Statistical methods versus machine learning techniques for donor-recipient matching in liver transplantation.

Donor-Recipient (D-R) matching is one of the main challenges to be fulfilled nowadays. Due to the increasing number of recipients and the small amount of donors in liver transplantation, the allocation method is crucial. In this paper, to establish a fair comparison, the United Network for Organ Sharing database was used with 4 different end-points (3 months, and 1, 2 and 5 years), with a total of 39, 189 D-R pairs and 28 donor and recipient variables. Modelling techniques were divided into two groups: 1) classical statistical methods, including Logistic Regression (LR) and Naïve Bayes (NB), and 2) standard machine learning techniques, including Multilayer Perceptron (MLP), Random Forest (RF), Gradient Boosting (GB) or Support Vector Machines (SVM), among others. The methods were compared with standard scores, MELD, SOFT and BAR. For the 5-years end-point, LR (AUC = 0.654) outperformed several machine learning techniques, such as MLP (AUC = 0.599), GB (AUC = 0.600), SVM (AUC = 0.624) or RF (AUC = 0.644), among others. Moreover, LR also outperformed standard scores. The same pattern was reproduced for the others 3 end-points. Complex machine learning methods were not able to improve the performance of liver allocation, probably due to the implicit limitations associated to the collection process of the database.

Deceased by default: Consent systems and organ-patient mortality.

Previous research shows that countries with opt-out consent systems for organ donation conduct significantly more deceased-donor organ transplantations than those with opt-in systems. This paper investigates whether the higher transplantation rates in opt-out systems translate into equally lower death rates among organ patients registered on a waiting list (i.e., organ-patient mortality rates). We show that the difference between consent systems regarding kidney- and liver-patient mortality rates is significantly smaller than the difference in deceased-donor transplantation rates. This is likely due to different incentives between the consent systems. We find empirical evidence that opt-out systems reduce incentives for living donations, which explains our findings for kidneys. The results imply that focusing on deceased-donor transplantation rates alone paints an incomplete picture of opt-out systems' benefits, and that there are important differences between organs in this respect.

Ethical decision-making in simultaneous heart-liver transplantation.

PURPOSE OF REVIEW: Simultaneous heart-liver (SHL) transplants are only a small proportion of overall heart and liver transplantation, they have been increasing in frequency and thus challenge the equitable allocation of organs. RECENT FINDINGS: The incidence of SHL transplants is reviewed along with the outcomes of SHL transplants and their impact on the waitlist, particularly in the context of solitary heart and liver transplantation. The ethical implications, most importantly the principles of utility and equity, of SHL transplant are addressed. In the context of utility, the distinction of a transplant being life-saving versus life-enhancing is investigated. The risk of hepatic decompensation for those awaiting both solitary and combined organ transplantation is an important consideration for the principle of equity. Lastly, the lack of standardization of programmatic approaches to SHL transplant candidates, the national approach to allocation, and the criteria by which programs are evaluated are reviewed. SUMMARY: As with all multiorgan transplantation, SHL transplantation raises ethical issues of utility and equity. Given the unique patient population, good outcomes, lack of alternatives, and overall small numbers, we feel there is continued ethical justification for SHL, but a more standardized nationwide approach to the evaluation, listing, and allocation of organs is warranted.

Delayed Implantation of Pumped Kidneys Decreases Renal Allograft Futility in Combined Liver-Kidney Transplantation.

BACKGROUND: Combined liver-kidney transplantation (CLKT) improves survival for liver transplant recipients with renal dysfunction; however, the tenuous perioperative hemodynamic and metabolic milieu in high-acuity CLKT recipients increases delayed graft function and kidney allograft failure. We sought to analyze whether delayed KT through pumping would improve kidney outcomes following CLKT. METHODS: A retrospective analysis (University of California Los Angeles [n = 145], Houston Methodist Hospital [n = 79]) was performed in all adults receiving CLKT at 2 high-volume transplant centers from February 2004 to January 2017, and recipients were analyzed for patient and allograft survival as well as renal outcomes following CLKT. RESULTS: A total of 63 patients (28.1%) underwent delayed implantation of pumped kidneys during CLKT (dCLKT) and 161 patients (71.9%) received early implantation of nonpumped kidneys during CLKT (eCLKT). Most recipients were high-acuity with median biologic model of end-stage liver disease (MELD) score of, 35 for dCLKT and 34 for eCLKT (P = ns). Pretransplant, dCLKT had longer intensive care unit stay, were more often intubated, and had greater vasopressor use. Despite this, dCLKT exhibited improved 1-, 3-, and 5-year patient and kidney survival (P = 0.02) and decreased length of stay (P = 0.001), kidney allograft failure (P = 0.012), and dialysis duration (P = 0.031). This reduced kidney allograft futility (death or continued need for hemodialysis within 3 mo posttransplant) for dCLKT (6.3%) compared with eCLKT (19.9%) (P = 0.013). CONCLUSIONS: Delayed implantation of pumped kidneys is associated with improved patient and renal allograft survival and decreased hospital length of stay despite longer kidney cold ischemia. These data should inform the ethical debate as to the futility of performing CLKT in high-acuity recipients.

