10. Liver

We recommend that:

• All centres should be prepared to use livers from DCD donors for transplantation. (1B)
• The outcome of transplanting DCD livers recovered without normothermic regional perfusion is improved with short CIT, and that CIT should be kept under 8 hours. (1B)
• Ex situ preservation time can be extended beyond 8 hours when normothermic regional perfusion has been used. (1B)
• Ex situ preservation time can be extended beyond 8 hours when ex situ machine perfusion is used, but the impact on ischaemic cholangiopathy is unknown. (1B)
• If the donor functional warm ischaemia time exceeds 30 minutes and organs are not being recovered using in situ normothermic regional perfusion or ex situ hypothermic machine perfusion, there is an increased risk for graft loss, however further donor and recipient characteristics should be taken into account before considering rejecting the graft in borderline cases. (1B)
• The use of in situ normothermic regional perfusion and ex situ hypothermic machine perfusion can reduce the incidence of symptomatic ischaemic cholangiopathy when compared to static cold storage. (1A)
• Future studies comparing the effects of different machine perfusion technologies on the biliary tree in DCD donors as well as studies to find adequate assessment parameters of the viability of the biliary tree are necessary. (1A)
• The use of normothermic regional perfusion is an effective way to increase the number of viable livers recovered. (1B)
• Future studies evaluating the possible mechanisms protecting against ischaemic cholangiopathy in DCD donors are needed. (1B)
• Excellent short- and medium-term outcomes can be achieved in paediatric DCD liver transplantation with highly selected and careful donor and recipient selection. (1B)
• Use of paediatric or young adult DCD grafts is an effective approach to expand the donor pool and remains an underutilised resource for children in need of liver transplantation. (1B)
• An international registry of paediatric DCD liver transplant recipients is needed to determine whether there is a significant difference in outcomes from DBD transplantation. (1B)
• A national differential analysis of outcomes in paediatric DCD liver transplantation is required, depending on whether a paediatric or an adult DCD is used. (1B)

We suggest that:

• DCD donors may be used without an age limit if other surrogates of donor organ quality are favourable. (2B)
• High donor BMI is a risk factor for graft loss both in DCD and DBD donation, therefore a higher BMI alone should not be a contraindication for accepting a DCD graft if other factors are favourable. (2B)
• Serial blood gases during the withdrawal phase should be used as an additional tool to determine the onset of anaerobic respiration by providing lactate measurements. (2D)
• The total preservation time could be extended beyond 8 hours if any of the machine organ preservation techniques are utilised, but there is no recommendation of a safe upper limit of preservation based on current evidence and this should be at the discretion of the implanting surgeon. (2D)
• Potential recipients of DCD liver grafts which have not been subject to in situ or ex situ perfusion should be informed of the potential risk of both early and late graft loss. (2C)
• The emphasis should be on minimising donor hepatectomy time; in ideal scenarios, hepatectomy time should not be longer than 30 minutes. A longer hepatectomy time is associated with graft failure in non-NRP DCD donors. (2C)
• Dual aortic and portal perfusion during DCD liver retrieval and flushing of the bile duct should be standard. (2C)
• Time between knife-to-skin and liver placement into the ice box should ideally be less than one hour; this is a target that all NORS teams should be encouraged to achieve. (2B)
• DCD livers can be used in children as whole, reduced or split grafts, if they are of excellent quality, the FWIT is <30 minutes and the CIT <8 hours. (2B)
• Paediatric DCD livers recovered without normothermic regional perfusion are less likely to present with ischaemic cholangiopathy as they may be more resilient to ischaemia reperfusion injury and have higher regenerative capacity. (2B)
• Machine perfusion in paediatric liver transplantation can play a role in halting the effects of the CIT, improving the liver quality in whole grafts for older children or young adults, and facilitating splitting and utilisation of both lobes. (2C)

10.1 Introduction

The burden of chronic liver disease continues to grow worldwide and the UK is no exception. Consequently, the indications for liver transplantation continue to expand with increasing numbers of patients listed, though there is a continuing shortage of donor livers. The liver transplant waiting list mortality in the UK is currently 8-10% per annum (1).

