Best Practice & Research Clinical Gastroenterology 28 (2014) 281–292

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Best Practice & Research Clinical Gastroenterology

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Liver, pancreas and small bowel transplantation: Current ethical issues Gert van Dijk, MA, Assistant Professor of Medical Ethics and Philosophy a, *, Medard Hilhorst, M.Sc., M.Th., Ph.D., Associate Professor of Medical Ethics and Philosophy a, Edmond Rings, M.D., Ph.D., Pediatrician, Professor of Pediatrics b, c,1 a

Department of Medical Ethics and Philosophy of Health Care, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands b Department of Pediatrics, Sophia Children’s Hospital, Erasmus Medical Center, Rotterdam, The Netherlands c Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands 1 Address: P.O. Box 2040, 3000 CA Rotterdam, The Netherlands

a b s t r a c t Key words: Liver transplantation Pancreas transplantation Small bowel transplantation Kidney transplantation Donation Consent Risks Benefits Fairness

We describe the medical state of the art in liver, pancreas and small bowel transplantation, and portray the ethical issues. Although most ethical questions related to these transplantations are not specific for liver, pancreas and small bowel, they do challenge ethical analysis as well as new policies and clinical procedures. Firstly, outcomes continue to be of utmost concern, as information is only limited available, is developing over time and is surrounded by many uncertainties. Secondly, characteristics of donors and recipients should be carefully evaluated. The question of what qualifies a donor and a recipient should be considered against the background of a quest for extended criteria, embracing marginal cases, and a judgment with regard to what counts as a good enough outcome. Thirdly, ethical principles of autonomy and fairness are pushed, given the circumstance of severe scarcity, towards limits that can easily be crossed. Ó 2014 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: þ31 10 7038482. E-mail addresses: [email protected] (G. van Dijk), [email protected] (M. Hilhorst), [email protected] (E. Rings). http://dx.doi.org/10.1016/j.bpg.2014.02.003 1521-6918/Ó 2014 Elsevier Ltd. All rights reserved.

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Introduction: current medical possibilities in liver, pancreas and small bowel transplantation The first section deals with relevant medical possibilities in the field of liver, pancreas and small bowel transplantation. Different types of transplants for different recipients will be outlined, as well as the current state of the art. In the second section the ethical issues are portrayed, by referring to the prevailing ethical framework, the ethical challenges, and the actual issues still subject of ethical debate. Liver Orthotopic liver transplantation (OLT) is the definitive treatment for end-stage liver disease in both children and adults. Advances over the past decades have resulted in excellent patient and graft survival rates in what were previously cases of fatal disorders [1,2]. These developments have been due to innovations in surgical technique, increased surgical experience, refinements in immunosuppressive drugs and regimens, quality improvements in intraoperative anaesthetic management, better understanding of the pathophysiology of the liver diseases, and better preoperative and postoperative care. This part of the review will discuss the major aspects of liver transplantation with respect to surgical technical considerations for orthotopic liver transplantation, indication for transplantation, optimal timing of liver transplantation, and patient and graft survival outcomes. Post-mortem donors Establishment of standard liver transplantation techniques in which post-mortem donors are most frequently used, development of immunosuppressive medications and accumulated experience using them safely, and improvement of intensive care and anaesthesia played major role to have current 88%–90% one-year survival after liver transplantation [3]. Living-related liver transplantation Living donor liver transplantation (LDLT) is a well-established strategy to plan the procedure and to decrease the mortality in the waiting list and recent studies have demonstrated its value even in patients with low model for end-stage liver disease (MELD) score. However, LDLT is still under a high level of scrutiny because of ethical and logistical challenges as demonstrated by a decline in the number of procedures performed in the last decade in Western Countries. Many aspects make LDLT different from deceased donor liver transplantation, including timing of transplantation, procedure-related complications in donor and recipient, as well as immunological factors that may affect graft outcomes. In selected cases, LDLT offers advantages over deceased donor liver transplantation [4]. Advantages include controlled timing of the procedure and sophisticated collection of anatomical and biological information of the donor. Living donor liver transplantation (LDLT), originally used in children with left lateral segment grafts, has been expanded to adults who require larger grafts to support liver function. Most adult LDLT procedures have been performed with right lobe grafts, and this means a significant risk of morbidity for the donors. To minimise the donor risk, there is renewed interest in smaller left lobe grafts. The smaller graft size increases the recipient risk in the form of small-for-size syndrome (SFSS), which results in suboptimal perfusion and function of the graft. This essentially transfers the risk from the donor to the recipient. The surgical team has to pay particular attention to the different types of liver grafts and the use of graft inflow modification to ameliorate the risk of SFSS. Adult-to-adult (AA) LDLT is viewed as a viable alternative to whole liver transplantation on the treatment of end-stage liver disease. Over the past two decades, right lobe AA-LDLT has been the standard because of concerns related to graft size. SFSS is an entity that presents in recipients of small grafts. It negatively affects patient and graft survival and recipients of grafts with a graft weight-torecipient weight ratio (GW/RW) lower than 1.0 being at the highest risk. Over the last decade, our understanding of SFSS has identified portal vein pressure (PVP) as a major determinant in the development of SFSS. Direct or indirect surgical PVP modulation has demonstrated a way to prevent the

