For many end-stage organ diseases, transplantation remains the most effective and often the only option for curative treatment. This is especially true for liver disease, where supportive care and disease-specific therapies are the only treatment options readily available for fulminant liver failure outside of transplant. While alternatives are under investigation, there are currently no proven extracorporeal systems that can replace the liver function as dialysis does for the kidney. All healthcare systems across the globe face the challenge of demand for liver transplantation that exceeds the supply. Each country has to consider cultural factors, infrastructure, healthcare structure, and economics to successfully create their national transplantation system and limit waitlist mortality (see Fig. 4.1 ). To aid this process, the World Health Organization (WHO) led the World Health Assembly to endorse the revised Guiding Principles on Human Cell, Tissue and Organ Transplantation, which created a framework and guide to countries as they develop their transplant systems. Every healthcare system can build upon these guidelines to maximize donations, candidate conversion, and procurement in addition to improving patient selection, allocation, quality of surgery, and long-term care. Individual countries have addressed their challenges in particular ways, and their experiences can aid others as they confront common and sometimes unique obstacles in the application of liver transplantation in pediatric populations.
At a basic level, transplantation systems operate like any other market with supply and demand. Globally, all systems must address the fact that demand outstrips supply. Efforts toward increasing supply are constantly underway, maximizing donations of organs and thus limiting waitlist mortality. Early in this process is the acceptance of the public to contribute to the transplant system by becoming an organ donor, either as a living donor or after death. The United States operates on an opt-in system with the assumption that one cannot presume consent without direct expression. Members of the public register to become donors when applying for a driver’s license at the Department of Motor Vehicles or directly to their state’s donor registry via public awareness drives or their own initiative. Despite these geographical and sometimes inconsistently applied efforts, demand continues to outpace supply in the United States. Countries such as Spain, Austria, and Chile have transitioned to a system of presumed consent for organ donation. In Chile, for example, this was initially a simple opt-out at the time of renewing a driver’s license, but in 2013, Chile amended the Organ Donor Act, which both required a notarized statement to become a nondonor and made donors prioritized for transplantation. Although there are many differences between countries that choose opt-in versus opt-out systems, based on a 2014 study by Shepherd et al. that analyzed 48 different countries’ transplantation rates, there is a general increase in the number of liver and kidney transplants in countries that choose an opt-out system.
Whether a system chooses opt-in or opt-out, the public still needs to consent without coercion to participate in organ donation. This requires addressing the incentives for a population to choose to participate while avoiding the excessive monetization that can place vulnerable populations at risk. In 2008, Israel passed two laws, the Brain-Respiratory Death Law and the Organ Transplantation Law, in an attempt to improve organ donation rates in the country. Those who give consent to donate organs after their death, living donors, and first-degree relatives (at variable levels) are given priority allocation. This has resulted in an increase in donation in Israel from 7.8 in 2008 to 11.4 donors per million population in 2011 as well as registered donors and those who consent for donation. Although the increase in donations should be celebrated for the benefit to waitlist recipients, there are still ethical considerations under debate. For example, does the law give an advantage to the highly educated, who would be more aware of the new law? To combat this dilemma, Israel engaged in a public education campaign to make sure its population was fully aware of the changing laws.
Additionally, a system must remove disincentives so that potential donors do not opt out because of the excessive burden from altruistic living donation. The 2008 Israeli laws included clauses that addressed earning loss reimbursement, fixed-sum transportation refund, reimbursement for 7 days of recovery, 5 years’ reimbursement of medical/work capability loss/life insurance, and reimbursement of psychological consultations and treatments following donation. This led to an increase in living kidney donation from 71 total cases in 2010 to 117 in 2011. The removal of disincentives is important but must be balanced to avoid undue compensation, which we will discuss later.
