EASL Clinical Practice Guidelines

Organ donation

Organ donation

Consent systems

In the EU, organs cannot be procured without the consent of donors and/or their relatives. However, the establishment of consent differs between Member States. National provisions usually foresee that citizens (donors or relatives) can “opt-in” (explicit consent) or “opt-out” for donation (presumed consent). Mixed solutions also exist, with or without central databases that register the wishes expressed by citizens. The ACTOR study found that most European countries have “opt-out”, i.e. presumed consent systems, according to which no explicit consent is required for a person to become a potential donor. In practice, and in the absence of such explicit consent, most laws require the deceased’s next of kin to consent to post-mortem organ removal. Though to date the majority of European countries have transplant laws based on the presumed consent principle, the practical application of national legislation particularly, with regard to the role of next of kin in objecting or consenting to organ donation, varies substantially between countries, regions, hospitals, and even individual requestors and thus may impact on ultimate efficiency of national laws. Regardless of the consent system, the opinion of relatives or “next of kin” is almost always asked and respected in almost all European countries.

A combination of legislation, potential of medically suitable donors, investments in health care and infrastructure, education, public attitudes, culture and religion may all play a role in determining the number of deceased organ donors in a country or region. Donation figures within the Eurotransplant area, however, seem to show a rather direct effect of legislative measures: donation rates per million population are nearly twice as high in Austria and Belgium (presumed consent) compared to those in Germany and the Netherlands [146].

Deceased and living donation

It is also the Member States’ decision on whether they organise their transplant systems based purely on deceased donation or whether they also encourage living donation. While deceased donation is highly developed in several Southern European countries, some Northern European countries are more advanced in the area of living donation.

Brain death and circulatory death

A further distinction can also be made between different types of deceased donation that are allowed and organised within a country. Donation after brain death (DBD) is the most common type of deceased donation, while donation after circulatory death (DCD) is increasingly used as an additional source of organs for transplantation. These two kinds of deceased donation raise different ethical concerns and require different organisational set-ups.

Bilateral and multilateral agreements

Some countries have chosen to take part in multilateral “European organ exchange organisations”, such as Eurotransplant (Austria, Belgium, Croatia, Germany, Hungary, Luxembourg, the Netherlands and Slovenia) or Scandiatransplant (Sweden, Finland, Denmark, Norway and Iceland), and manage waiting lists and allocation criteria (at least partially) together. The recently created Southern Alliance for Transplantation foresees a similar collaboration. Bilateral organ exchange agreements have been set up by some countries, e.g. just focusing on the exchange of a specific type of organ with a neighbouring country. Examples include:

  • Italy and Malta 2008–2010: 20 organs (kidney, heart, liver, split liver) from Malta were transplanted in Italy.
  • Spain and Portugal 2009: 41 organs offered to Spain from Portugal.

Such organ exchanges need, for being fully operational, to be supported by a wide set of organisational and practical agreements, aimed also at ensuring compliance with Article 3(2) c) of the EU Charter of Fundamental rights and excluding any risk of organ trafficking.

Waiting lists

The management of waiting lists is a national competence (which can partially be delegated to and co-managed with a “European Organ Exchange Organisation”). It includes the definition of criteria to place patients on the list or exclude patients from a waiting list. The lists are usually specific to the types of organ and transplant needed (kidney, liver, lung, heart, pancreas, small bowel, combined transplants) and are also specific for paediatric transplants.

Indirect effect of legislation on transplantation

Some legislation has had an indirect but significant effect on LT, for example the law restricting over-the-counter paracetamol pack sizes, introduced in the UK in September 1998. This was because of the large number of people taking paracetamol overdoses, and increasing numbers of deaths and liver transplants due to paracetamol induced hepatotoxicity. Such legislation was introduced following recommendations by the UK government agency currently known as Medicines and Healthcare Products Regulatory Agency, and restricted pack sizes of paracetamol to a maximum of 32 tablets in pharmacies and to 16 tablets for non-pharmacy sales.

These measures were followed by persistent significant reductions in deaths due to paracetamol overdose, with some indication of fewer registrations for transplantation at liver units during the 11 years after the legislation [147].

A similar but much amplified effect may be expected in the future as a consequence of legislation on the funding of new direct-acting antiviral agents (DAA) against hepatitis C. Newer DAA with simplified dosing regimens and/or minimal toxicity which, when used in combination, have the potential to lead to viral eradication in most if not all HCV patients who undergo treatment. This is an area of vertiginously rapid basic sciences and clinical development, but the costs of DAA are currently prohibitive for funding of treatment on a large-scale. The implication of near-eradication of HCV in Europe in the next decades is that of a significant reduction of patients needing a liver transplant for HCV and HCC in the future.

Organ allocation

Liver allocation in Europe

Data from LT activity in Europe is collected by the ELTR [40], which is a service of the European Liver and Intestine Transplant Association (ELITA), with the following objectives:

  • Registry of all LT procedures in Europe.
  • Link between European liver transplant centres.
  • Scientific use and publications.
Between 1968 and December 2012, the ELTR has collected data regarding 112,554 liver transplant procedures performed in 153 centres from 27 European countries.