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development of SFSS in recipients of small grafts and has improved the survival outcomes of small grafts. These improved outcomes coupled with concerns for donor safety have led to the renaissance of the use of left lobe grafts. Based on the current clinical data, the use of small grafts GW/RW greater than 0.6 is viewed as well as tolerated when PVP is modulated to achieve a target PVP less than 15 mmHg after reperfusion and the left lobe is currently viewed as the ideal graft for AA-LDLT [5]. Split liver transplantation As liver transplantations became more successful with the growing experience and development in the field, the increased demand for liver allografts could not match the available supply of donor organs. As a result of this imbalance, each year nearly 3,000 patients die in the United States awaiting liver transplantation on the national waiting list. Split liver transplantation (SLT) has been perceived as an important strategy to increase the supply of liver grafts by creating two transplants from one allograft [6,7]. The bipartition of a whole liver also carries utmost importance by increasing the available grafts for the pediatric patients, where size-matched whole liver allografts are scarce, leading to increased incidence of waiting list mortality in this group. In the common approach of the split liver procedure, a liver is divided into a left lateral segment graft (LLS) to be transplanted to a child and a right extended liver lobe graft for an adult recipient. In a technically more challenging variant of this procedure, the principle is to split the liver into two hemigrafts and use the left side for a small adult or a teenager and the right for a medium-sized adult patient. Donor selection for splitting, technical expertise in both OLT and hepatobiliary surgery, logistics to decrease total ischaemia time, and manpower of the transplantation team are important factors for successful outcomes after SLT. The liver can be split on the back table (ex situ) or in the donor hospital before the donor cross-clamp using in situ splitting technique, which was developed directly from living donor liver transplantation. The most important advantage of in situ splitting is to decrease the total ischaemia time and increase the possibility of inter-centre sharing. The in situ technique of splitting has other advantages, including evaluation of the viability of segment IV in case of LLS splitting and better control of bleeding from cut surface upon reperfusion on the recipient. Recipient selection for split liver grafts is also crucial for success after SLT. Remarkably, the use of split-liver and living-related liver transplantation surgical techniques has helped mitigate the well-recognised organ shortage. Sequential (domino) liver transplantation Improved outcomes have expanded the indications for liver transplantation, thus aggravating the already limited supply of donor organs. One particularly innovative strategy is sequential (domino) liver transplantation in which a select group of liver transplant recipients can donate their explanted native livers for use as liver grafts in other patients. Several hereditary metabolic diseases (such as familial amyloid polyneuropathy, maple syrup urine disease, and familial hypercholesterolemia) are caused by aberrant or deficient protein production in the liver, and these conditions can be cured with an orthotopic liver transplant. Although their native livers eventually caused severe systemic disease in these patients, these livers are otherwise structurally and functionally normal, and they have been used successfully in domino liver transplants for the past two decades [8]. To qualify for a domino liver transplantation, the following preconditions must be fulfilled: (1) extrahepatic disease must exist, (2) liver must be fully functional, and (3) the genetic defect in the host should recur within a sufficient latency period. Pancreas Pancreas transplant is most commonly performed along with kidney transplant in diabetic end-stage renal disease patients. Pancreas transplantation consistently induces insulinindependence in beta-cell-penic diabetic patients, but at the cost of major surgery and life-long immunosuppression. One year after grafting, patient survival rate now exceeds 95% across recipient categories, while insulin independence is maintained in some 85% of simultaneous pancreas and kidney recipients and in nearly 80% of solitary pancreas transplant recipients. The

