The outcomes of a successful DCD transplantation, as opposed to donation after brain death (DBD), rely on particular events occurring during the whole process of organ retrieval. In most countries, controlled DCD Maastricht category III is the most frequent form of donation, where withdrawal of life-sustaining therapies (WLST) is planned in a controlled environment. After WLST, the donor warm ischemia time (dWIT) starts and subsequently the vital parameters drop until circulatory arrest. The no-touch period is variable between countries
[1]. After confirmation of death, donor surgery is commenced and organs are retrieved. Defining dWIT is crucial as it has been shown to impact outcomes
[2][3]. Guidelines developed from the International Liver Transplantation Society have summarised the definitions of dWIT: (1) total dWIT is defined as time from donor WLST to cold perfusion; (2) functional dWIT is defined as the timepoint where saturation (SpO2) drops below 70% and/or mean arterial blood pressure (MAP) drops below <50 mm Hg until the start of cold organ flush
[4]. During the recent consensus conference in Venice, a new uniform definition for functional dWIT was introduced, corresponding to the guidelines practised in Spain, where this time starts at a saturation below 80% and a MAP below 60 mmHg
[4]
In the early reports, DCD livers have been linked to inferior long-term outcomes when compared to DBD
[5][6], related to donor risk, graft selection, management of recipients and additional ischemic damage caused by dWIT
[7].
DCD liver transplantation is a common practice in the Western world, mainly in the adult population. A recent report from the UNOS database showed a 10-fold lower utilisation of DCD livers in paediatric recipients compared to adults
[9]. This is related to a more conservative approach in the donor selection for paediatric recipients with a need for optimal grafts. A recent study has shown interesting data regarding paediatric DCD liver procurement and utilisation
[10], where the authors have analysed the Organ Procurement and Transplantation Network (OPTN) and data set contained US recipients undergoing transplantation of livers from DCD donors from 1993 to 2018. Some 17071 DCD liver donors were identified. Groups were divided into paediatric aged 0–12 years (
n = 856, 5%) and adolescent aged 13–17 years (
n = 757, 4.4%), which were compared to donors aged 18–40 years (
n = 6504, 38.1%). Overall, there were 7293 (42.7%) livers recovered with a total of 5124 (30%) DCD livers transplanted. With a thorough analysis, they have demonstrated that paediatric DCD allografts were retrieved at a significantly lower rate (
n = 234/856, 27.3%) compared to donors aged 18–40 (3664/6504, 56.3%), but once procured, these paediatric organs are transplanted at a similar rate to those from the 18–40-year-old cohort. Interestingly, the highest rate of recovery was recorded in the 13–17-year-old group (
n = 486/757, 64.2%). The authors argued that this could be related to the misperception of poor outcomes when smaller organs are transplanted. However, they have shown that the 10-year relative risks for graft failure and patient death were similar between paediatric and adult DCD donors.
2. DCD Liver Transplantation: Overview on Risk Scores and Benchmarking
There are several scores that have been developed in LT based on a relatively limited number of parameters, and they express the total risk up to a risk threshold
[11][12][13][14]. However, their applicability in DCD liver transplants is limited, as they include the variable DCD as overall risk factors without considering some key parameters involved in the DCD injury, e.g., dWIT.
In 2011, authors from UCLA
[15] identified six multivariate factors predictive for graft failure in DCD livers, three from the recipients (diagnosis of hepatitis C virus with malignancy, non–hepatitis C virus with malignancy, or hepatitis C virus only, re-graft, and BMI > 30 and three from the donors (hepatitis B core antibody positivity, mean arterial pressure lower than 60 mm Hg for longer than 20 min after WLST and CIT > 6 h).
The team from Kings College has identified among 261 DCD LT six donor, graft and recipient factors to predict DCD graft failure by the DCD-RI. The score also included 18 (6.9%) paediatric DCD donors and 15 (5.7%) DCD paediatric recipients as there was no difference in adult and paediatric DCD graft survival. The DCD-RI combined functional dWIT, duration of donor hepatectomy, MELD > 25, CIT, indication for transplantation and retransplantation
[16]. According to the calculated DCD-RI score, three risk classes could be defined of low (DCD-RI < 1), standard (DCD-RI 2–4) and high risk (DCD-RI > 5) having graft survival at 5 years of 86%, 78% and 34%, respectively. However, it needs to be highlighted that the DCD cases were not equally distributed to the three risk classes of this score.
The UK-DCD-Risk score was recently developed to define futile donor-recipient combinations in DCD liver transplantation
[17]. Seven parameters (donor age, donor BMI, functional dWIT, CIT, recipient age, recipient MELD and retransplantation) have been found to correlate with graft survival. Although most parameters in the UK-DCD-Risk score are the clinically relevant factors, also described in the paediatric DCD population, the specific role of this model in this recipient category remains unexplored. In addition to the identification of futile DCD constellations, the best possible outcome is of importance to assess the impact of novel treatment modalities. In this context, the tool of Benchmarking was recently developed for DCD liver transplantation.
Among 2219 controlled DCD LT, benchmark values were identified for the adult transplant population as follows: PNF ≤ 2.5%, intensive care unit stay ≤3, in hospital stays ≤16 days, post-operative bleeding ≤ 10.3%, renal replacement therapy ≤ 9.6%, any complications ≤ 95%, ischemic cholangiopathy ≤ 16.8% anastomotic strictures ≤ 28.4% biliary leak ≤ 8.3%, one-year graft loss ≤ 14.4%, retransplantation ≤ 6.9%, one-year mortality ≤ 9.6%
[2]. Of note, paediatric LT from DCD donors reported today were found within these values, particularly the donor risk (i.e., dWIT) was within 15 min asystolic and 30 min total dWIT and also the main outcome parameters, for example, biliary complications and graft survival
[2]. The benchmark tool provides a large comparator cohort to assess the risk and outcome accepted and achieved in a specific cohort.