Within Europe the LT activity and organ donation rates vary in the different countries and regions reflecting different organ allocation systems and organisations. Further differences in legislation, organ donation rates, indications for LT, and traditions in the practice of medicine exist in different countries and regions of Europe.

There are no uniform rules or systems for organ allocation in Europe or within the European Union. There are several organ exchange organisations for different countries and geographical areas, including:

  • Organización Nacional de Trasplantes (ONT) in Spain.
  • NHS Blood & Transplant (NHSBT) for the United Kingdom and Ireland.
  • Scandiatransplant (Sweden, Norway, Finland, Denmark, and Iceland).
  • Eurotransplant (Austria, Belgium, Croatia, Germany, Hungary, Luxembourg, the Netherlands and Slovenia) for a total population of over 112 million.
  • Centro Nazionale Trapianti (CNT) in Italy.
  • Agence de la biomedécine in France.

Most organisations have similar rules with an urgent priority group that includes acute hepatic failure and early retransplantation following primary-non-function (PNF) as well as hepatic artery or PVT. There are also similarities in allocation for children and rules to favour splitting of the best liver grafts. There are, however, important differences as well. Organ allocation can be patient-directed, as is the case in the US and some European countries, or centre-directed, which is the case of other European countries including the UK, Spain and Scandiatransplant. There is an increasing collaboration between the organ procurement organisations.

ONT – Spain

Liver transplant activity started in Spain in 1984 and has a mean activity of more than a 1000 liver transplants performed yearly [148]. There are 25 liver transplant teams, four of which are paediatric. The ONT provides essential support for organ procurement, allocation support, and management of waiting list at a national level [149]. Spain has one of the highest organ donation rates in the world thanks to the outstanding donor detection and organ procurement organisation, which is often referred to as the Spanish model. In 2013, deceased donor organ donation rate reached 35.12 donors per million population [148]. The ONT has set a large-scale, comprehensive strategy to achieve and sustain an important improvement in donation and transplantation in Spain [150].

Liver allocation in Spain is centre-oriented as all available organs are referred to the national coordinating office.

National priority is given to liver emergencies. Livers are allocated sequentially to the hospital, city or region in the effort to reduce cold ischaemia time. The decision about the donor-recipient matching is made by the transplant team of the accepting unit with the aid of consensus guidelines developed with the support of the Spanish Liver Transplant Society [[151], [152], [153]].

Emergency LT in Spain is considered in two situations: 1) acute liver failure in the absence of any previous liver disease; or 2) retransplantation within seven days after transplantation (up to 30 days in paediatric recipients).

Clearance of candidates from the liver transplant waiting list in Spain has not changed in the last five years with a waiting list ranging from 103 to 124 days.

NHSBT – United Kingdom

An organ donation taskforce was recently set up in the UK to improve the poor donation rates. The taskforce recommendations were implemented, which were followed by an increase in the number of DBD of 7% over the last 4 years. Since 2007, the numbers of DCD have rapidly increased by 118%. The total number of deceased organ donors reached a record total of 1320 in 2013. Of these, 780 were DBD and 540 were DCD [154].

In 2013, 871 liver transplants were performed. There are seven transplant units in the UK. Three of which also have a paediatric liver transplant program. In April 2014 there were 512 patients registered on the liver transplant waiting list. Currently, on average, adult patients wait 142 days for a liver transplant while paediatric patients wait on average 78 days.

The key players in regulating organ donation, allocation and transplantation in the UK include NHSBT, a special health authority of the National Health Service (NHS) and the Human Tissue Authority (HTA). The latter is an independent watchdog that protects public confidence by licensing and inspecting organisations that store and use tissue for transplantation and other purposes. Liver allocation in the UK is centre-oriented, though there is a plan to change the system to a patient-oriented, national allocation scheme. Donor zones are allocated to each centre based on the number of new registrations of prospective candidates to match the scale of the centre’s waiting list. If the organ is declined, it will be offered, according to a rotation system, to the second in line centre through the liver allocation sequence.

The allocation priority at each centre is decided by a multidisciplinary meeting, which includes liver transplant professionals, following a UKELD-based prioritisation system.

There are nine categories of patients suitable for listing on the super urgent national list and these are divided into paracetamol overdose and non-paracetamol overdose [155].

In summary for adult (age >16 years or weight >35 kg) and paediatric (age <16 years or weight <35 kg) liver donors the sequence for allocating liver grafts is similar and as follows:

  • Super urgent list.
  • Combined liver and small bowel adult recipients.
  • Patients with hepatoblastoma.
  • Designated zonal retrieval centre.
  • Other designated UK and Ireland liver transplant centres.
  • Designated zonal retrieval centres for adults.

Scandiatransplant

Scandiatransplant is a collaboration of all organ transplant centres in the Nordic countries—Sweden, Norway, Finland, Denmark and Iceland. There are currently five liver transplant centres within Scandiatransplant (two in Sweden and one in each other Nordic country except for Iceland). In 2013, out of a total of 421 actual deceased donors, 362 liver transplants were performed in the Scandiatransplant network [[156], [157]].