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half-life of the pancreas graft currently averages 16.7 years, being the longest among extrarenal grafts, and substantially matching the one of renal grafts from deceased donors. The difference between expected (100%) and actual insulin-independence rate is mostly explained by technical failure in the postoperative phase, and rejection in the long-term period. Death with a functioning graft remains a further major issue, especially in uraemic patients who have undergone prolonged periods of dialysis. Refinements in graft preservation, surgical techniques, immunosuppression, and prophylactic treatments are expected to further improve the results of pancreas transplantation. The comprehensive follow-up data reported to the International Pancreas Transplant Registry (IPTR) has revealed that as of December 2010, more than 35,000 pancreas transplantations have been reported to the IPTR: more than 24,000 transplantations in the US and more than 12,000 outside the US. Cases with follow-up information until March 2011 were included in the analysis. Pancreas transplantations in diabetic patients were divided into three categories: those performed simultaneously with a kidney (SPK) (75%), those given after a previous kidney transplantation (PAK) (18%), and pancreas transplantation alone (PTA) (7%). The total number of pancreas transplantations steadily increased until 2004 but has since declined. The largest decrease was seen in PAK, which decreased by 50% from 2004 to 2010. Comparatively, the number of SPK decreased by 7% during this time. Era analysis of US transplantations between 1987 and 2010 showed changes in recipient and donor characteristics. Recipient age at transplantation increased significantly as well as transplantations in type 2 diabetes patients. The trend over time was towards tighter donor criteria. There was a concentration on younger donors, preferable trauma victims, with short preservation time. Surgical techniques for the drainage of the pancreatic duct changed over time, too. Now enteric drainage is the predominantly used technique in combination with systemic drainage of the venous effluent of the pancreas graft. Immunosuppressive protocols developed towards antibody induction therapy with tacrolimus and MMF as maintenance therapy. The rate of transplantations with steroid avoidance increased over time in all three categories [9–13]. Small bowel Intestinal transplantation includes a heterogeneous group of procedures in which different compositions of organs are transplanted. The current classification includes four groups according to the inclusion of the liver and/or the stomach in the graft: isolated intestinal transplantation, liver-intestinal transplantation, multivisceral transplantation, and modified multivisceral transplantation [14,15]. Variants exist, the technical evolution having been slow, yet constant over years. The most relevant early technical improvements were aimed at achieving better feasibility and safety of the most difficult aspects of the different procedures, such as removal of the recipient’s diseased organs, performing of vascular reconstructions and prevention of complications as with retention of the donor’s duodenum and pancreas in liver-intestine transplantation. More recently, apart from a clear definition of the classification of the procedures, progress has been more directed in a conservative direction such as the preservation of the native spleen with and without the pancreas in multivisceral transplants. With new tactics to further improve long-term survival including social support measures, visceral transplantation has achieved excellent nutritional autonomy and good quality of life [14,15]. After achieving consistent satisfactory short-term results, the technical interest in intestinal transplantation is now moved to solutions that, in spite of a possible increased difficulty, may offer better opportunities of mid-term and long-term successes, both in terms of survival and quality of life. The comprehensive follow-up data reported to the Intestinal Transplant Registry (ITR) has revealed that as of June 2013, almost 3,000 intestinal transplantations worldwide have been reported to the ITR: Half of the patients are younger than 18 years. The ethical challenge The preceding description of the state of the art points to all kinds of ethical questions. Most of them are familiar and do not require a new ethical framework [16]. Concerns refer to the donor, the recipient(s), and their particular relationship – if any – to each other. The assessment of risks and