The use of livers from DCD donors has increased considerably in recent years and has come to represent almost 20% of liver transplantations performed in the UK (1). The majority of these grafts continue to undergo super rapid recovery, however the use of preservation machines, both in situ and ex situ, have expanded further the utilisation of these grafts.

Historically, the long-term outcome for liver transplantation from DCD donors has been inferior to livers from DBD donors. However, comparable outcomes for DBD and DCD livers after transplantation can be achieved (2). It is also becoming apparent that the outcome of DCD livers depends on a number of donor and recipient factors, as well as technical factors in relation to the organ retrieval and implantation.

10.2 Donor Selection

Donor age has played an important role in risk stratification, and in the early era, donors more than 50-60 years old were considered high risk (4,5). Recent experience and published literature suggest that good outcomes with older DCD can be achieved (6). Therefore, the influence of donor age (namely >60 years) on the results of liver transplantation using a DCD graft is debatable.

Adoption of a maximum age limit and expanding the donor pool are dependent on many factors, including the centre policy and the burden on the transplant waitlist. Centres that have conservative approaches should be encouraged to expand their donor selection criteria because the overall benefit will then lean towards reducing the national wait list (3).

A previous study has reported comparable outcomes including ischaemic cholangiopathy with DCD grafts from donors older than 60 years old (4). A further single centre series found no difference in complications when comparing livers transplanted from donors less than 70 years old compared with donors >70 years old(6). On the other hand, a retrospective cohort study performed on the Eurotransplant database highlighted a linear association between donor age and graft failure with the increased risk of graft failure associated with prolonged CIT (7). We would suggest the use of DCD donors without age limit if the rest of the donor demographics and other variables (e.g., short ischaemic times) are favourable.

Donors with high BMI are considered to be at risk of graft loss in DCD transplantation as well as DBD. A higher BMI is likely to be a surrogate for steatosis in liver grafts. Previous experience has shown a negative impact of donor BMI >25 kg/m² at any donor age on graft and patient survival (4). However, more recent studies have demonstrated good outcomes with DCD grafts from donors with BMI >35 kg/m² (8). We would suggest that donor BMI alone should not be a decision-making factor in DCD liver transplantation.

10.3 Donor Warm Ischaemic Times

The withdrawal time is defined as the time from donor withdrawal of treatment to initiation of cold perfusion or the start of normothermic regional perfusion (see Chapter 3, section 3.2). The functional warm ischaemia time (FWIT) starts when the systolic blood pressure has a sustained (i.e., at least 2 minutes) fall below 50 mmHg and extends up to the onset of cold in situ perfusion or normothermic regional perfusion. There are several published definitions in the literature as well as several analyses regarding the relationship between post-transplant graft loss and ischaemic cholangiopathy. Absolute cut-off values to define the onset of FWIT are less clear in the published literature as different countries have different thresholds.

The UNOS registry identifies FWIT as the period of time from when donor SBP drops below 80 mmHg and/or donor SpO2 drops below 80% (9). A period of time longer than 30 minutes has been considered an increased risk for graft loss.