There is no common waiting list in Scandinavia. Centre-oriented allocation is used and each transplant centre has its own waiting list and the right to transplant livers procured from a defined geographical area. The MELD score and/or the Child-Pugh scores are used in conjunction with clinical and non-clinical parameters (e.g. waiting time) to select patients to be transplanted.

Patients with acute hepatic failure (urgent call status) have priority to receive a liver from the next available deceased donor in the Scandiatransplant region for 72 h. The high urgent status is based solely on the diagnosis and clinical status. All livers that were received on urgent call status or as a kind request have to be paid back to the sending centre within a 6-month period.

High urgent status also applies for patients in need of an acute retransplantation within 14 days of the transplant due to PNF, hepatic artery or PVT.

Paediatric LTs represent 5% of all LTs performed in Scandinavia. In 2011, a common waiting list for paediatric patients in need of a left lateral segment liver graft was established in order to improve organ availability for children.

DCD donation is not practiced among the Scandiatransplant countries with the exception of Norway.

Eurotransplant

Eurotransplant is responsible for the allocation of donor organs in eight European countries: Austria, Belgium, Croatia, Germany, Hungary, Luxembourg, the Netherlands and Slovenia. This international collaborative framework includes all donor and transplant hospitals and tissue-typing laboratories. In Eurotransplant, allocation is governed by the different national laws on transplantation, resulting in a standard allocation algorithm; the Eurotransplant Liver Allocation System (ELAS) based on medical and logistical criteria with modifications according to the different national laws [158].

The allocation system for LT in Eurotransplant was changed in 2006 for elective recipients from a waiting time based allocation to an urgency-based system using the MELD scoring. Patient-oriented allocation according to MELD is effective in four Eurotransplant countries (Germany, Belgium, the Netherlands, and Luxembourg), whereas a centre-oriented allocation system is effective in Austria, Slovenia and Croatia. On the Eurotransplant matching list all patients have to be registered with a lab MELD which must be updated by the transplant centres at scheduled intervals. Patients whose disease severity is not adequately reflected by lab MELD can be requested for an exceptional MELD. Some diseases have been identified as standard exceptions and are comprised in a country-specific list.

Besides allocation in elective recipients, some urgency categories within Eurotransplant are given priority based on their respective medical urgency:

  1. High urgency, which is the highest priority internationally.
  2. Approved combined organ, which is a multiorgan liver transplant with exception of liver-kidney.

Urgency status is granted only after approval by Eurotransplant, and patients in these categories are ranked by the time they have spent in their current urgency [159]. A pay-back system ensures that the donor centre is re-offered the next available liver of the same blood group.

In contrast to adult recipients ranked by their calculated MELD, paediatric recipients are automatically assigned an initial paediatric MELD equivalent depending on age that is upgraded each 90 days until transplantation.

In conclusion different systems are used, ranging from centre-oriented to patient-oriented. Some systems are constructed using rigorous rules based on points and scores, whereas others are based on the clinical judgment of the responsible transplant surgeon. The current diversity makes it unlikely that we will manage to produce a uniform organ allocation system in Europe in the near future.

Extended criteria donors

The success of LT has resulted in a growing demand for transplantable grafts. The discrepancy between supply and demand and the increased morbidity and mortality of patients on the waiting list has led to a search for alternatives to the standard pool of organs from DBD. In the past 20 years the paediatric waiting lists have been successfully reduced due to the introduction of segmental LT including reduced/split LT and living donor LT (LDLT). These techniques have only marginally increased the organ pool for adults in the Western world. The most immediate source of organs capable of expanding the donor pool is that of extended criteria donors (ECD) also called marginal donors. These, although not universally defined, include a wide range of donors with unfavourable characteristics, historically associated with poorer graft and patient survival. These include advanced age, steatosis, hypernatremia, DCD and others. DCD is associated with severe ischaemia-reperfusion injury, which is responsible for PNF or delayed graft function and biliary ischaemia. However, if carefully selected and matched with appropriate recipients, livers from DCD donors can be used safely and effectively [160].

Scores have been developed to quantify the risk of graft failure of ECD donors, including the donor risk index (DRI), and more recently the Balance of Risk score (BAR score) (see chapters Donor risk index and Balance of risk score).

Protocols have been developed for the selection of ECD and DCD livers to allow a safer utilisation and an effective expansion of the donor pool.

Definition of ECD donors

The ECD graft represents an organ with unfavourable characteristics associated with suboptimal post-transplant outcomes that fall into two main risk categories: poor graft function and potential for disease transmission. Within the poor graft function category it is possible to differentiate two groups, the DCDs and the non-DCDs.

The Eurotransplant definition refers to the category of graft dysfunction [161]. According to this definition the following criteria defines a liver donor marginal:

  • Donor age >65 years.
  • ICU stay with ventilation >7 days.
  • BMI >30.
  • Steatosis of the liver >40%.
  • Serum sodium >165 mmol/L.
  • Transaminases: ALT >105 U/L, AST >90 U/L.
  • Serum bilirubin >3 mg/dl.