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uncertainties, autonomy and consent, and the proportionality of benefits and harms are guiding our policies and decisions. In addition, society is involved, by setting a legal and financial framework for common practices and new developments. Ethical principles of fairness direct the allocation and retrieval of organs and procedural safeguards are in place to protect human subjects. Finally, professional responsibility is called for in order to make sure that ethically justified clinical decisions are made and professionals behave ethically in ordinary situations as well as under new circumstances [17–22]. However, in liver, pancreas and bowel transplantation, as depicted above, some issues should deserve special attention. Firstly, outcomes should be of constant concern, as information is only limited available [16]. The weighing of benefits, risks and harms changes continually over time. In particular in small bowel transplantations, the pressing question is how we should delicately balance short- and long-term successes, survival and quality of life, and weigh the fact that relatively many young recipients (minors) qualify for transplantation. Have we been right in treating these patients despite the long-term uncertainties? What counts as good enough outcomes and can parental consent simply justify a treatment? [16] Secondly, shifts in recipient and donor characteristics should be carefully evaluated: a significant increase of recipient age and of type 2 diabetes patients in pancreas transplantations reflect the prevailing nature of pancreas scarcity. At the same time, a trend towards tighter donor criteria, younger donors, and a decrease in the number of pancreas transplantations, suggest a certain restraint in clinical practice. What precisely establishes the balance: harm, success, and autonomy? Also in living liver transplantation a decline in the number of transplantations has been found. Although expanded to adult recipients, the risks of morbidity for the donors are significant. When balancing risks, one issue shows up in particular: is it ethically justified to plainly weigh the risks for the donor against those for the recipient? Or should the protection of the donor be our first and foremost concern? When the Ethics Statement of the Vancouver Forum (the Ethics Committee of The Transplantation Society TTS, meeting in 2006) declares that we should aggregate benefits of the donor–recipient pair and aggregate risks for the pair, and weigh them, even more questions come up [16]. Thirdly, the development of split liver and domino liver transplants has raised questions with respect to the acquisition and allocation of organs: expanded indications for recipients, even with low priority, and specific donor and recipient selection, including children, in which time constraints and logistics play a crucial role. How to optimise outcomes and nonetheless give due weight to considerations of fairness? As always, there will be a tension between what we ideally aim for and the actual options at hand, in particular tough when confronted with the choice for marginal donors and expanded criteria for recipients [23]. In sum, despite the settled ethical framework we have, it requires careful analysis when applying general principles to the particulars of each situation. Hereafter, most significant ethical issues are discussed in relation to post-mortal and living donors, harm, benefits, autonomy, fairness, contra-indications with regard to lifestyle, and procedural safeguards. Post-mortal donors Two types of post-mortal donors can be distinguished: Donors after Brain Death (DBD) and Donors After Cardiac Death (DCD). DBD-donors, also known as Heart-beating or HB-donors, are donors with severe brain damage, generally from CVA or trauma, that have been pronounced brain dead after a strict procedure for diagnosing brain death has been followed. DCD-donors, also referred to as Non-Heart-beating or NHB-donors, are not brain dead, but are pronounced dead after circulatory arrest. Categories of DCD-donors are discerned in the so called Maastricht criteria [24]. The ‘controlled’ DCD type III donors are most commonly retrieved for transplantation, patients with severe brain trauma, who do not meet the formal criteria of brain death. Due to the poor prognosis, further life support is deemed futile. After the decision to withdraw life support is taken, the physician seeks permission from the relatives for organ donation. When granted, life support is withdrawn. After circulatory arrest, that has to occur within a specified time frame, and a certain period of ‘no touch’ (generally five minutes) the organs can be