On the other hand, publications from the SRTR (Scientific Registry of Transplant Recipients) data have identified that livers with withdrawal to perfusion time (termed by them as the donor warm ischaemic time, DWIT) of between 30-40 minutes showed similar graft survival compared to livers from DCD donors with <30 minutes. It would be reasonable to consider the use of DCD livers from donors with withdrawal to perfusion times slightly longer than 30 minutes in selected recipients (10), in the absence of NRP. FWIT with SpO₂ <60% was found on univariate analysis among patients who developed a post-transplant complication. When controlling for the effect of CIT and donor age, FWIT was not found to be a significant predictor of the development of post-transplant complications (11). The hypothesis is that ischaemic hepatic injury is more closely related to the onset of hypoxia rather than hypotension. Hypoxia would be more detrimental to DCD donor livers than hypotension during the agonal phase; and a drop in SpO₂ to <80% is much more relevant to assess the potential severity of hepatic ischaemia-reperfusion injury (IRI). The rationale behind this is that the lack of oxygenated metabolism leads to energy depletion; the anaerobic metabolism is insufficient to meet energy demand, culminating in cellular oedema and death. However, the accuracy of pulse oximetry is limited in the setting of severe hypoxia or hypotension, which is an issue with the evidence in this area (see Chapter 3, section 3.2). We therefore suggest that serial arterial blood gases during the withdrawal phase should be used as an additional tool to determine the onset of anaerobic respiration by providing lactate measurements above normal range or rising from baseline. One of the first analyses on the field of warm ischaemia time and use of DCD grafts comes from Ho et al in 2008 (12). This study (among the few multicentre studies) examined DCD donor post-extubation hypotension and subsequent liver and kidney graft outcomes in terms of graft survival. This paper was the first one to report that the time period from SBP less than 50 mmHg to aortic flush was the best predictive test for graft survival. Another multicentre study published by Coffey et al has measured FWIT as SBP less than 50 mmHg, however, no association with graft survival was analysed (11).

The previous British Transplantation Society DCD guidelines defined the start of FWIT to be when SpO₂ drops below 80% or SBP <50 mmHg and it recommended not to use liver grafts for transplantation if this time exceeded 30 minutes (12). It was seen in previous studies that the duration of SBP <50mmHg is directly correlated with increased rates of ischaemic cholangiopathy, graft loss or death and there is no new solid evidence to suggest that these thresholds should be changed when traditional rapid recovery is employed(13).

We suggest that the onset of FWIT is defined as the time period between the systolic blood pressure drop <50mmHg following the withdrawal of life support, until aortic cold flush is instituted or NRP is commenced.

10.4 Donor Hepatectomy Time, and Time Between Donor Hepatectomy and Into the Ice Box

Maintaining the organ temperature is key in organ preservation and has been linked to PNF. Once cross-clamping is performed, arterial and portal perfusion is started in addition to ice slush in the abdominal cavity. Evidence suggests that organ core temperature is lowered down to 16°C within approximately 11 minutes after initiation of organ cold flush (14). During the next phase, the liver is explanted and by the end of this phase, liver temperature descends to 10°C. The final desired core temperature of 4°C is achieved and maintained only after the liver is packed and inserted in the transport box.  Until the liver has cooled down it will continue to experience a higher metabolic rate in an ischaemic environment. It takes a short period of time to cool livers down to 10°C but after flushing is stopped, temperature depression is markedly decreased. An experimental study has observed that static storage at +1°C improved liver function compared with +4°C or -0.5°C (15).

In a study performed by Farid et al, the median donor hepatectomy time (DHT – time between start of cold perfusion to liver on the back-table) was 35 minutes and in the multivariate analysis, the factors associated with graft survival were hepatectomy time longer than 60 minutes, donor older than 45 years, CIT longer than 8 hours and recipient with previous abdominal surgery (16).

Goussous et al have described in a comparative retrospective review (historic group before 2014 and modern group after 2014) that when DHT was dichotomized at <22 minutes versus >22 minutes, a longer DHT was associated to development of ischaemic cholangiopathy (IC) (17).

Jochmans et al found that DCD liver grafts are more susceptible to poor outcomes compared to DBD when DHT is longer. If DHT is prolonged, there will be insufficient cooling in the abdominal cavity leading to rewarming of the graft, with the initiation of ischaemic injury to the donor liver, impacting the graft survival (18).

Evidence is still less clear at which point exactly the DHT starts to have a detrimental effect. Gilbo et alsuggested that there is a linear relationship between DHT and IC and there is a 19% increment in the rate of IC for every 10 minutes increase in DHT (this effect is similar to a one-hour increase in CIT) (19). Other studies have reported that DHT is a significant independent risk factor for IC after DCD liver transplantation (20).