DCD

In recent years, renewed interest in DCD has emerged as a strategy to increase the number of viable grafts, and to decrease the mortality on the waiting list. According to the setting in which circulatory death occurs, DCD can be classified using the Maastricht criteria [[162], [163]] (Table 3). In Europe, the United Kingdom, the Netherlands, Spain, Belgium, and France have the highest DCD activity. DCD is based on the type III category in most countries; type II DCD is predominant in Spain and in France. DCD may be also divided into two main categories: controlled (CDCD) and uncontrolled (UDCD). The ethics, assessment, logistics, techniques of retrieval, and outcomes of transplant are very different with controlled and uncontrolled liver DCD.

Table 3
Categories of donation after circulatory death (modified from [[162], [163]]).


Controlled donors (Maastricht type III) are generally victims of a catastrophic brain injury of diverse aetiology, deemed incompatible with meaningful recovery, but whose condition does not meet formal criteria for brain death and whose cardiopulmonary function ceases before organs are retrieved. The procedure of withdrawal of life support therapy (WLST) is planned by the medical team in agreement with the family of the injured patient. It is important to emphasise that this decision precedes, and is independent from the one to donate. In category III, circulatory arrest is induced by WLST and occurs either in the ICU or in the operating room. In type IV, a brain dead donor suffers an unpredicted cardiac arrest prior to the donation procedure or the latter is delayed after cardiac arrest if the family wishes so for religious or cultural reasons.

CDCD occurs in the presence of organ retrieval teams and limits the ischaemic injury associated with death. The process of dying in type III DCD; however, may be associated with a prolonged agonal period of hypotension and/or hypoxia, which are ultimately responsible for ischaemic injury that may prevent organ donation, or be accountable for graft dysfunction or non-function of the transplanted organ. In this respect it is crucial that we recognise that there is a total lack of arterial and portal blood flow through the liver long before the time of cardio-circulatory arrest [164].

UDCD occurs following the unanticipated cardiac arrest of a patient; due to logistical reasons and the associated degree of ischaemic injury only deaths occurring at a centre with established organ retrieval teams and pathways are suitable for donation of liver grafts (category II). It is possible to overcome some of these logistical challenges by directing intensive medical care resources outside of the hospital. In Madrid and Barcelona a network of mobile ICU teams are tasked to patients in out-of-hospital cardiac arrest. The subsequent effect is that this also maximises rates of UDCD.

Several groups have reported excellent results with the use of CDCD grafts for LT. In this sense, 1- and 3-year graft survivals are 80% and 70%. Regarding the development of intrahepatic biliary strictures also defined as ischaemic-type biliary lesions (ITBL) or ischaemic cholangiopathy (IC), groups with specific expertise including King’s College Hospital in London have reported less than a 3% rate of ITBL. It is important to remark that this is not only a reliable graft source for the adult population; in the paediatric population, where graft scarcity is even greater than among adults, CDCD grafts achieve excellent results. Results from the UDCD programs are excellent as well. With a median follow-up between 20 and 34 months, Spanish groups have reported graft and patient survivals between 70% and 87.5% with rates of PNF and ITBL around 10%. Grafts obtained from DCD are not optimal; graft and patient survival comparisons with standard DBD generally show a lower performance. On an intention-to-treat basis though DCD may compare better with DBD grafts as there may be an advantage with an earlier transplant accepting a DCD liver rather than deteriorating and possibly dying, waiting for a DBD organ.

Moreover, recipients of DCD grafts show mortality rates comparable to other well-established, accepted risk predictors such as advanced age, hepatitis C or HCC, in recipients and older donor age. As recently suggested, combining DCD grafts with these risk factors must be carefully considered as it may create an unacceptable risk. For this reason, physicians should not shy away from using DCD grafts. Perhaps the optimal environment for a DCD graft is a low risk recipient. Malignancy seems to be a good indication as the risk of dropping out of the HCC criteria on the waiting list may outweigh that of receiving a graft from a DCD. In conclusion, both controlled and uncontrolled programs have a huge potential to clearly expand the pool of donors for the adult and paediatric populations. Future advances in the fields of in situ donor recirculation and ex situ perfusion will surely not only add but also rescue grafts. The process to obtain a valid consent is probably the most important legal requirement associated with DCD programs. In this sense, legislation can be based on either the opting out (presumed consent) or the opting in (explicit consent) principle. From an ethical point of view, two problems may arise in UDCD and CDCD programs. In the first group, there is an urgent need to start preservation to ensure organ viability. This commonly happens when the family is not present. In an opt-out system, the next of kin have the right to object to organ donation, even when the deceased themselves have not declined the option. In an opt-in system, the family can decide whether to donate when the deceased has not made a choice. From a legal point of view, this means that when the next of kin are not available to consent or to object, there is no legal basis to start manoeuvres, and the organs would be lost. An optimal example of a legal pathway to gain sufficient time for proper consent and to avoid unnecessary conflicts may be the one proposed by Dutch legislation: “The necessary measures to maintain the organ in a suitable condition for transplantation may be taken after death, so long as the procedure for obtaining the necessary consent in accordance with this law has not been completed”.

In the CDCD group, the ethical conflict will emerge in the context of decisions regarding WLST or ending of resuscitation efforts. Teams should ensure that there are no conflicts of interest; thus, transplant team members cannot be involved in decisions related to patient prognosis, withdrawal of ventilatory or organ perfusion support or determination of death.