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removed. Due to the ischaemic time, mostly kidneys, livers and pancreases can be successfully transplanted from DCD-donors [25]. Currently DCD donation is therefore not a viable option for transplantation of pancreas and bowel. While illegal in certain countries (e.g. Germany), and subject of ethical debate, DCD donors now comprise the majority of donors in other countries, such as the Netherlands, as confirmed in the EULOD report, comprising results and recommendations of a coordinated action on Living organ donation in Europe [26]. Conditions and safeguards have been further discussed and refined, but may also be relative to the availability of living donors, as a more or less desirable option [4]. Ethical issues in deceased donation include definitions of death, interventions to keep organs in good condition before death is pronounced, and the acceptability and range of presumed consent. Living donors Due to the scarcity of post-mortal organ donors, there has been an increasing interest in LDLT. While medically and ethically controversial due to the risks for the donor, especially in Western European countries, LDLT has become an accepted procedure [4,26]. Living donors are classified by a working group of ELPAT, a European platform on ethical, legal and psychological organ donation [27] into specified and unspecified, directed and undirected, related and unrelated living donors. Developments in living kidney donation have set the agenda. Specified direct living donors donate directly to the intended recipient, for instance a parent to a child, or one spouse to another. When no genetic relationship exists between donor and recipient the donation is called ‘directed, unrelated’. In case of incompatibility, direct donation is not an option, but it is still possible to specify the intended recipient when donating to ‘a pool’ of potential recipients. In these cases, the donation is called ‘specified indirect donation’, to be accomplished through an exchange program (paired exchange or domino-paired). Secondly, living donation can be ‘unspecified’, rooted in a mainly altruistically motivated act, also referred to as ‘Samaritan’. These donors give (part of) an organ anonymously, without knowledge of the recipient (and vice versa). As a matter of principle the organs should be allocated to the most needy on the waiting list. However, in living kidney transplantation these organs are often utilised to start a chain of ‘domino’ transplantations, with permission of the donor, thus maximising the number of transplantations [28–30]. Due to the risks for the donor in living liver transplantation these anonymous liver donations are still rare [31,32], whereas close relationships between donor and recipient, family members as well as friends, are regular options. An issue of debate concerns anonymity: altruistic donations need not be anonymous per se, and ethical debate about the requirement of anonymity in exchange programs as well as in Samaritan donations is ongoing [33]. Moreover, at present personal contacts can easily be effectuated through digital media, internet and Facebook. This has led to quick, novel, new-defined relationships, hardly known before [34–36]. Vancouver recommendations point to ‘non-directed or distant acquaintance’, and the risk of donor exploitation that it can entail [16,37]. Harm Although living donation of kidneys is now considered an accepted, low risk procedure, living liver and bowel donation are still controversial, given the high risks for the donor. At issue is a basic problem in all living organ donation: are we allowed to harm one individual in order to benefit another? This is, no doubt, a violation of the ‘first do no harm’ principle, predominant in medicine. In living donation a third party gets involved, whose physical wellbeing is put at risk. The ethical justification is delicate and not always satisfactory, and the debate is not brought to an end. Should autonomy be given priority or harm, should the risks be decisive or the donor’s wish; where is the ‘equipoise’? If one tries to balance both principles, how to find the middle? When ‘the best interests’ principle is taken as guiding, whose perspective should get most weight: the donor’s, the patient’s or the professional’s viewpoint? In the end, of course, society has to decide what to permit within legal constraints, but this does not take away responsible clinical judgment [38–40].