Simply having incentives and removing disincentives is not enough if the public is not aware of a system’s efforts to improve. Education and public awareness programs are key to gain the trust of a population to donate. At the same time Israel was changing its incentives, Australia established the Australian Organ and Tissue Donation and Transplantation Authority Act 2008 and created the Organ and Tissue Authority government agency in 2009. This agency developed the DonateLife program to educate the public alongside several grassroots efforts to work together and make reforms to the Australian transplant system. Although this has improved donation rates from 11.9 donors per million people in 1990 to 14.9 donors per million people in 2011, a single change is not enough to transform a national transplant system, and local opinion holds that there is still more work to be done. Additionally, effective education needs to evolve over time as the methods used to spread information and misinformation change. Social media and web-based applications have dramatically changed how the public obtains information and communicates, but they have varying levels of engagement in the medical community despite their ubiquity among potential donors and recipients.
Several efforts are also underway to expand the available donor pool beyond the ideal healthy young donor. Extended criteria donors (ECD) include donations after circulatory death (DCD), steatotic allografts, high-risk behavior, advanced age, and multiple comorbidities. In the United States, The Joint Commission (the primary US healthcare-accrediting organization) requires that transplant programs develop DCD policies to increase their use. In India, the majority of deceased donor grafts are ECD with very acceptable outcomes. Scoring algorithms such as the United Kingdom DCD Risk Score can help identify ECD that carry a relatively lower risk of ischemic cholangiopathy or primary graft nonfunction. Grafts with stage 1 or 2 fibrosis have been shown to have acceptable long-term patient survival. Additionally, domino donation for specific conditions, such as maple syrup urine disease, allows for increased organ donation without the risk of recurrence in the domino recipient. Various treatment modalities are being developed to limit the risk of complications. With the availability of effective direct-acting antiviral agents with excellent safety profiles, hepatitis C is no longer an absolute contraindication to organ donation, although the high financial burden of these medications may limit their widespread use.
Deceased donors are one side of the equation. Living directed and undirected liver donations are also used at variable rates between countries. These donations can be further classified into living related, emotionally related, and altruistic donors. In the United States, living donation is increasing every year but remains a fraction of the total performed liver transplants. In Japan, however, the reverse is true, with living donation representing the vast majority of liver transplantation in adults and children. These differences are the result of complex intersections of culture, public knowledge, legislation, and health system infrastructure resulting in different approaches to fit the needs of the particular population. The vast majority of these organs come from related donors such as parents to children. Altruistic donation from unrelated donors is performed, but the degree of risk assumed by the donor makes this practice controversial and, if not carefully monitored, open to abuse. Should living donation fail, families may be reassured that deceased donation is still available as a backup, often as a status 1A priority, depending on the transplant system. Careful planning must take place to limit this, as live donation transplant failure will further stress the already scarce deceased donor pool.
Potential living donors inherently assume a higher degree of risk in transplantation because they do not receive any benefit from the removed organ. Strategies to maximize donation need to be made with efforts to protect vulnerable populations who are at potential risk by unfair systems. This is especially true in pediatrics where the population cannot always speak with its own voice or have access to advocacy. Additional high-risk groups include those with limited education, limited capital, and prisoners. The Declaration of Istanbul on Organ Trafficking and Transplant Tourism helps provide guidance on minimizing some of these risks.
Unethical practices of organ donation monetization and the use of capital prisoners highlight these high-risk groups, with opposition stemming from the long-felt aftermath of historic abuses. There remains, however, a continued call for reasoned ethical debate about donation monetization and the use of capital prisoners. These arguments support the use of the context of a country’s own culture with appropriate checks and balances. Marketplace models have been developed to show how monetary incentives could help bridge the gap between the number of donations and those on the waiting list. Arguments have been advanced that an ethically run and legal commercial marketplace could reduce the incentive to use a violent and coercive illegal market.
Without the above-mentioned structures in place, any country will have difficulties implementing an effective transplant system. Australia struggled with a decreasing donation rate to eight donors per million people in 2000 despite having been active since 1988, in part because of a fractured and dysfunctional national system. It took several years and 150 million Australian dollars with the efforts of dedicated community advocates and motivated government officials to reorganize and restructure the national transplant system into the Australian Organ and Tissue Authority and DonateLife, which then steadily improved donation. With these structures in place, candidates for donation or their families can be approached for donation.
