded them from retransplantation. The patients who did not necessitate retransplantation did require multiple biliary procedures to minimize morbidity and maintain allograft function. We agree with Lee et al. that less severe IC can be treated without retransplantation as long as the strictures are few and accessible for endoscopic or percutaneous therapy.
The rates of overall biliary complications, IC, the presence of casts, stones and sludge, and abscess and biloma formation were significantly elevated in the DCD vs. DBD group. The differences were mostly driven by the presence of IC. Others, who have reported on the incidence of IC in DCD liver transplants, diagnosed all cases of IC within 120 days of transplantation.13
In our study, 83% of IC diagnoses were made within the first 120 days after transplant. We did see additional diagnoses of IC made beyond 120 days, and thus chose to define our complication rate as incidence within one year of transplantation. We recommend continued close monitoring for IC out to one year after transplantation.
There have been two published reports on the identification of risk factors for graft survival after DCD liver transplantation. Mateo et al. performed a retrospective review of the United Network for Organ Sharing database and analyzed 367 DCD and 33,111 DBD liver transplants. In addition to identifying recipient risk factors that increase risk of DCD allograft loss, they confirmed that donor WIT >30 min and CIT >10 h negatively impact graft survival. In addition, donor age and CVA as donor cause of death increased risk of graft loss.16
Lee et al. used the UNOS database and identified 874 DCD liver transplants to calculate a DCD risk index. Favorable DCD donor criteria included donor age ≤45 years, donor WIT ≤15 min, and CIT ≤10 h. Increasing donor age was more highly predictive of poor outcomes in DCD compared to DBD.15
Studies examining the risk factors for the development of biliary complications in DCD liver transplantation are limited. Chan et al. reviewed 52 DCD liver transplants to identify risk factors for the development of IC. Seven patients (13.7%) in the DCD group developed IC. Donor WIT and total ischemic time, were found to be significant risk factors for the development of IC. Donor age and CIT were not found to increase risk of IC. In addition, donor age >50 years, CIT ≥9 hours, and donor weight >100 kg predicted the development of IC in the DCD group.13
In contrast, our univariate analysis revealed donor age as a continuous variable and donor age ≥40 years as the only variables that significantly increased the risk for overall biliary complications. Additional univariate and multivariate analyses of the 26 patients with IC revealed donor age, donor age ≥40 years, and CIT >8 h as significant risk factors for the development of IC.
It is unclear what the upper age limit should be for DCD livers to avoid biliary complications and optimize allograft survival. Our data and other data presented here suggest that a cutoff of between 40 and 50 years would be appropriate. In contrast, a previous report has suggested that the use of selective DCD donor livers over age 55 results in similar one-year graft survival compared to DCD livers <55 years provided that the CIT is brief.25
Another recent report suggests that the use of DCD livers >60 years results in similar patient and graft survival compared to both transplantation of DCD livers <60 years and DBD liver transplantation.21
Based on our data, donor age is a significant risk factor for the development of both overall biliary complications and IC in DCD liver transplant recipients. We currently use 45 years as the upper age limit for DCD liver donors, as we feel age is the strongest predictor for the development of IC in these recipients.
Recent analyses of DBD liver transplantation have been unable to demonstrate CIT as a risk factor for the development of biliary complications.9,11
In contrast, CIT >8 hours in the DCD group resulted in a 2.5 times increased risk for the development of IC. The calculated mean CIT for the entire DCD group was 7.2 h. We also performed an analysis assessing the effects of changing our protocol in a recent era of transplants to decrease CIT in the DCD recipients. Although we had a significant reduction in mean CIT from 8.7 h to 4.9 h, we did not see significant differences in DCD recipient outcomes. These data suggest that multiple factors in addition to CIT contribute to outcomes, and it is likely greater numbers are needed to achieve sufficient power for statistical analysis. Based on our analyses, we suspect that the bile ducts in DCD livers are more susceptible to ischemia reperfusion injury in the presence of prolonged donor WIT and CIT >8 hours. We therefore aim for the shortest CIT possible and CIT of no longer than 8 hours.
It was surprising to us that donor WIT did not impact the development of overall biliary complications or IC in our study. This finding is similar to the study by Chan et al., where donor WIT did not impact the development of IC.13
As we have consistently kept the definition of donor WIT as the time of extubation to organ flush, we have no explanation for this based on various definitions described in the literature. The main difference between DCD and DBD procurement and transplantation is the presence of donor WIT that occurs prior to the declaration of death. It seems intuitive that longer donor WIT would result in a higher incidence of biliary complications, and specifically IC. For that reason, we have been reluctant to expand the donor WIT >30 min throughout the history of our program. It is unclear why donor WIT was not significant but CIT was in our study. It may be due to insufficient power of the analysis or because we do not have a sufficient number of prolonged WIT for that to make a difference in the analysis. It is likely that a combination of donor age, CIT and donor WIT contribute to the development of IC.
Two recent studies have demonstrated that donor post-extubation hypotension correlates with poor outcomes after DCD liver transplantation. Chan et al. showed the time that donor mean arterial blood pressure was less than 35 and 50 correlated with significantly increased risk of IC.13
Ho et al. studied 37 DCD liver transplants performed at multiple transplant centers with organs recovered from the same OPO. They identified a composite endpoint of death, primary nonfunction, and graft loss within one year, or diffuse biliary ischemia. Fourteen DCD liver recipients reached the composite endpoint. The study showed that if the time that the donor systolic blood pressure drops below 50 mmHg is >15 min, there is a statistically higher chance of reaching the composite endpoint.26
Both studies suggest that the time of profound hemodynamic instability may be a better predictor of subsequent function or injury. Based on these studies, we included donor physiologic parameters in our univariate analyses. We had data on 55 DCD donors and were unable to identify any of these parameters as potential risk factors for the development of overall biliary complications or IC. We do suggest close monitoring of these variables in all DCD donors. These times may be more helpful in identifying acceptable donors with shorter periods of hypotension or hypoxemia despite longer WIT (defined as times from extubation to organ flush). We currently use donor WIT of 30 min as our cutoff, but we feel this parameter may be expanded if the times of post-extubation hypotension are shorter than 15 minutes.