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Given the risks in living liver transplantation, one may expect a higher threshold: clear benefits and no doubts regarding the voluntariness of the wish. In case of parent-to-child transplantations, risks are lower, but concerns are expressed about consent [41–46]. In this context the donation, even when autonomously made, can hardly be seen as a free choice. The interests of donor and recipient are entirely intertwined, which makes it difficult to assess them individually. The ethical justification can be found in the special relationship between parent and child: benefits to the child do not only compensate the harm to the parent, but imply also benefits to the parent. Best interests refer to both parent and child. Moreover, as the argument goes, choices in unfree situations can nevertheless be well informed and fully autonomous, and express a well-considered wish. The Nuffield Council on Bioethics, an independent body in the UK that is internationally respected, states that it is not required that informed consent is ‘complete’ but that it be ‘genuine’, freely given at the basis of relevant information in a comprehensive manner [47]. For sure, accurate safeguards should be in place to direct the process of decision making, which is in particular delicate in situations where time pressure pushes us to limits. Benefits Living organ transplantation is most successful where donors specify their intended recipient, and the procedure is performed either in a direct way or indirect through an exchange program. In these circumstances the special relationship is the key to understand the value and significance of the transplantation. Mostly, a strong emotional bond lies at the base of it, bonds between parents and children, spouses, family members, or friends. Although donor motives may differ considerably, and donation may be felt as a gift out of love, an act of reciprocity, or – in the end – of self-interest, prevailing ethical justification emphasises the often clear benefits to the donor, as a compensation for the harms and risks. Harm to the donor, besides physical harm, can include psychological harm but also financial harm, when the donor suffers complications. Benefits to the donor result directly from the improved health of a loved one, a higher quality of (shared) life in many respects, but also psychological benefits are noteworthy, for instance, a sense of satisfaction and fulfilment. Moreover, we should acknowledge that refusal of an offer by the transplantation centre can also have serious consequences for the potential donor, psychologically and materially. Given these highly relevant but diverse interests, procedural safeguards are of great significance to protect what should be protected in the first place, that is: the position of the donor. Donors should decide, free of coercion and not led by questionable motives. Most national laws and regulations exclude benefits in terms of financial payments, set aside as the wrong motive, and leading to exploitation [16,37], but ethical arguments supporting some form of financial reward remain omnipresent in the ethics literature [48,49]. Again, with regard to the proper benefits that could justify the transplantation, the hard kernel of the ethical debate is not taken away. On the one hand we have referred already to the Vancouver Forum [16], suggesting that benefits to a donor–recipient pair can be aggregated, as well as the risks to the pair aggregated, and outweighed – one may ask: simply, in an utilitarian way (by maximising outcomes)? On the other hand there are the Recommendations of an International Consensus Report [50] observing considerable disagreement among experts with respect to what the acceptable risk for the donor should be and expected survival threshold for the recipient – which seems to suggest a more Kantian approach (not all options are allowed, however large the benefits might be). When special relationships are seen as central in the ethical justification of living donations, nonspecified donations can easily lead to suspicion. If no bond exists, how then do we assess ‘altruistically’ (‘Samaritan’) motivated donations, when benefits to the donor are less evident? On the other hand, free choice, if ever, seems to be predominant under these circumstances. In living kidney donation, the number of unspecified donations is increasing significantly. Most donors are motivated by the prevailing organ scarcity and the suffering of patients in need, often – in some way or another – this suffering is part of their personal experience and life story. As evaluations over the years have shown, motives of these donors are genuine and their decisions well-considered [31,51] and provide no reason to reject their offer in advance as odd. A closer look reveals clear benefits to the donor: in terms of

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quality of life, personal values and self-esteem. Point of ethical debate still remains how strict assessment procedures should be required to test motives and willingness. Should, for instance, the absence of family support be a contra-indication; should a psychiatrist always be involved; should additional counselling be required in case the donation is motivated by a particular event in a donor’s life story to investigate whether the considerations are genuine? Or do we do injustice to these donors by treating them different from other donors? [31,32]. Autonomous wishes Informed consent is a necessary requirement to ethically justified living organ donation. It presupposes a well-considered, autonomous judgment based on the relevant facts. However, an autonomous wish can never be a sufficient justification [16]. For instance, a live heart donation, entire living liver donation or the donation of a second living kidney cannot be granted, even if the donor wishes to save the life of a beloved one. Both national laws and physician rules of ethical conduct rule out these options. Physicians are not only free to refuse, but have the duty not to honour every wish. Patients have no right to treatment that is judged futile, or that would endanger their health or lives, and consent in itself does not turn a potential donor into a donor. Additional justification is required and a better understanding of consent in theory and practice [52,53]. Nevertheless, in the clinic it still remains tempting to follow potential donors in their wish out of respect for their autonomy, a modern core principle in the doctor-patient relationship. In particular in cases of unspecified transplantation, potential donors cherish their own ideals and life projects, and sometimes refer for their wish to their own life-fulfilling ends. One then should be reminded of the core and limits of the medical profession: it is a transplant doctor’s mission to relieve the need of patients with organ failure, not to fulfil the personal projects of a donor. Altruistic donors can be welcomed as partners in the transplant mission, but their own needs and ambitions should not be part of the equation [54]. Fairness Organ scarcity induces questions of fairness: the fair acquisition and allocation of organs. It is important not to miss potential (deceased) donors and raise the numbers of transplantations (both deceased and living). A long history of debate has shown that donor acquisition systems (opt-in; opt-out; obligation to register; bonus points when registered) presuppose their own ideas of what fairness essentially is. Several principles have to be balanced: efficiency, autonomy, equality. The same is true for allocation systems. Best outcomes (maximum benefits) can be stressed, implying very strict indications and cost-effectiveness, but also a more equal allocation, with as a consequence broader indications, longer waiting lists, and less survival [67]. Allocation systems, transparent and based on objective criteria are ethically important, but fair allocation is more than a mathematical endeavour. This is why MELD or other models based on Milan or MORAL criteria will be debated all the time [38,55,56]. We should keep in mind that different views on fairness compete with each other, in particular utilitarian, Kantian, Rawlsian (with a particular focus on the least advantaged, vulnerable groups) notions. Veatch has pointed to the fact that different traditions and cultures – USA, UK, Europe – have found different solutions [17,19]. Most pressing is the question of how to include more marginal donors on the one hand, and more marginal patients, within extended criteria, on the other. In fact this concerns both donors and recipients in vulnerable positions: less healthy, more difficult to treat, children, sick, and others. No doubt, it is a challenge to reach international consensus, e.g. for hepatocellular carcinoma. But consensus meetings should not distract our attention from the fundamental ethical issues behind it, e.g. the above mentioned disagreement about a threshold or an aggregation perspective [50,57,58]. These issues cannot be solved by medical experts only, in the end they are ethical and political in nature, and concern the fair treatment of the most vulnerable groups [59–62]. Equally complex are fairness questions such as: why not reward those who register for deceased donation; should donor registration be a requirement for becoming a transplant recipient;