Liver transplant for alcoholic hepatitis: a current clinical overview.

INTRODUCTION: Current management of severe alcoholic hepatitis is based on corticosteroid therapy and abstinence from alcohol. As liver transplantation is lifesaving in alcoholic hepatitis patients at high risk of early death, refractory alcoholic hepatitis has become a new indication for liver transplantation in highly selected non-responders to corticosteroids. AREAS COVERED: This review summarizes the conditions under which liver transplantation may be considered, the available data on liver transplantation for refractory alcoholic hepatitis and explores the ethical considerations surrounding the use of liver transplantation in these patients. EXPERT OPINION: Selection of candidates should be made according to available scientific results on post-liver transplantation outcomes and the risk of alcohol relapse. Currently, a strict selection process based on a good psychosocial profile, including social stability, no previous treatments for alcohol dependence, no current drug use, and no co-existing severe mental disorder, seems to be the best way to manage these issues. Well-defined selection criteria for candidate selection and accurate tools to predict alcohol relapse after liver transplantation are still needed.

An international multicenter study of protocols for liver transplantation during a pandemic: A case for quadripartite equipoise.

BACKGROUND & AIMS: The outbreak of COVID-19 has vastly increased the operational burden on healthcare systems worldwide. For patients with end-stage liver failure, liver transplantation is the only option. However, the strain on intensive care facilities caused by the pandemic is a major concern. There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources. METHODS: We performed an international multicenter study of transplant centers to understand the evolution of policies for transplant prioritization in response to the pandemic in March 2020. To describe the ethical tension arising in this setting, we propose a novel ethical framework, the quadripartite equipoise (QE) score, that is applicable to liver transplantation in the context of limited national resources. RESULTS: Seventeen large- and medium-sized liver transplant centers from 12 countries across 4 continents participated. Ten centers opted to limit transplant activity in response to the pandemic, favoring a "sickest-first" approach. Conversely, some larger centers opted to continue routine transplant activity in order to balance waiting list mortality. To model these and other ethical tensions, we computed a QE score using 4 factors - recipient outcome, donor/graft safety, waiting list mortality and healthcare resources - for 7 countries. The fluctuation of the QE score over time accurately reflects the dynamic changes in the ethical tensions surrounding transplant activity in a pandemic. CONCLUSIONS: This four-dimensional model of quadripartite equipoise addresses the ethical tensions in the current pandemic. It serves as a universally applicable framework to guide regulation of transplant activity in response to the increasing burden on healthcare systems. LAY SUMMARY: There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources during the COVID-19 pandemic. We describe a four-dimensional model of quadripartite equipoise that models these ethical tensions and can guide the regulation of transplant activity in response to the increasing burden on healthcare systems.

Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19), the illness caused by the SARS-CoV-2 virus, is rapidly spreading throughout the world. Hospitals and healthcare providers are preparing for the anticipated surge in critically ill patients, but few are wholly equipped to manage this new disease. The goals of this document are to provide data on what is currently known about COVID-19, and how it may impact hepatologists and liver transplant providers and their patients. Our aim is to provide a template for the development of clinical recommendations and policies to mitigate the impact of the COVID-19 pandemic on liver patients and healthcare providers. APPROACH AND RESULTS: This article discusses what is known about COVID-19 with a focus on its impact on hepatologists, liver transplant providers, patients with liver disease, and liver transplant recipients. We provide clinicians with guidance for how to minimize the impact of the COVID-19 pandemic on their patients' care. CONCLUSIONS: The situation is evolving rapidly, and these recommendations will need to evolve as well. As we learn more about how the COVID-19 pandemic impacts the care of patients with liver disease, we will update the online document available at https://www.aasld.org/about-aasld/covid-19-and-liver.

Is there an ethical obligation to split every donor liver? Scarce resources, medical factors, and ethical reasoning.