Within the hospital itself, there need to be policies and a culture in place to approach potential living donors or the families of deceased donors. Great care, ideally by specifically trained personnel, must be taken when approaching the potential donor families, as these are emotionally charged situations. In the United States, eligible pediatric donors were identified with a consent rate of 69.2% and found most often in hospitals that had level 1 trauma programs and a pediatric critical care medicine fellowship. These hospitals are the locations most likely to care for a potential donor and would have policies and education to prepare staff for approaching families. These policies and education need to include relevant cultural factors that will impact the ultimate decision of the potential donor. The importance of the family unit has been described in the process of informed consent in China, whereas Greek studies emphasize the importance of transplant outcomes to families who consent for donation.
The process of organ procurement needs timely consent and efficient management by agencies that are seen as ethical and independent. In the United States, the federal Medicare conditions of participation require hospitals to reach out to their organ procurement organization (OPO) or identify a trained hospital representative to sensitively approach families of potential donors. Public trust is undermined by the appearance of revenue generation and decreased rates of consent. The WHO Guiding Principles on Human Cell, Tissue and Organ Transplantation state that providers involved in procurement should be prohibited from receiving any payment that exceeds the justifiable fee for the services rendered. It is also recommended that OPOs remain independent from the hospital and transplant center, again to avoid the perception of revenue generation.
Living donation requires a thoughtful yet efficient workup and consent process to ensure that donation occurs without coercion or undue risk to the donor. Proper informed consent with recognition of full donor autonomy and without coercion is required. It is recommended that this be performed by an independent entity whose sole responsibility is to the donor. Although living donation from a minor is not recommended given a child’s lack of autonomy and inability to provide true informed consent, it has been performed in exceptional circumstances rarely and frequently with controversy. Many programs also use the recommendation from the ethics committee of the transplantation society and include a reflection period during their workup. Emotional conflict and ambivalence can play a large role in the decision of potential living donors to consent. Ambivalence in potential living donors in Taiwan was influenced by potential costs to the donor, questions regarding the success of the donation, resources available after the procedure for support, and opposition of a significant other. Intimacy between the donor and recipient as well as a strong social support network between family, friends, and healthcare professionals most strongly reduced a donor’s ambivalence before donation.
Given organ scarcity, proper management of patients with liver disease will help limit those who require transplantation. Studies have suggested that in cases of biliary atresia, centralized centers with both experienced hepatobiliary surgeons and a pediatric liver transplant program have improved outcomes over a decentralized structure. In a multinational study, the Pediatric Acute Liver Failure Study Group found that incorporating a standardized order set on admission was able to reduce the number of indeterminate diagnoses of pediatric acute liver failure and rates of liver transplantation without increasing mortality.
Inevitably, some patients will progress to end-stage liver disease despite optimal management. At this point, transplant programs need to be proper stewards of their potential recipients. Pediatric indications are similar to adults and can include chronic end-stage liver failure, fulminant acute liver failure, quality of life (growth failure and intractable pruritis), unresectable tumors, and injury to other organs prevented by liver transplant such as metabolic disease. Informed selection will ensure that this scarce resource will not be used in patients who will have limited benefit. A Model for End-Stage Liver Disease (MELD) score of 15 or higher has been shown to help determine when 1- to 2-year mortality rates are improved by liver transplantation in adult patients with liver disease. However, growth and development concerns in infants and children make this cutoff less meaningful for pediatric populations. Certain conditions may also require emergent or timely transplantation to optimize outcome, such as the child with fulminant hepatic failure or unresectable hepatoblastoma who needs transplant between cycles of chemotherapy. For these patients, ABO-incompatible allografts have been successfully used to aid in timely transplantation with very acceptable safety profiles.