Non-DCD

Older donors, usually deceased from cerebrovascular disease, are generally affected by a number of medical comorbidities including, diabetes, hypertension, previous history of malignancy and obesity. The latter, now pandemic in the Western world, is responsible for steatotic transformation of a large proportion of potential donor livers.

Older donor age

Utilisation of livers from older donors represents a logical means to expand the donor pool. In the non-transplant setting, the liver’s physiologic function remains well preserved throughout life, likely a result of its unique regenerative capacity. However, patients transplanted with livers from older donors are at increased risk of developing graft failure and mortality due to an increased vulnerability to ischaemia/reperfusion and a diminished regenerative ability of older livers [165]. A further mechanism could be the increased burden of comorbidities in older donors such as, hypertension, diabetes, dyslipidaemia and obesity, which may lead to atherosclerotic vessels and steatotic grafts. Several studies have shown that older donor livers are associated with PNF [166], hepatic artery thrombosis [167] and ischaemia-reperfusion injury.

Although increasing donor age adversely affects survival after LT [168], liver grafts have been used from selected deceased donors older than 70 years. While there are reports of excellent short-term results, long-term follow-up with septuagenarian and octogenarian deceased donors showed no differences in long-term patient or graft survival between hepatitis C negative recipients of livers from older compared with younger donors. In contrast, the 7-year survival for HCV positive recipients of older donor livers was less than half that of HCV negative recipients. Transplantation of livers from septuagenarian and octogenarian donors can achieve excellent long-term patient and graft survival for selected HCV negative patients [169].

There is consistent evidence of an interaction between older donor age and positive recipient HCV status that predisposes patients to fibrosing cholestatic hepatitis, post-transplant infections, graft failure and mortality [170].

Liver grafts from donors with diabetes

A retrospective analysis of the Scientific Registry of Transplant Recipients database (2004–2008) (25,413 patients) showed that recipients from diabetes mellitus donors experienced worse 1- and 5-year graft survival than recipients from non-diabetes mellitus donors and this was particularly lower for recipients from donors with diabetes mellitus duration >5 years. However, in patients without HCV infection, using diabetes mellitus donors was not independently associated with worse post-transplantation graft survival. Matching these diabetes mellitus donors to recipients without HCV may be safe [171].

Steatotic liver grafts

Hepatic steatosis is defined as the accumulation of droplets of fat in the hepatocytes and is associated with a range of post-transplant complications and poor graft function in particular. The key to this dysfunction is the ischaemia-reperfusion injury. The reported incidence of steatosis in the liver graft is between 9–26% among the liver donor population [172].

Steatosis is classified as mild (10–30%), moderate (30–60%), or severe (>60%) [173], but it is believed that steatosis will disappear after LT. There are two patterns of hepatic steatosis, microvescicular and macrovescicular. Microvescicular steatosis refers to the accumulation of tiny lipid droplets measuring <1 mm giving a foamy appearance of the cytoplasm and it is associated with rare conditions including drug toxicity, acute fatty liver in pregnancy and Reye disease. Macrovescicular steatosis is defined by the presence of small to large droplets that may end up occupying the whole cytoplasm; it is typically associated with alcohol, obesity and diabetes. Small fat droplets seem not to be involved with poor graft function. The volume of large droplet macrosteatosis in the liver graft is closely linked to its suitability for transplantation.

Mild macrosteatosis (<30% volume) is considered suitable for transplantation. Livers with moderate macrovescicular steatosis (30–60%) may result in acceptable outcomes in select donor-recipient combinations. Severe macrosteatosis (>60%) is linked with unacceptable risks of graft failure, acute kidney injury, biliary complications and mortality [[174], [175]].

Low-grade macrosteatotic liver grafts (⩽30% macrosteatosis) resulted in a 5-year graft survival rate of 60% or more up to BAR 18, comparable to non-steatotic grafts [176]. Microsteatotic or ⩽30% macrosteatotic liver grafts can be used safely up to BAR score of 18 or less, but liver grafts with more than 30% macrosteatotis should be used with risk adjustment, that is, up to BAR score of 9 or less. Microvescicular steatosis does not preclude the use of grafts.

Current developments of extracorporeal normothermic machine perfusion devices may allow in the near future to assess moderately and severely steatotic grafts prior to implantation, furthermore it is foreseeable that normothermic machine perfusion-based defatting protocols may be developed to allow further expansion of the donor pool.

HBcAb positive donor grafts

One of the current efforts to overcome the organ shortage is based on the use of grafts from anti-HBV core antigen (anti-HBc) positive donors. These grafts are common in countries with high prevalence of HBV infection, such as Asia and the Mediterranean countries. This is despite the risk of HBV transmission to the recipient after LT [177].

HBcAb positive donor grafts have better outcomes when transplanted into HBsAg positive than HBsAg negative recipients. These findings suggest that donor HBcAb positivity requires more stringent allocation strategies.