3. The Potential Role of Machine Perfusion in DCD Liver Transplantation for Paediatric Recipients
Machine perfusion has gained wide interest during the last decades. In adult LT, there is evidence that the different perfusion techniques have an impact on the rate of early allograft dysfunction (EAD), post-transplant complications and graft survival
[18][19][20]. In the setting of DCD liver transplantation, hypothermic oxygenated perfusion (HOPE) was shown to protect recipients from the development of overall and liver-specific complications, including ischemic cholangiopathy and graft loss
[21][22][23][24][25]. Van Rijn et al. have recently demonstrated in the first randomised controlled trial (RCT) a significant reduction in ischemic cholangiopathy with a two-hour dual HOPE in DCD liver grafts
[26].
In 2019, the Groningen group
[27] published the first case of paediatric DCD liver transplantation with the HOPE technique. A graft from a 13-year-old DCD donor was retrieved with the super rapid technique, having a total dWIT (from withdrawal of life support to in situ cold perfusion) of 34 min. Subsequently, after 6.4 h of CIT, the graft underwent pressure-controlled dual HOPE using the Liver Assist (Organ Assist, Groningen, The Netherlands) for 2 h. This DCD liver was used for a 16-year-old recipient affected by progressive familial intrahepatic cholestasis type 2. The surgery was complicated by a relaparotomy due to post-transplant bleeding on day 4. The further recovery and follow up of the recipient were uneventful with no additional complications at the one-year follow-up. Importantly, there were no clinical signs of vascular or biliary complications and a routine liver biopsy was normal. This report showed that HOPE can be safely performed in paediatric livers from DCD donors with successful outcomes.
The hypothermic perfusion techniques were found to protect the recipients from complications through mitochondrial protection
[18][24][25][26][28][29]. In fact, the underlying mechanism of protection through HOPE is directly linked to mitochondria. Cold oxygenation of ischemic tissue reduces previously accumulated Succinate and recharges ATP. The subsequent IRI—cascade of inflammation, which occurs once the organ undergoes normothermic reperfusion (either on a device or in vivo during implantation), is significantly reduced
[30]. Based on the reduced succinate concentration, the initial reoxygenation is less toxic to mitochondrial complex I, which produces less reactive oxygen species (ROS), which is the main instigator of downstream inflammation in the entire organ. As a direct consequence, the release of danger signals, including mitochondrial DNA and damage-associated mitochondrial patterns (DAMPs), is reduced
[31][32][33]. This leads to a reduced activation of the innate immune system and decreases the inflammatory response in the recipient. Morphological features of such HOPE protections are a reduced number of biliary complications, a decreased graft stiffness with lower acute rejection rates and less intrahepatic vascular resistance
[33]. Particularly the rejection and vascular resistance appears beneficial for paediatric grafts with their higher risk of vascular complications and immune system activation. Such interesting mechanisms of protection of the liver graft could pave the way for routine utilisation of HOPE in paediatric DCD and, as such, expand the donor pool.
In addition to ex situ preservation technologies, in situ normothermic regional perfusion (NRP) provided clinical evidence of adequate outcomes in adult LT with DCD grafts
[34][35][36] in terms of biliary complications and graft loss. Italy, Spain and France procure DCD livers routinely with normothermic regional perfusion (NRP) in the donor. Such grafts are obtained based on the macroscopic appearance during 2–4 h of NRP, biopsy results and the level of parameters of injury in circulating donor blood (liver enzymes and lactates). Outcomes after transplantation of such adult DCD grafts appeared good with very low IC rates, although the grafts are of better quality with shorter dWIT
[2][34][35][36]. To date, no reports are available with regards to the utilisation of NRP in DCD livers for paediatric recipients, but this option has been explored in DCD heart transplantation with good outcomes.
[37]
Furthermore, machine perfusion could also promote paediatric LT allowing a split transplantation. This interesting concept of splitting livers during machine perfusion was recently explored by different authors who demonstrated feasibility with both normothermic and hypothermic perfusion techniques
[38][39][40][41][42]. Two case series
[41][43] have shown the feasibility of splitting liver grafts during HOPE. Spada et al. have reported a mono-segmental (SII) split procedure during HOPE, which was successfully transplanted in a 3.7 kg neonate with acute liver failure, whereas the extended right lobe was transplanted in a 9-year-old patient
[40]. Unfortunately, the SII recipient developed a portal vein thrombosis 2 weeks after LT and underwent re-transplantation. Thorne et al. reported a classical splitting procedure with a successful transplant of LLS in a paediatric recipient
[41]. Although both the grafts were retrieved from DBD, the procedure could potentially be applied to DCD grafts, allowing an expansion of organ availability. However, the liver splitting process itself can release inflammatory cytokines as a result of the parenchyma transection, as shown in experimental models
[43][44], and this could potentially contribute to an elevated inflammatory response in the recipient
[43]. In this regard, machine perfusion itself could be a compelling tool to mitigate and downregulate the recipient’s innate immune response. However, such protection from post-transplant IRI and inflammation has been demonstrated for the HOPE technique in the clinical setting and in experimental models
[26][32][33].
Advances in the optimisation of donor stability with extracorporeal membrane oxygenation (ECMO), which is used to support cardiopulmonary failure, could represent another important modality to expand the donor pool
[45][46]. Although no cases of livers donated from DCD donors supported by ECMO have been reported for paediatric recipients, one DBD case was successfully transplanted
[31]. In addition, the availability of a mobile ECMO team could enable the use of this technology in smaller hospitals, as recently demonstrated by authors in Spain
[47].