A key period is also the time from aortic/portal flush in situ until the liver is placed into the transport ice box and in the previous study that time was a median of a further 33 minutes (19). Although the fluid in the bowl is cold this is not enough to guarantee the rewarming of the graft doesn’t occur causing a deleterious effect on the bile duct viability. Therefore, we would suggest aiming for no more than one hour from knife-to-skin to liver placement into the ice box time as an achievable target that all NORS teams should be encouraged to achieve. This requires good coordination, communication and teamwork between surgeons and other members of the scrub team.

10.5 Use of Ex situ Machine Perfusion

Ex situ machine perfusion is a preservation method occurring outside the donor’s body, developed to protect organs from the detrimental effects of ischaemia-reperfusion injury (IRI), enable assessment of function, and facilitate the repair/regeneration of DCD grafts in order to expand the donor pool and improve graft function after liver transplantation. Ex situ machine perfusion may be at normal body temperature (normothermic) using a blood-based perfusate, this is termed normothermic machine perfusion (NMP). Ex situ machine perfusion may also be hypothermic, termed hypothermic machine perfusion (HMP). The current evidence favours oxygenating the perfusate, a technique called hypothermic oxygenated machine perfusion (HOPE), running at a temperature of 4 to 10°C. NMP offers the advantage to assess graft viability under more physiologic conditions (21).

To date, there are no clinical trials directly comparing SCS to NMP specifically for DCD livers. The first randomised controlled trial comparing SCS and NMP was the COPE study, which included DBD and DCD liver grafts. The rate of non-anastomotic strictures in the NMP DCD group (11.1%) was non-significantly lower than in SCS (26.3%) despite longer functional warm ischaemia time, although the study was not powered sufficiently to show any statistically significant difference in this outcome measure (22).

A retrospective study analysing the rate of discarded livers concluded that NMP reduces the discard rate of procured livers despite its use in donors traditionally considered of more marginal quality. In that study the NMP group had a 3.5% discard rate versus 13.3% in the SCS group and this was despite NMP donors being older and more frequently DCD (18% vs 7%, p<0.001). The second most common reason for liver discard in the SCS group was DCD warm ischemic time (11%) (23).

In one multicentre, randomised controlled trial, patients received transplantation of a liver obtained from a DCD donor either after dual hypothermic oxygenated machine perfusion (machine perfusion group) or after conventional static cold storage alone (control group). The authors used a dual perfusion approach (both portal vein and hepatic artery) and the argument for this is that the bile duct is dependent on the delivery of oxygen through the hepatic artery. However, previous studies using only HOPE (without hepatic artery perfusion) stated that perfusion through portal vein of high concentration of oxygen would be enough to supply the entire graft. They have described a lower risk of symptomatic non-anastomotic biliary stricture after using hypothermic oxygenated machine perfusion of 6% compared to 18%, and a four-fold decrease in the number of treatments for this complication. Interestingly, the rate of asymptomatic biliary abnormalities was high (~60%) for both groups (24,25).

Protective effects of HOPE or dual perfusion HOPE (DHOPE) were investigated in a retrospective study in extended criteria donor (ECD) DBD and overextended WIT DCD grafts. This retrospective case series included 50 grafts subjected to end-ischaemic HOPE or DHOPE. All the DCD grafts were subjected to normothermic regional perfusion before organ procurement. Cold preservation time greater than 9 hours was associated with early allograft dysfunction (EAD) indicating the need to reduce cold preservation time in the setting of DHOPE (26).

A retrospective multicentre comparative outcomes study (one Swiss and six French centres) compared grafts recovered from NRP with grafts preserved in hypothermic machine perfusion. Both techniques achieved similar one year post-transplant recipient and graft survival rates exceeding 85% and comparable to the benchmark values observed in standard DBD liver transplantation (27). An Italian retrospective study comparing DCD livers recovered after NRP+DHOPE compared with conventional static cold storage subjected to long warm ischaemia time, as per the Italian policies, showed a lower incidence of acute kidney injury in the NRP-DHOPE group, but no statistical differences regarding IC (28).