Anti-HBc positive liver donors frequently have occult HBV infection, i.e. persistent liver and/or serum HBV DNA without serologic evidence of active HBV infection so that viral replication may increase with the use of post-transplant immunosuppression and in particular with corticosteroids. The liver grafts from anti-HBc positive donors are currently the main sources of de novo HBV infection after LT [178]. Many centres now use grafts from anti-HBc positive donors for HBsAg negative recipients. Since the probability of such de novo HBV infection is substantially lower in anti-HBc and/or anti-HBs positive compared to HBV naïve recipients (15% vs. 48%), it is reasonable to recommend that liver grafts from anti-HBc positive donors should be preferentially directed to HBV-exposed liver transplant candidates. The presence of anti-HBs seems to protect from de novo HBV infection and both anti-HBc and anti-HBs positive recipients can safely receive anti-HBc positive liver grafts without any post-transplant HBV prophylaxis (probability of de novo HBV infection <2%). Pre-transplant vaccination alone does not appear to be an effective strategy, as de novo HBV infection after LT developed in 10% of successfully vaccinated recipients without any post-transplant prophylaxis. However, HBV vaccination should be offered to all naïve HBV patients early in the course of non-HBV chronic liver disease (i.e. in the pre-cirrhotic stage), even though additional anti-HBV prophylaxis will be needed in cases of LT with grafts from anti-HBc positive donors.

If de novo post-LT HBV infection develops, antiviral treatment is needed and it is reasonable to think that the efficacy of treatment is similar to that of post-transplant HBV recurrence. Given the poor resistance profile of long-term lamivudine monotherapy and the low potency of adefovir, both entecavir and tenofovir may be the agents of choice at present, despite the current lack of data.

In summary, liver grafts from anti-HBc positive donors can be safely used, preferentially in HBsAg positive or anti-HBc/anti-HBs positive recipients. HBsAg negative recipients should receive prophylaxis with lamivudine, while both anti-HBc and anti-HBs positive recipients may need no prophylaxis at all [[179], [180]].

Lastly, a series of eight cases of LT using grafts from deceased HBsAg positive in HBsAg positive recipients showed that it is feasible, and may provide further expansion of the pool of organ donors with appropriate antiviral management and monitoring [181].

HCV positive donors

Chronic donor shortages, made it necessary to consider HCV positive donors as an alternative organ source. While the use of HCV antibody–positive grafts in recipients with HCV infection is a common practice and is generally considered safe [[182], [183]], LT of HCV positive grafts in HCV negative recipients is avoided. The transplantation of HCV positive donor livers into HCV positive recipients has not been associated with greater disease progression or graft loss [184] and has shown similar graft and patient survival to HCV positive recipients who received HCV negative livers. Superinfection with a different donor genotype from that of the recipient may occur with all genotypes. HCV positive donors (whose genotype may not be known at the time of procurement) are often avoided for candidates with non-type 1 infection, since there is a reduced ability to treat type 1 genotype superinfection. However, the newer generation DAAs may change the recommendation in the future [[185], [186]].

The use of HCV antibody–positive grafts in recipients with HIV and HCV co-infections has been associated with poorer graft and patient survival [[134], [187]]. Optimal strategies for donor and recipient selection have not been fully defined in this population to date.

It is important to note that stored fresh arterial and venous grafts from HCV- and HBV-infected donors used for different types of vascular reconstruction during LT, were recently found to be the route of transmission of infection from donor to uninfected recipients [188]. In order to avoid these problems the HTA in England has set rules and a registry to avoid wastage of these vessels, the American Organ Procurement and Transplantation Network (OPTN) policy was amended to preclude their storage for use in recipients other than the recipients of the corresponding organ [189].

Donors with previous or current malignancy

Livers from a donor with previous history of malignancy can be used in selected situations, as donor tumour transmission through LT has been rare. Between 1965 and 2003, thirty-eight such cases have been reported by the Israel Penn International Transplant Tumour Registry.

Transmission of donor-related malignancy by organ transplantation may occur and is often a fatal complication in immunosuppressed transplant recipients. Acceptance of livers from donors with a current or past history of cancer is a challenging decision for both surgeons and patients.

Primary intracranial malignancy have generally a low risk of spread outside the central nervous system, hence the relatively low risk of transmission to transplant recipients [190].

However, case reports describe transmission of malignancy has occurred from donors with primary malignancy of the central nervous system. These cases are typical of donors with high-grade malignant tumours and who have undergone debulking surgery, radiotherapy and ventricular-systemic shunt interventions that compromise the blood brain barrier. Advice from the Council of Europe in 1997 stated that while the use of organs from donors with low-grade primary malignancy was safe, organs from potential donors with high-grade malignant tumours of the central nervous system, especially where the integrity of the blood brain barrier is compromised, should no longer be considered safe for transplantation. In 2003 a monothematic ASTS meeting issued recommendations about the use of organs from donors with a history of malignancy. Glioblastoma multiforme, along with melanoma, choriocarcinoma and lung cancer were considered absolute contraindications to liver donation [191].