Controversy exists in the selection of nonresident candidates who require resources designed for the country’s own population. The Declaration of Istanbul defines this as transplant tourism when it involves trafficking or commercialism or if the resources required for the transplant undermine the country’s ability to provide transplant services for its own resident population. Instances of trafficking and coercion can be straightforward; however, defining at what point a nonresident of a country is placing undue burden on the native population and transplant system can be fraught with nuance.
Once donors and recipients have been identified, a health system requires an allocation policy to determine who receives an organ and who does not. A directed living donation can avoid this process to the benefit of the recipient, but both living undirected and deceased donation still require a fair process to allocate an organ. These systems are impacted by the size, infrastructure, and policy of a country. Nations as large as the United States and China have different transportation concerns than smaller countries encounter. The United States has based allocation and procurement in 11 regions and is further subdivided into donor service areas as a way of preserving graft integrity during transportation. However, the United States is currently in the midst of a policy debate regarding organ allocation and the fairness of such geographically arbitrary policies. Currently, all US organs must be allocated according to the Final Rule, which stipulates that organs must be allocated in a way that is medically safe and fair and reduces waste but shall not be based on a geographic location except when it pertains to the above. Legal challenges to the US lung allocation system led to an active debate on whether the current regional and donor service area model properly fulfills the Final Rule. Federally mandated and immediate changes in policy had to be implemented and have since expanded to include all solid organ transplants. The Health Resources and Services Administration has recently instructed the Organ Procurement and Transplantation Network (OPTN) to implement specific policy change to fully comply with the Final Rule, the specifics of which, for liver allocation in particular, are currently subject to open and public debate.
Allocation in pediatrics is of special concern given that these patients cannot advocate for themselves and are often born with the very diseases that lead to transplant. Many countries have implemented a pediatric priority in their transplant policies for undirected donation. This priority has been justified by several different bodies. In the United States, the Unified Network for Organ Sharing (UNOS) Pediatric and Ethics Committee created a white paper to support pediatric priority in 2015 and broke down the justifications into several arguments. The Prudential Lifespan Account argues that investing resources early in life while a child is developing maximizes their ability to thrive later in life. The “Fair Innings” concept suggests that every individual deserves the opportunity to live a full life expectancy, and transplantation in childhood best helps achieve this. The “Maximin” principle concludes that the inequality inherent in systems should only be tolerated if the maximum benefit should be given to the most disadvantaged groups, which would include children. Lastly, the idea of utility helps prevent waste of a scarce resource and that younger patients can be expected to have longer survival with a liver allograft.
Specific implementation of pediatric priority is influenced again by multiple factors, including societal and ethical concerns. Different countries address this issue in different allocation structures with either pediatric priority or mandatory splitting summarized by Hsu and Mazariegos. Pediatric priority can either be given to a select group of recipient diagnoses, such as hepatoblastoma, or a select group of deceased donors, such as pediatric recipient priority for all pediatric donors. The splitting of deceased donor livers is especially promising in transplantation, with two recipients benefiting from the same organ. Mandatory splitting is reserved for a select group of deceased donors, with a pediatric priority given to one side, typically the left, during allocation. Although technically more challenging, outcomes remain excellent when compared with the whole livers in both pediatric and adult recipients.
Children are not able to benefit from the priority given to those who have already donated or consented to deceased donation because they cannot consent. However, some countries, such as Israel, give priority to the first-degree family members of those who have already donated, and a child may benefit from parental or sibling donation. Despite pediatric priority, some countries still struggle to transplant children at acceptable rates using their standard models. In the United States, over one-third of pediatric patients are transplanted using exception narratives to award extra points to those whose MELD or Pediatric End-Stage Liver Disease (PELD) score does not adequately reflect the impact of their illness.