We consider that before engaging in further RCT comparing different types of MP or SCS, surrogate biomarkers as endpoints need to be better defined, mainly in the DCD field. The concept of EAD defined following a cohort of DBD grafts cannot be applied and expect the same utility in a DCD cohort (29). Also, the use of AST/ALT as an endpoint in these types of studies should not be advised as they reflect hepatocyte damage and they are of very limited value in predicting biliary complications. Bile duct injury has emerged as the most relevant factor determining the performance of an organ in the DCD and machine perfusion era.

We recommend that machine perfusion technologies, regardless of the type, have allowed safe transplantation of DCD liver grafts. However, evidence is less clear on which technique is superior and preventive of ischaemic cholangiopathy as there is a lack of properly randomised studies. So, the use of machine perfusion technology should be based on individual centre preference and experience.

10.6 Organ Retrieval Specifics

10.6.1 Preservation Solution

In order to minimise the detrimental effects of warm ischaemia, the abdominal organs are required to be immediately flushed with an ice-cold preservation solution as soon as possible after death has been declared. As a result of the donor warm ischaemia, ATP levels are progressively depleted.

University of Wisconsin (UW) solution has been used for the majority of DCD donor procedures in the UK, in contrast to data from the European Liver Transplant Registry where cold organ flush was performed using mainly HTK. A retrospective and comparative study related to DCD liver retrieval concluded that HTK compared with the use of UW has a higher rate of biliary complications (30). Data suggest that the use of HTK may be associated with higher liver graft loss in cases where CIT is estimated to be more than 8 hours (31,32).

10.6.2 Aortic-only Versus Dual Perfusion

Regarding aortic versus dual perfusion, the latter should in theory achieve more comprehensive liver perfusion and cooling at a faster rate, however, the final liver temperature appears to be very similar to that achieved via aortic flush alone. Some authors have recommended dual perfusion during DCD liver retrieval, and this is recommended in NHSBT guidance. Although the evidence supporting this practice is relatively limited (33,34), we suggest that dual perfusion during DCD liver retrieval should be the standard.

10.7 Immunosuppression

The utilisation of DCD grafts is associated with increased ischaemia-reperfusion injury predisposing to both acute and chronic renal injury. There is a theory that induction therapy with antibodies may provide an umbrella of protection allowing the delayed introduction of calcineurin inhibitors. However, there is currently no evidence indicating that there should be a difference in the immunosuppression protocol for DCD when compared to DBD liver transplantation.

10.8 Outcomes

We have observed an improvement in graft survival in DCD recipients over the last decade, mainly in the first year of transplantation (1). An improvement in surgical and endoscopic techniques, reduction in ischaemic times and better recipient selection have considerably contributed to this improvement. Trends for DCD outcomes according to two different eras (2008-2011 and 2012-2016) have been reported. In the second era, there were no differences in mortality rates between those receiving a DCD versus a DBD graft (2). One of the major improvements from a procurement and organ preservation point of view has been the use of normothermic regional perfusion combined and/or ex situ machine perfusion. The use of NRP has improved not only organ utilisation but also survival outcomes. From 1470 DCD first liver transplants, 94 (6%) were recovered in NRP. In the NRP group, the event death or graft loss within 12 months was 7% versus 13% in the non-NRP group (35).

10.9 Paediatric Liver Transplantation

The burden of the paediatric liver transplant waitlist does not exceed 50 patients and waitlist mortality is less than 5% per annum. For reasons of early inferior outcomes, the use of DCD liver grafts in the paediatric population should be done only in highly selective situations.

Historically, the use of DCD grafts has been associated with higher risks of PNF, IC, acute kidney injury, vascular thrombosis, and lower graft survival (36,37), hence, the reluctance to use DCD donors for liver transplantation in the paediatric population. With better donor selection and strict acceptance criteria, similar outcomes to those from DBD donors have been achieved with adequate donor and recipient selection (38).