A retrospective analysis of UK registry data has shown that none of the 448 recipients of organs from 177 donors with primary intracranial malignancy developed a transmitted tumour. Among donors with high-grade tumours, there were 23 grade IV gliomas (glioblastoma multiforme) and nine medulloblastomas. Despite the reassuring study there remains a small but definite risk of transmitting cancer from donors with primary intracranial malignancy. The surgeon should be aware of all the relevant donor information, including tumour histology and treatment, including radiotherapy and surgery. At the time of organ retrieval a thorough examination of the thoracic and abdominal cavities for metastatic tumour should be undertaken.

In terms of non-central nervous system tumours, as previously mentioned, melanoma, choriocarcinoma and lung cancer constitute absolute contraindications to donation. More common tumours such as colorectal and breast cancers are absolute contraindications to donation if in advanced stage (CRC >T3 or breast cancer >T1c). Organ donation needs careful consideration depending on the exact tumour stage and the disease-free interval.

Finally, it is paramount to counsel potential recipients regarding the small but definite risk of transmission of malignancy, as well as their chance of survival if they choose to remain on the waiting list.

Use of liver grafts from infected donors

Organ transplantation is not without risk of microbial infections, since in contrast to the US CDC principle of ‘zero’ risk, the European philosophy is that risk cannot be eliminated, but must be put in a clinical context (Table 4). In general, a risk classification has been used to evaluate the safety and the acceptability of donors according to the type of infection.

Table 4


*Including multi-drug resistant gram-negative infections.

Unacceptable risk

This classification includes absolute contraindication. An example of a donor with unacceptable infections is the positivity for HIV-1 or HIV-2. Despite the important progress in the treatment of this infection, which have led to a significant increase in the survival and to an important improvement in the QoL of patients with HIV, the absence of definitive therapies makes this infection an absolute contraindication for accepting a donor.

The same principle has to be applied to all the systemic infections due to micro-organisms, such as multidrug-resistant bacterial infections or WNV, for whom a practical therapeutic option does not exist. Donors with proven WNV infections of the central nervous system should not be considered eligible because of the risk of recipient transmission [192]. The detection of IgM occurs approximately 4 days after viremia, and seroconversion to IgG occurs at approximately 8 days. Nonetheless, WNV serum IgM may persist for up to 500 days after acute infection. Thus, neither the presence of WNV serum IgM nor its absence is sufficient to exclude active infection; donor screening requires the use of nucleic acid test to identify acutely infected donors [193]. Transmission from infected donors to transplant recipients has not occurred in every instance, and pre-existing immunity in recipients may limit transmission. Once an infection occurs, symptomatic disease is more common among immunocompromised patients, and significant persistent neurological morbidity or mortality may ensue. There are no proven treatments for WNV at this time.

In general, encephalitis, particularly with fever, without a documented source is typically associated with viral infectious disease transmission. In many instances of transmission, encephalitis is not initially suspected in the donor. Therefore, most experts believe that donors with clinical encephalitis without a proven cause should likely be avoided [194].

Donors with evidence of active tuberculosis should not be considered as organ donors; if donors with untreated latent Mycobacterium tuberculosis infections are used, the recipients should be treated following the recently published guidelines [195]. Isoniazid seems to be effective and its hepatotoxicity occurs in 6% of treated recipients. Donor-derived tuberculosis infections usually become symptomatic less than 3 months after transplantation. It is important to note that symptoms, particularly in liver recipients, may be atypical and include fever, sepsis, and elevated liver enzymes. If recognised early, recipient with active tuberculosis have a better chance of survival [196].

 

Increased, but acceptable risk

This classification includes cases where transmissible organisms or diseases are identified during the evaluation process of the donor, but organ utilisation is justified by the specific health situation of the recipient or the severity of their clinical condition. Specifically, this category includes those cases in which the risk of death of the recipient without transplantation is higher compared with the risk of transplantation [197]. An example is the use of HCV or HBsAg positive donors in HCV or HBV negative recipients.

Although the transmission of syphilis from an infected donor has been rarely reported, the prophylactic treatment of recipients who receive organs from donors with positive syphilis serology generally prevents transmission. Typically, recipients are treated for late latent syphilis (i.e., 3 doses of intramuscular penicillin G benzathine (2.4 million units) [198]. Donors with a positive non-treponemal serology (i.e., rapid plasma reagin or VDRL test) should have confirmatory testing performed even if these results become available after transplantation because the rate of false positivity among organ donors is high [199]. Confirmed positive syphilis serology is considered a marker for risk behaviours that place the donor at an increased risk for HIV, HBV, and HCV, as stated by the US Public Health Service guidelines.

Calculated risk

This classification includes all cases where, even in the presence of transmissible diseases, transplantation is allowed for recipients with the same disease or with a protective serological status; this risk applies also to donors with documented bacteremia and/or bacterial meningitis provided that the donor was on targeted antimicrobial treatment for a minimum duration of 24–48 h [197]. Donors with HCV or HBV infection belong to this category (see previous sections).