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can lifestyle – drinking, smoking, obesity – provide us with a reason to treat patients only conditionally? Another source of debate relates to the existence of two completely different systems ‘living apart together’: deceased and living transplantation. Both are governed by their own sets of ethical norms and principles, for acquisition as well as for allocation. The deceased donor system is mostly anonymous and impartial, the living donor system is mostly non-anonymously and partial. This causes all kinds of tensions, with respect to what fairness means [63,64]. For instance, patients who receive a ‘living’ kidney are in general much healthier than those on the waiting list when receiving a ‘deceased’ kidney. In fact, they bypass the waiting list, but can we say that they take priority over others, or that, if so, this is unfair? [36] It may also be that liver patients opt for living liver donation, in case they do not qualify for deceased donation [65], or for deceased donation when living liver transplantation has failed [66,67]. The ethics debate is, whether we should and can keep both systems strictly separate. Is it possible to defend two sets of fairness principles independent of each other, e.g. by establishing that living donations are not directed by general principles of efficiency and equality? Or should we conclude that this is highly unsatisfactory, given the fact that public money is involved, the needs of all patients should be addressed in equal respect, and that persistent tensions between both systems call for adaptations and new policies? A crucial element in this debate seems to be relative to context, the numbers of deceased and living transplantation in a country. This determines whether deceased donation is still the standard (norm), and living donation an exception (a last resort, or second best), or deceased is the exception, or becoming a less obvious possibility, and living donation the first and foremost option to consider [4,26]. Allocation and lifestyle Should lifestyle be a factor in patient selection? Lifestyle factors, such as smoking, alcohol abuse and other unhealthy behaviour can have a negative effect on the outcomes. Since long this has been debated: would it be permissible to exclude patients from transplant treatment or make lifestyle changes conditional? [68,69] Some claim that nicotine levels should be routinely checked and active smoking an exclusion criterion [70]. End stage alcoholic liver disease is an accepted contra-indication for transplantation. Moreover, patients with a history of alcohol abuse might relapse after a successful transplantation, thereby harming the organ and compromising the outcomes. Medically and ethically, however, there are many concerns to indicate a ‘self-inflicted’ disease as a reason for patient selection. The debate is about fairness, attributing responsibility and establishing causality. Widely accepted considerations focus on outcomes. Most transplant centres now require a certain abstinence period from alcohol – mostly six months – before transplantation. This requirement aims at improvement of liver function, which could make transplantation unnecessary, moreover it aims at strengthening a patient’s wish for a transplantation and prevent a possible relapse. Smoking can also have a negative effect on outcomes: an increased risk of graft failure and thrombosis. Often alcohol (ab)use and smoking go hand in hand [71]. But is this in itself sufficient reason not to transplant lung cancer patients? Again, in order to evade the charge of unjustified discrimination, we should get the reasons right [17,18,72]. Not self-infliction, but the fact that chances of success are too low and risks and costs too high, should rather guide our decisions. Although also in kidney transplantation obesity is considered a risk factor, and BMI above 30/35 has been an exclusion criterion, data seems insufficiently conclusive to justify exclusion [73]. Procedural safeguards Procedural safeguards are essential, as noticed above [16,32]. Safeguards ensure safe procedures to minimise risks, guarantee consent and secure fairness. It is worth highlighting a few. - To avoid conflicts of interests, exclusive donor advocacy is required both in deceased and living donation. This includes also appropriate post-care and financial compensation in living donation for