Donor BMI and donor weight were studied in all univariate analyses. Previous reports have suggested that donor weight >100 kg in combination with long total ischemic times and older donor age are predictive risk factors for the development of IC.13
In our study these variables did not impact the development of overall biliary complications or IC in the DCD donors. However, donor weight and BMI were significant risk factors for the development of anastomotic biliary strictures in the DCD group. We then extended our analysis and studied these variables in the DBD cohort. We found that donor weight and donor BMI were significant risk factors for the development of strictures in the DBD group as well. It appears that the risk of developing of anastomotic biliary strictures due to donor weight or BMI is not unique to the DCD liver. We do not know the mechanism based on this analysis, but we hypothesize that these donors may have more advanced vascular disease that predisposes the liver to ischemic anastomotic strictures. More analyses are needed to elucidate the mechanisms of these risk factors.
It is critical to discuss the disparity of outcomes between DCD liver transplantation with potential DCD liver recipients. The decision to accept a DCD liver should be an individual patient’s decision after adequate informed consent is obtained. Adequate informed consent needs to include not only patient and graft survival rates, but also the morbidity associated with the increased rate of biliary complications. We believe informed consent is a dynamic process that should start at the initial evaluation and continue periodically during return visits while on the waiting list and at the time of organ offer. If a patient has significant encephalopathy and it is felt that adequate comprehension cannot be attained, it is critical to have the discussion with a family member or power of attorney.
Critical questions that remain include which recipients are good candidates for DCD livers or which recipients gain a survival benefit from receiving a DCD liver vs. waiting on the list for a DBD liver. Although we have had an active DCD liver transplant program for over 16 years, we still do not have sufficient numbers to answer these questions with certainty. Currently, we limit DCD liver transplants to consented patients undergoing primary transplants with MELD score >18. We avoid using DCD livers in the setting of retransplantation for chronic allograft failure due to the potential for increased CIT seen with prolonged transplant hepatectomies. Some have suggested using these livers for patients with HCC outside Milan criteria with low physiologic MELD scores. We do not select this group as sole recipients for DCD livers. In 14 DCD recipients with known HCC prior to transplant, the vast majority (86%) were within Milan criteria. In addition, we have performed DCD liver transplants on patients with primary nonfunction, acute liver failure and high MELD scores.
Some have investigated survival benefit after liver transplantation with the use of high-risk allografts. Amin et al. used a Markov decision analytic model to estimate survival benefit of an immediate ECD liver transplant vs. waiting for an SCD liver. In patients with MELD >20, immediate ECD liver transplant provided a survival benefit despite a higher risk of primary graft failure.27
A recent study suggested that patients with MELD score >20 attain a survival benefit regardless of the donor risk index (DRI), of which DCD liver transplantation is a significant component.28
New data recently presented at the Academic Surgical Congress also suggested that patients with MELD >20 receive a survival benefit from receiving a DCD liver compared to waiting for a DBD liver. Subgroup analysis revealed that survival benefit is also dependent upon wait-list time to receiving a DBD liver.29
Others have demonstrated that critically ill recipients with MELD >30 at a single center had similar graft survival with DCD compared to DBD liver transplants.3
In our analysis, MELD score was not found to impact the risk of biliary complications. Based on our experience and these recent studies, we feel that higher MELD patients are suitable candidates due to their severity of illness and the higher likelihood of obtaining a survival benefit. We suspect that the lower MELD limit should be approximately 20, but published data at this point is inconclusive to know with certainty the MELD score above which a true benefit is attained. Until more definitive data are available, the MELD cutoff should likely be individualized by center, expertise, potential for retransplantation in the region and available resources. We hope to expand on our analysis in the future when we have sufficient power to answer these questions.
There are several limitations to our study. Due to its retrospective nature, there is selection bias in the decision to choose certain livers for transplantation and which patients should undergo retransplantation. This bias can have an impact on our results. In order to have a maximal number of patients for our analysis, we have included all patients since the inception of the program. Previously described technical modifications over time are included, possibly impacting our results. We initially attempted a multivariate analysis using all variables that we felt could likely contribute to the development of biliary complications. Because of the limited number of patients in our study, many of the independent variables were highly correlated and the effects were not well estimated. We therefore performed our multivariate analysis only on the variables that were significant on univariate analyses. In addition, we did not include recipient WIT as a potential risk factor for biliary complications due to limited tracking of these times in our database. Others have shown that prolonged recipient warm ischemic time, or the time for implantation, may impact liver allograft survival in expanded criteria DBD liver transplants.30
Total ischemic time has been show to influence the development of IC in DCD liver transplant recipients.13
We have recently begun to track recipient WIT so that future analyses can include these times as a potential risk factor.
In summary, long-term patient and graft survival after DCD liver transplantation remain significantly lower but acceptable when compared to DBD liver transplants. A significant cause of allograft failure in DCD liver recipients is the development of severe biliary complications including ischemic cholangiopathy. It is likely that a combination of donor WIT, CIT, and donor age contribute to the development of severe biliary complications. Our data suggest that donor age and CIT are the strongest predictors for the development of ischemic cholangiopathy. Donor WIT does not appear to be a significant risk factor for the development of these complications. Careful selection of younger DCD donors and minimizing CIT may limit the incidence of severe biliary complications and improve the successful utilization of DCD donor livers.