The transmission of bacterial infections is frequently mitigated by the common use of perioperative antibiotics. Much has been learned about the risk of bacterial infections in donors: donors with select bacterial infections can be safely used as long as appropriate therapy is provided to both the donor before procurement and the recipient after transplantation. Available information suggests that organs from a donor with a bacteremia who has received active antibacterial treatment for at least 48 h can be safely used as long as the same effective antibiotic therapy is continued in the recipients [200]. Although the ideal duration of antimicrobial therapy in the recipient has not been prospectively studied, most experts recommend treating the recipient with active therapy directed against the cultured bacteria for at least 14 days [[200], [201]]. The donor should be assessed for disseminated foci of infection because this may represent a higher risk of transmission, which is especially high if the organ to be retrieved has evidence of involvement. The strongest data come from donors with documented bacterial meningitis who received effective antimicrobial therapy for at least 24 to 48 h: the risk of transmission was exceptionally low with the active treatment of the donor and the recipient. Infection at sites other than the liver or the biliary tree (e.g., sputum and urine), without demonstration of disseminated infections, do not typically require treatment of recipients. Bacteremia with virulent organisms such as Staphylococcus aureus and Pseudomonas aeruginosa in particular, may result in early post-transplant sepsis or mycotic aneurysm formation at the site of allograft vascular anastomoses. The standard of care is to administer longer courses of therapy in the recipient (e.g., two weeks) if the donor is known to have been bacteremic with a virulent organism [202].

EBV is of particular concern because of its association with post-transplant lymphoproliferative disorder, especially in the paediatric population. Donor and recipient screening should be performed, and there should be consideration of pre-emptive monitoring in high risk situations (i.e. D+/R−). A concomitant reduction in immunosuppression is a mainstay of treatment. Early graft dysfunction should prompt an evaluation for hepatic involvement of post-transplant lymphoproliferative disorder; later presentations of post-transplant lymphoproliferative disorder are more likely to present with disseminated disease.

Livers from donors who are seropositive for the parasite T. cruzi, responsible for Chagas disease, can be considered for transplantation [203]. T. cruzi can remain asymptomatic for a prolonged period of time after infection. Symptoms include fever, often associated to a painful, erythematous rash. Recipients whose donors have proven T. cruzi seropositivity should be screened regularly after transplantation for parasitemia and, if found positive, should undergo treatment [204]. Donors with proven Naegleria meningoencephalitis, can be used with a low risk of transmission [205].

Non-assessable risk

This classification includes cases where the evaluation process does not allow an appropriate risk assessment for transmissible diseases [197]. Organs from donors infected with highly resistant bacteria (i.e., vancomycin-resistant Enterococcus, Acinetobacter baumannii, carbapenemase-producing Klebsiella pneumonia) have rarely been used safely and such offers should be discussed with an experienced infectious diseases physician, given the high risk of graft loss and mortality in case of transmission of infection to the recipient [198].

Turning to fungal infections, the most commonly transmitted from donors to recipients include Candida species, endemic mycoses (particularly Coccidioides immitis), and Cryptococcus. When transmitted, these mycoses are associated with significant morbidity in addition to frequent graft and/or recipient loss. Contamination of the organ during procurement and preservation appears to occur more commonly than transmissions of infection. Positive cultures for Candida species of the preservation fluid should prompt for treatment. Most centres include azole antifungals in their post-transplant prophylaxis regimen. Appropriate dosing and close monitoring of drug levels is necessary as azoles interact with calcineurin inhibitors (CNIs) and mammalian target of rapamycin inhibitors [206].

Standard risk

This classification includes cases where the evaluation process did not identify a transmissible disease [197].

Recommendations

Donor risk index

Feng et al. [207] developed, in 2006, a DRI with the aim to quantify the effect of specific donor characteristics on the risk of post-transplant graft failure. The value of such information is heightened by the life-saving and life-threatening potential of every decision to either accept or reject a particular opportunity for transplantation. The characteristics of the donor that independently predict and significantly increase risk of graft failure are 5: age (>40 years), race (African American vs. White), cause of death (cardiovascular accidents, others, DCD), partial/split liver graft and height (per 10 cm decrease). Two independent transplant factors, cold ischaemia time and donor location respect to recipient location, are also significantly associated with increased risk of graft loss. To note, a limitation of the DRI is that it does not include liver steatosis.

Balance of risk score

The BAR score was calculated on 37,255 patients in the UNOS (United Network for Organ Sharing) database and identifies the six strongest predictors of post-transplantation patient survival [208]. Partial transplants (split and living donor LT), DCD and combined liver transplants were excluded to reduce confounding variables. Six strongest predictors of post-transplant survival included: recipient MELD score, cold ischaemia time, recipient and donor age, previous transplantation, and dependence from life support prior to transplantation. With increasing BAR points, patient survival decreases. However, while mortality is linearly increasing with higher MELD or SOFT scores, mortality remains stable in the BAR up to 16, and then increases exponentially at BAR 18.

The BAR seems appropriate to define the threshold when the risk of LT is too high. This threshold was determined at 18 BAR score points, being the sum of several independent risk factors. Interestingly, high MELD situations can be balanced in BAR system by accepting only a low donor and recipient age and short cold ischaemia. In regards to steatosis, liver grafts with microsteatosis or 30% or less macrosteatosis could be used safely up to a BAR score of 18 or less, but liver grafts more than 30% macrosteatotic should be used with risk adjustment, that is, up to BAR score of nine or less [176].