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verifiable costs and losses, whereas payment for organs is ruled out. Care refers to short-term and long-term, with special attention to social security and insurance. - With regard to appropriate consent, and given the high risks and uncertainties in living liver and bowel donation, it is of utmost importance that centres ensure long-term follow-up, register outcomes and report complications. All parties should be informed and counselled, based on the best available evidence. In addition, specific requirements for minors and mentally incapacitated adults should be in place: no living liver donation and only kidney donation as ultimum remedium [26].

Summary - Ethical issues in deceased donation include definitions of death, interventions to keep organs in good condition, and the acceptability and range of consent - In living donation personal contacts can easily be effectuated through modern media, leading to novel relationships with risk of exploitation - Ethical justifications to overrule the ‘first do no harm’ principle, are not all satisfactory, whereas legal constraints can never take away responsible clinical judgment - Two opposing views signify considerable disagreement: should we evaluate in terms of thresholds for both donor and recipient (taken apart), or in terms of aggregation, by taking a donor–recipient pair together? - It is disputable whether we should counsel non-specified donors more strictly than specified donors - An autonomous wish (or given consent) can never be a sufficient justification for treatment; in transplantation it is not doctor’s mission to fulfil donors’ ends - Consensus meetings should not distract attention from underlying ethical issues, e.g. competing views on fairness - Two prevailing systems, deceased and living donation, are governed by two different sets of ethical principles, can and should they be kept separately? - Not self-inflicted disease, but too low successes and too high costs should guide our allocation decisions. Conflict of interest None. Acknowledgement A special word of thanks to Krista Tromp MSc, junior researcher in the Dept. of Medical Ethics and Philosophy for dealing with the recent ethically relevant literature. References [1] Colledan M, Zanfi C, Pinna AD. Technical aspects of intestinal transplantation. Curr Opin Organ Transpl 2013;18(3):291–7. [2] Emre S, Umman V, Cimsit B, Rosencrantz R. Current concepts in pediatric liver transplantation. Mt Sinai J Med 2012;79(2): 199–213. [3] Nyckowski P, Boudjema K, Jaeck D, Wolf P, Zieniewicz K, Krawczyk M. Technical aspects of orthotopic liver transplantation. Ann Transpl 1996;1(4):10–21. [4] Quintini C, Hashimoto K, Uso TD, Miller C. Is there an advantage of living over deceased donation in liver transplantation? Transpl Int 2013;26(1):11–9. [5] Gruttadauria S, Pagano D, Luca A, Gridelli B. Small-for-size syndrome in adult-to-adult living-related liver transplantation. World J Gastroenterol 2010;16(40):5011–5. [6] Emre S, Umman V. Split liver transplantation: an overview. Transpl Proc 2011;43(3):884–7. [7] Busuttil RW, Goss JA. Split liver transplantation. Ann Surg 1999;229(3):313–21. [8] Domino liver transplantation: indications, techniques, and outcomes. Transpl Rev (Orlando) 2011;25(4):167–77. [9] Boggi U, Rosati CM, Marchetti P. Follow-up of secondary diabetic complications after pancreas transplantation. Curr Opin Organ Transpl 2013 Feb;18(1):102–10.

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