Current Challenges in Liver Transplantation Following Donation After Cardiac Death

Abstract

There is a resurgence of interest in liver transplantation using donation after cardiac death (DCD) donor livers. Careful donor and recipient selection can result in excellent outcomes, but injury to the biliary system remains a serious challenge to DCD liver transplantation. This mini review addresses the current challenges to DCD liver transplantation.

Today, the dual drivers of a shortage of donation after brain death (DBD) organ donors and increasing mortality on the waiting list have prompted many centers to revisit donation after cardiac death (DCD) liver transplantation. This in turn has raised new challenges.

PREDICTING THE TIMING OF ASYSTOLE IN POTENTIAL DCD DONORS

Donor selection is crucial not only to predict those organs that are likely to function well in the recipient but also to make sense of a limited resource in terms of retrieval teams. Currently, in the United Kingdom, between 30% and 40% of offers for DCD organ retrieval do not yield a usable liver, although they may yield other valuable organs. Better prediction of potential DCD donors likely to proceed rapidly to asystole is a challenge that will usefully rationalize organ procurement services and identify the optimal liver donors (¹).

ADOPTING PRACTICES TO GET THE BEST FROM DCD LIVERS

Although the reported incidence of primary nonfunction requiring retransplantation is higher with DCD than DBD livers, the reality is that the transplant community is becoming good at selecting livers that will have good synthetic function. Posttransplantation transaminase levels are consistently higher after DCD compared with DBD liver transplantation; however, these derangements usually normalize rapidly. Careful selection of donors and the additional effort spent in minimizing cold and warm ischemic times have paid dividends with excellent short- and long-term results in both adult and pediatric DCD liver transplantation (^2–4). Such good practice does not come without a cost, and this activity has necessarily seen a return to nocturnal transplantation and is labor and resource intensive.

LIMITING NONANASTOMOTIC BILIARY STRICTURES

Although careful DCD donor selection means that hepatocyte function does not often present a problem in DCD liver transplantation, the same cannot be said of the biliary epithelium. Nonanastomotic biliary strictures arising from ischemic cholangiopathy are the curse of DCD liver transplantation and remain difficult to predict. Typically presenting weeks to months after liver transplantation, it is often refractory to treatment and results in a requirement for medium-term retransplantation (⁵). Factors such as a long warm ischemic time, chaotic donor physiology before asystole, and bile salt toxicity are believed to lead to a higher risk of nonanastomotic biliary stricture, but there is a pressing need to provide evidence of other factors that genuinely contribute risk. It has been suggested that initial reperfusion of the implanted graft through the arterial system (which contributes most to the integrity of the biliary system) may be a mechanism for reducing this complication, but comparative evidence is lacking. The biliary epithelium is more sensitive to ischemia/reperfusion injury than hepatocytes (⁶). Therefore, learning how to preserve the biliary system in adversity is a priority that could contribute greatly to the outcome and safety of DCD liver transplantation. Studies have begun investigating strategies to protect DCD grafts (⁷) but are limited by a lack of good experimental models of biliary injury. Clinical initiatives using extracorporeal membrane oxygenation suggest a potential to protect both hepatocytes and biliary epithelium in human DCD transplantation (⁸).

SELECTING THE BEST RECIPIENTS

The majority of the focus for DCD liver transplantation has centered on the donor, but what about the recipient? The main issue here is whether marginal organs such as a DCD liver should be given to sick patients or to patients who remain relatively fit. The commonly voiced argument states that if a marginal organ is given to a sick (but needy) recipient, they may have less capacity to withstand the complications that may arise from stuttering posttransplant liver function. The counter argument states that transplanting a marginal liver graft into a relatively fit (but less needy) recipient is more likely to result in a successful outcome but at a higher personal risk to the recipient. Balancing the utilitarian argument with personal risk will only achieve objectivity with the provision of hard evidence, and this in turn will require large studies. Experiences suggest that hepatitis C-positive recipients are less likely to benefit from DCD liver transplantation (⁹) and may develop accelerated recurrent fibrosis. Justice and equity of access would suggest that patients who receive a DCD graft and develop a need for retransplantation should be afforded the same priority as other patients on the waiting list, although one study from the United States has questioned whether this is the case (¹⁰).

REDUCING CENTRE VARIATION

One of the striking observations in DCD liver transplantation practices are the wide variations in outcomes and complication rates between centers (^{2–5, 8–10}). Some of these differences can be accounted for by variation in procurement procedure and some by recipient selection and implantation procedures. As with many areas of clinical transplantation, the large number of variables makes it difficult to understand the importance in what are for the most part small series. Large registry studies or multicenter trials could contribute greatly to our understanding of the unsolved issues remaining around DCD liver transplantation and would undoubtedly improve safety and the development of common protocols (¹¹). With greater sharing of DCD livers between centers, information on issues such as the relation between ischemic times and ischemic cholangiopathy become more important.

So, where does DCD fit into the future scheme of liver transplantation? Reports suggest that a surge of interest in DCD liver transplantation in the United States in the early to mid 2000’s has dwindled in recent years (¹²). Whether this number shift represents natural variation or has occurred as a consequence of recognition of the complications associated with this mode of transplantation (¹³) is unknown. Evidence from the United Kingdom suggests a continued increase in DCD donors but at the cost of fewer DBD donors (¹⁴). It seems likely that unless there is a major increase in the number of DBD donors, DCD liver transplantation will be here to stay. DBD liver transplantation remains numerically more important and is lower risk than DCD transplantation. Careful selection of donor and recipient mean that DCD livers can contribute effectively to the provision of livers for transplantation.