SLT has the potential to counter the worldwide shortage of donor organs. Although the preferred recipients of SLT are usually pediatric patients, a more stringent ethical argument than the fundamental prioritization of children is to demonstrate that SLT of deceased donor organs could increase access to this potentially lifesaving resource for all patients, including children. Several empirical studies show that SLT also makes it possible to achieve similar outcomes to WLT in adults if several factors are observed. In general, it can be regarded as ethically permissible to insist on splitting a donor liver if, in an individual case, SLT is expected to have a similar outcome to that of WLT. The question is therefore no longer whether, but under what conditions SLT is able to achieve similar results to WLT. One of the main challenges of the current debate is the restricted comparability of the available data. We therefore have an ethical obligation to improve the available empirical data by implementing prospective clinical studies, SLT programs, and national registries. The introduction of 2 modes of allocation-one for patients willing to accept both SLT and WLT, and a second for patients only willing to accept WLT-would help to resolve the issue of patient autonomy in the case of mandatory splitting policy.

Needs must: living donor liver transplantation from an HIV-positive mother to her HIV-negative child in Johannesburg, South Africa.

The world's first living donor liver transplant from an HIV-positive mother to her HIV-negative child, performed by our team in Johannesburg, South Africa (SA) in 2017, was necessitated by disease profile and health system challenges. In our country, we have a major shortage of donor organs, which compels us to consider innovative solutions to save lives. Simultaneously, the transition of the HIV pandemic, from a death sentence to a chronic illness with excellent survival on treatment required us to rethink our policies regarding HIV infection and living donor liver transplantation . Although HIV infection in the donor is internationally considered an absolute contraindication for transplant to an HIV-negative recipient, there have been a very small number of unintentional transplants from HIV-positive deceased donors to HIV-negative recipients. These transplant recipients do well on antiretroviral medication and their graft survival is not compromised. We have had a number of HIV-positive parents in our setting express a desire to be living liver donors for their critically ill children. Declining these parents as living donors has become increasingly unjustifiable given the very small deceased donor pool in SA; and because many of these parents are virally suppressed and would otherwise fulfil our eligibility criteria as living donors. This paper discusses the evolution of HIV and transplantation in SA, highlights some of the primary ethical considerations for us when embarking on this case and considers the new ethical issues that have arisen since we undertook this transplant.

Bi-organ paired exchange-Sentinel case of a liver-kidney swap.

Organ transplantation is the optimal treatment for patients with end stage liver disease and end stage renal disease. However, due to the imbalance in the demand and supply of deceased organs, most transplant centers worldwide have consciously pursued a strategy for living donation. Paired exchanges were introduced as a means to bypass various biologic incompatibilities (blood- and tissue-typing), while expanding the living donor pool. This shift in paradigm has introduced new ethical concerns that have hitherto been unaddressed, especially with nondirected, altruistic living donors. So far, transplant communities have focused efforts on separate liver- and kidney-paired exchanges, whereas the concept of a transorgan paired exchange has been theorized and could potentially facilitate a greater number of transplants. We describe the performance of the first successful liver-kidney swap.

Malleable Transplant Criteria: At What Cost?

An 18-year-old male who had been diagnosed at age 7 with a rare, progressive liver disease was referred to the transplant center and received a transplant, even though he did not meet the center's criteria for a patient with hepatopulmonary syndrome (HPS). Complications required relisting the patient urgently, but he eventually fully recovered; total hospital charges for his treatment exceeded $5 million. Reflection upon the case resulted in analysis of two ethical questions: primarily, clinician obligation to balance the provision of actuarially fair health care to society against the healing of a single patient; secondarily, the effects of malleable transplant criteria on trust in the patient selection process. We affirmed that physicians should not be principally responsible for justifying financial investment to society or for upholding beneficence beyond the individual physician and patient relationship in order to contain costs. We concluded, however, that such instances, when combined with manipulation of transplant center criteria, pose a potential threat to public trust. We therefore suggested that transplant centers maintain independent ethics committees to review such cases.

Evolving swaps in transplantation: global exchange, vouchers, liver, and trans-organ paired exchange.