10.9.1 Donor Selection

Two centres in the UK have published outcomes of DCD liver transplantation in children, and both suggest highly selective donor criteria (39,40). Both centres concluded that donor selection is paramount to achieving good outcomes. The recommended criteria considered for appropriate donor selection in children in the UK are:

– Donor age <40-45 years-old

– ITU stay <5 days

– Normal liver function tests

– FWIT <30 minutes

– Normal liver appearance and perfusion after recovery

The graft type could be a full graft if the donor size matched the intended recipient, or a cut-down (reduced size liver). Splitting an organ to two transplantable lobes is not recommended as there is no data to support this approach.

10.9.2 Recipient Selection

Despite the good outcomes reported by different centres, the decision to use DCD livers in critically ill children should be taken carefully, analysing the risk-benefit case-by-case, and when a good quality DBD liver or a suitable living donor is not available in a timely manner.

The main controversies when utilising DCD livers in children are the difficulty to find a size-matched graft in case of requiring an emergency re-transplantation for PNF or hepatic artery thrombosis (HAT), and the unknown long-term outcomes of these grafts in patients likely to have a longer life expectancy when compared to the adult population.

10.9.3 Outcomes

Despite the limited experience around the world in paediatric DCD liver transplantation, single-centre series reported by large volume transplant units have published patient and graft survival rates of 100% at three-years follow-up, with no increased incidence of PNF, vascular complications or biliary complications (39,40).

A multi-centre retrospective study in the Netherlands reported the outcomes of 20 paediatric DCD donors used in either children or adults.  They reported a graft survival rate of 65% at one year in the DCD group, compared to 82% at one year in the DBD group, with most cases of graft failure occurring in the first three months. When excluding those donors with FWIT >30 minutes, one-year graft survival rate in DCD LT was 81%, like the DBD group.  All cases with FWIT >30 minutes lost the graft because of PNF or HAT.

In the Dutch study, the incidence of IC in paediatric DCD grafts was relatively low and similar to the incidence in paediatric DBD grafts (5% versus 4% respectively) and lower than the incidence of IC in adult DCD LT. These findings suggest that the regenerative capacity is better preserved in younger donors and that the biliary epithelium in children is more resilient to ischaemia and reperfusion injury (41).

Long-term complications were observed in two patients who had biochemical evidence of persisting cholestasis, both of whom had histological features of chronic rejection. No difference was observed in the prevalence of post-transplant cholestasis in paediatric recipients of DCD livers depending upon the type of biliary enteric anastomosis. In the presence of a normal recipient bile duct, choledocho-choledochostomy is the preferred method. However, due to the large number of children with biliary atresia, or the small size of the bile duct, Roux-en-Y hepatico-jejunostomy is commonly required.

10.9.4 Machine Perfusion in Paediatric Liver Transplantation

The first successful paediatric DCD LT after hypothermic machine perfusion has been reported by a team in the Netherlands. A whole DCD liver from a 13-year-old donor underwent a dual combined arterial and portal hypothermic oxygenated ex situ for two hours before implantation in a 16-year-old patient with progressive familial cholestasis. After one year of follow-up, the liver function and a routine liver biopsy were completely normal (42).

Different authors have shown the feasibility of splitting a DBD liver during HOPE, with the possibility of removing the left lateral segment from the circuit first, allowing the right lobe to stay perfused until it is utilisedor put in the ice box to be transported to another centre. All grafts were successfully transplanted in adult and paediatric recipients, but further evidence in DCD livers and careful implementation is required (43,44).

The feasibility of splitting livers during ex situ normothermic machine perfusion has also been demonstrated(45). The group from Birmingham published the first study demonstrating that splitting a DCD liver during NMP is feasible and viability is maintained when measuring good viability criteria separately in both hepatic arteries(46).

In summary, current experience shows that good outcomes can be achieved in paediatric liver transplantation from DCD donors, with lower risk of PNF and ischaemic cholangiopathy when donors are selected carefully.  Although data are limited, it is also suggested that the outcomes when using DCD grafts from paediatric donors are better than adult DCD donors.  Satisfactory outcomes of whole, reduced or split grafts from selected young DCD donors have been reported in small children if the CIT is kept below 8 hours and FWIT <30 minutes. Further experience is needed before recommending a wider practice of this approach.

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