Beyond pediatric priority, scoring systems are used to allocate organs such as MELD and PELD. Historically, time on the waitlist and clinician judgment were the main components of allocation. This has evolved over time using various scoring systems, but donor–recipient matching methods are constantly under development. They work to find a balance between patient-based policies (waitlist time, urgency, and utility), donor-based policies (donor risk index), and combined donor–recipient-based systems. Current lung allocation models factor in post-transplant survival/benefit, and this is being evaluated for other solid organ transplants.
After the policies are created, donors have consented, and recipients are allocated, the liver graft must still be physically procured and transported to the potential recipient. Proper evaluation of the potential donor will help limit the rate of discarded organs once the procurement procedure is underway. Organ procurement teams must move efficiently to limit cold ischemia time (CIT) to the liver. The process must be able to evolve as the transplant landscape changes in a country. In 2003, the US Department of Health and Human Services’ Gift of Life Donation Initiative–Organ Donation Breakthrough Collaborative was a national effort to identify best practices in effective OPOs that could help inform practices throughout the country. Initially successful at increasing donation, its success plateaued, and discard rates are above the goal in the United States from perceived high-risk donors. OPOs continue to evolve through new collaborations such as the Organ Donation and Transplantation Alliance, an independent, nonprofit US-based collaborative.
When OPOs identify an organ that is high risk and likely to be discarded, expedited organ placement has been used to quickly allocate an organ to a transplant program that has used such organs in the past. This can occur before the recovery procedure or in the operating room. However, there are several concerns for this method of placement without clear policies in place. The OPTN/UNOS identified several concerns from transplant centers, including a lack of transparency when this process is used, a lack of guidance for OPOs and transplant centers, a lack of consistency by the OPO, and inconsistent access to organs offered for the transplant program. Policies need to be developed to identify a trigger for the process to be initiated, a formal mechanism through a match system, and a clear set of qualifications to determine what programs participate in expedited placement.
Several procurement techniques can be adapted by OPOs to maximize donation and minimize risk to the recipient. Splitting of the liver already has well-established safety profiles, and performing the split in situ (in a hemodynamically stable cadaveric donor) rather than ex vivo (on the back table) can further improve outcomes. Efficient surgical technique during the process is essential to limit CIT, which is one of the main factors impacting graft health and survival.
The physical transport of the liver graft is the next determinant of CIT and organ preservation. Large distances between donors and recipients may or may not impact CIT. In the United States, it has been demonstrated that CIT may not increase even with broad sharing models. However, this is related to the infrastructure of the United States and would increase the transportation of organs by flight. Although this may be beneficial to patients who live in areas with fewer donors or poorly performing OPOs, it may also dramatically increase the cost of transportation and affect the sustainability of a system.
Preservation during transportation is currently achieved with ice and storage fluids. There is inadequate evidence to recommend one type of preservation fluid over another; commonly used solutions include the University of Wisconsin, Euro-Collins, and histidine-tryptophan-ketoglutarate solutions. Advances may make this technique obsolete as programs across the world develop normothermic or subnormothermic machine perfusion. These techniques have the potential to extend organ preservation, allow for viability testing, and provide the opportunity to rehabilitate currently unusable organs. The future also holds the promise of growing human(ized) replacement organs, either in a laboratory or in other mammalian sources.
Transplantation and Long-Term Care
Regardless of the mode of preservation and transportation, the liver graft must then be efficiently processed by the transplant center. This is followed by implantation of the donor graft into the recipient, and optimal surgical technique will limit long-term complications. Once the incision is closed, the patient then enters long-term care beginning with induction therapy and critical care management and is followed by a lifetime of medical care. Whereas the details of surgery and long-term management are covered in other chapters of this book, they remain no less important to the management of a scarce resource. Complications can result in the need for retransplantation of the liver or nonhepatic end-stage organ disease (commonly renal) that can again add to the waitlist and growing disparity between supply and demand. Although much has changed since Thomas Starzl first attempted an orthotopic liver transplantation in a 3-year-old child with biliary atresia in 1963, the fact that demand has outstripped supply remains the one true constant in liver transplantation.