PURPOSE OF REVIEW: With the ongoing organ shortage, several mechanisms to facilitate organ exchanges and expand the scope of living kidney or liver donation have been proposed. Although each addresses at least one barrier to transplantation, these innovative programs raise important ethical, logistical, and regulatory considerations. RECENT FINDINGS: This review addresses four recent proposals to expand living donor transplantation. For kidney transplantation, we discuss global paired exchange and advanced donation programs ('vouchers') and for liver transplantation, liver paired exchange. Lastly, this review considers trans-organ exchange. We explore the conceptual framework of the exchange, current status, benefits, and concerns for implementation among each of these evolving pathways. SUMMARY: Through highlighting novel mechanisms in organ exchange, greater awareness, discussion, or support can occur to create more avenues for transplantation. These innovative mechanisms require regulations and safeguards for donors to ensure informed consent, and proper follow-up is maintained.

Ethical dilemmas related to living donor liver transplantation in Asia.

Living donor liver transplantation (LDLT) has evolved rapidly in Asia with good outcomes for both donor and recipient. Nonetheless, LDLT remains a highly demanding technique and complex surgery. The potential risks to the donors provide the basis for many of the ethical dilemmas associated with LDLT. The transplant team must have a good knowledge of the principles of bioethics in order to handle these matters. To look after the need, donor's safety and the chance for good recipient outcomes, the principles of respect for the donor's autonomy, beneficence, and non-maleficence should be practiced. In accordance with the concept of equipoise, the risk to the donor must balance the benefit to the recipient. The transplant center should have adequate experience and proven expertise in LDLT. There are concerns regarding the validity of informed consent given by the donor. While donations to non-relative patients may, at first sight, indicate radical altruism, it is important to apply careful scrutiny. Though organ trading is strictly prohibited by the law, there seems to be an inherent risk with directed donations to strangers. Transplant tourism has flourished in some countries in spite of the existence of strict laws. There are reservations regarding transplantation done by foreign visiting teams. Donor websites facilitating patients and donors and Facebook pages bear no responsibility for the outcomes of their matches and cannot ensure sufficient and accurate information about donation, transplantation, and post-operation life. Telemedicine and virtual consultations appeared to work better when the clinician and the patient know and trust each other.

Combined liver-lung transplantation: Indications, outcomes, current experience and ethical Issues.

Combined liver-lung transplantation (CLLT) is a rare, life-saving procedure to treat concomitant lung and liver disease. There have been 93 combined lung and liver transplantations performed in the United States since 1994. Techniques include both lung first and liver first sequential transplants with selective extracorporeal circulation of either thoracic or abdominal portions, with either end-to-end or Roux-en-Y choledochojejunostomy for biliary reconstruction. This review evaluates the existing literature regarding combined lung and liver transplantation (CLLT), describing the candidates, operation, perioperative complications, associated management strategies, and recommendations for immunosuppressive therapy and follow up.

Transplantation for Alcoholic Hepatitis: Are We Achieving Justice and Utility?

Early liver transplantation for alcoholic hepatitis is a potentially life-saving treatment. As this practice becomes increasingly common, however, the liver transplant community is taking a fresh look at a familiar challenge: best stewardship of donor organs. Herein, we examine a few basic, necessary ethical and practical concerns relevant to this indication.

Liver transplantation for critically ill cirrhotic patients: Overview and pragmatic proposals.

Liver transplantation for critically ill cirrhotic patients with acute deterioration of liver function associated with extrahepatic organ failures is controversial. While transplantation has been shown to be beneficial on an individual basis, the potentially poorer post-transplant outcome of these patients taken as a group can be held as an argument against allocating livers to them. Although this issue concerns only a minority of liver transplants, it calls into question the very heart of the allocation paradigms in place. Indeed, most allocation algorithms have been centered on prioritizing the sickest patients by using the model for end-stage liver disease score. This has led to allocating increasing numbers of livers to increasingly critically ill patients without setting objective or consensual limits on how sick patients can be when they receive an organ. Today, finding robust criteria to deem certain cirrhotic patients too sick to be transplanted seems urgent in order to ensure the fairness of our organ allocation protocols. This review starts by fleshing out the argument that finding such criteria is essential. It examines five types of difficulties that have hindered the progress of recent literature on this issue and identifies various strategies that could be followed to move forward on this topic, taking into account the recent discussion on acute on chronic liver failure. We move on to review the literature along four axes that could guide clinicians in their decision-making process regarding transplantation of critically ill cirrhotic patients.

Liver transplantation and alcoholic liver disease: History, controversies, and considerations.

Alcohol consumption accounts for 3.8% of annual global mortality worldwide, and the majority of these deaths are due to alcoholic liver disease (ALD), mainly alcoholic cirrhosis. ALD is one of the most common indications for liver transplantation (LT). However, it remains a complicated topic on both medical and ethical grounds, as it is seen by many as a "self-inflicted disease". One of the strongest ethical arguments against LT for ALD is the probability of relapse. However, ALD remains a common indication for LT worldwide. For a patient to be placed on an LT waiting list, 6 mo of abstinence must have been achieved for most LT centers. However, this "6-mo rule" is an arbitrary threshold and has never been shown to affect survival, sobriety, or other outcomes. Recent studies have shown similar survival rates among individuals who undergo LT for ALD and those who undergo LT for other chronic causes of end-stage liver disease. There are specific factors that should be addressed when evaluating LT patients with ALD because these patients commonly have a high prevalence of multisystem alcohol-related changes. Risk factors for relapse include the presence of anxiety or depressive disorders, short pre-LT duration of sobriety, and lack of social support. Identification of risk factors and strengthening of the social support system may decrease relapse among these patients. Family counseling for LT candidates is highly encouraged to prevent alcohol consumption relapse. Relapse has been associated with unique histopathological changes, graft damage, graft loss, and even decreased survival in some studies. Research has demonstrated the importance of a multidisciplinary evaluation of LT candidates. Complete abstinence should be attempted to overcome addiction issues and to allow spontaneous liver recovery. Abstinence is the cornerstone of ALD therapy. Psychotherapies, including 12-step facilitation therapy, cognitive-behavioral therapy, and motivational enhancement therapy, help support abstinence. Nutritional therapy helps to reverse muscle wasting, weight loss, vitamin deficiencies, and trace element deficiencies associated with ALD. For muscular recovery, supervised physical activity has been shown to lead to a gain in muscle mass and improvement of functional activity. Early LT for acute alcoholic hepatitis has been the subject of recent clinical studies, with encouraging results in highly selected patients. The survival rates after LT for ALD are comparable to those of patients who underwent LT for other indications. Patients that undergo LT for ALD and survive over 5 years have a higher risk of cardiorespiratory disease, cerebrovascular events, and de novo malignancy.

Transplanting organs from hepatitis B positive donors: Is it safe? Is it ethical?

Liver transplant centres throughout the USA face a huge shortage of liver organs for their wait-listed patients. Various types of innovations are being considered for expansion of this donor pool. Organs that were previously deemed to be high risk are now being considered for transplantation. For the last 25 years, hepatitis B core antibody (anti-HBc+) organs have been used for liver transplantation. While the initial transplantations did reveal a high incidence of de novo hepatitis (DNH) in the recipients, the medical knowledge and experience have evolved and this risk has been markedly decreased. In this paper, medical literature evaluating the safety of such organ transplants has been reviewed. There is strong evidence to suggest that using anti-HBc+ organs with appropriate prophylaxis after transplant is a safe practice with good patient and graft survivals. In the second half of the paper, we discuss whether it is ethical to use anti-HBc+ organs. We argue that the use of such organs is in compliance with the principles of medical ethics and that society at large benefits from the use of these organs. Hence, we recommend that the use of such organs is both safe and ethical and this practice should be continued in the future.

Swaps and Chains and Vouchers, Oh My!: Evaluating How Saving More Lives Impacts the Equitable Allocation of Live Donor Kidneys.

Live kidney donation involves a delicate balance between saving the most lives possible and maintaining a transplant system that is fair to the many thousands of patients on the transplant waiting list. Federal law and regulations require that kidney allocation be equitable, but the pressure to save patients subject to ever-lengthening waiting times for a transplant has been swinging the balance toward optimizing utility at the expense of justice. This article traces the progression of innovations created to make optimum use of a patient's own live donors. It starts with the simplest - direct donation by family members - and ends with voucher donations, a very recent and unique innovation because the donor can donate 20 or more years before the intended recipient is expected to need a kidney. In return for the donation, the intended recipient receives a voucher that can be redeemed for a live kidney when it is needed. Other innovations that are discussed include kidney exchanges and list paired donation, which are used to facilitate donor swaps when donor/recipient pairs have incompatible blood types. The discussion of each new innovation shows how the equity issues build on each other and how, with each new innovation, it becomes progressively harder to find an acceptable balance between utility and justice. The article culminates with an analysis of two recent allocation methods that have the potential to save many additional lives, but also affirmatively harm some patients on the deceased donor waiting list by increasing their waiting time for a life-saving kidney. The article concludes that saving additional lives does not justify harming patients on the waiting list unless that harm can be minimized. It also proposes solutions to minimize the harm so these new innovations can equitably perform their intended function of stimulating additional transplants and extending the lives of many transplant patients.