Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This large open labelled multi-centre randomised control trial is an exciting development in the field of liver HMP. The key strength of this work is that 43% (n=27) of the HMP-O2 livers had continuous perfusion, having been placed on device at the donor. This is the first trial in liver HMP to do this and is an important development. Made possible by Organ Recovery Systems portable Lifeport Liver device, especially considering 81% travelled by air, a current limitation of the portable NMP devices. They demonstrated a nonsignificant reduction in EAD with 11% in HMP-O2 and 16% in SCS, while the finding is not significant it is in keeping with the 5 other published RCTs on HMP liver. The lack of significance may derive from the fact that within the intervention group only 24% were ECDs (including 5 DCD), upon sub-group analysis of these ECDs they find the reduction of EAD to be significant (20% in HMP-O2 and 33.3% in SCS p=0.004). This is in keeping with previous large RCTs that the beneficial effects of HMP-O2 are amplified in the ECD cohort, especially in DCDs seen in Rijn et al’s 2021 trial published in the New England Journal who perfused only DCD livers. None of their secondary outcomes reach significance, but with PNF only occurring in the SCS group with 3 patients and a further 2 (n=5 6.8%) went on to require re-transplant also due to ischaemic cholangiopathy. In HMP-O2 only 1 required retransplant, this was due to HAT. Biliary complications were nearly double in the SCS group (26.4% vs 12.7%) which is impressive, but again this failed to reach significance. The trends are encouraging, but the lack of significance is disappointing, the trial having not been powered for overall EAD rates. An increase cohort size and a focus on EADs could have led to more dramatic results with potentially significance in many of the outcomes. An interesting note is the preservation fluid used in HMP-O2 was Vasosol, a UW-like solution with the addition of nitric oxide donors and vasodilators, this is the first HMP RCT across all organs to utilise this solution and could, in part be responsible for some of the beneficial trends. Unfortunately, the study was not sufficiently powered to compare continuous HMP-O2 with end-ischaemic HMP-O2 and SCS, the overall storage duration being comparable, but the percentage of that time being perfusion obviously being highest in the continuous group. They demonstrate safety and non-inferior efficacy of a novel portable device, which as it becomes more popular and people become more familiar with placing livers on device at retrieval more data should emerge on continuous HMP-O2, this trial was an important step.
Aims:
To assess if HMP-O2 improves liver transplant outcomes compare to cold storage.
Interventions:
Livers were randomised to intervention, which was HMP-O2 on the Lifeport Liver Transporter device, perfused with Vasosol, or control, which was static cold storage.
Participants:
179 adult whole liver transplant recipients.
Outcomes:
The primary outcome was early allograft dysfunction (EAD) as defined by the Olthoff criteria. Secondary outcome measures were PNF, AKI, graft survival, biliary complications. Vascular complications and death. Additional exploratory outcomes were hospital LOS, ICU LOS, lactate clearance, bleeding, incisional hernia and SAEs.
Follow Up:
12 months
BACKGROUND AND AIMS:
In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic oxygenated machine perfusion (HMP-O 2 ) has shown benefits compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O 2 device in the first US randomized control trial.
APPROACH AND RESULTS:
The PILOT trial (NCT03484455) was a multicenter, randomized, open-label, noninferiority trial, with participants randomized to HMP-O 2 or SCS. HMP-O 2 livers were preserved using the Lifeport Liver Transporter and Vasosol perfusion solution. The primary outcome was early allograft dysfunction. Noninferiority margin was 7.5%. From April 3, 2019, to July 12, 2022, 179 patients were randomized to HMP-O 2 (n=90) or SCS (n=89). The per-protocol cohort included 63 HMP-O 2 and 73 SCS. Early allograft dysfunction occurred in 11.1% HMP-O 2 (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O 2 and SCS was -5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. The risk of graft failure as predicted by Liver Graft Assessment Following Transplant score at seven days (L-GrAFT 7 ) was lower with HMP-O 2 [median (IQR) 3.4% (2.4-6.5) vs. 4.5% (2.9-9.4), p =0.024]. Primary nonfunction occurred in 2.2% of all SCS (n=3, p =0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O 2 ( p =0.18). Nonanastomotic biliary strictures occurred only in SCS (n=4).
CONCLUSIONS:
HMP-O 2 demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. Early allograft failure by L-GrAFT 7 was lower in HMP-O 2 , suggesting improved early clinical function. Recipients of HMP-O 2 livers also demonstrated a lower incidence of primary nonfunction and biliary strictures, although this difference did not reach significance.
Ischaemic cold static storage (ICSS) is the gold standard in donor heart preservation. This ischaemic time frame renders a time constraint and risk for primary graft dysfunction. Cold oxygenated heart perfusion, known as non-ischaemic heart preservation (NIHP), theoretically limits the ischaemic time, while holding on to the known advantage of hypothermia and cardioplegia, a low metabolic rate.
METHODS AND ANALYSIS:
The NIHP 2019 study is an international, randomised, controlled, open, multicentre clinical trial in 15 heart transplantation centres in 8 European countries and includes 202 patients undergoing heart transplantation, allocated 1:1 to NIHP or ICSS. Enrolment is estimated to be 30 months after study initiation. The patients are followed for 12 months after transplantation.The primary objective is to evaluate the effect of NIHP on survival, allograft function and rejection episodes within the first 30 days after transplantation. The secondary objectives are to compare treatment groups with respect to survival, allograft function, cardiac biomarkers, rejection episodes, allograft vasculopathy, adverse events and adverse device effects within 12 months.
ETHICS AND DISSEMINATION:
This protocol was approved by the Ethics Committee (EC) for Research UZ/KU Leuven, Belgium, the coordinating EC in Germany (Bei Der LMU München), the coordinating EC in the UK (West Midlands-South Birmingham Research), the EC of Hospital Puerta de Hierro, Madrid, Spain, the EC of Göteborg, Sweden, the coordinating EC in France, the EC of Padova, Italy and the EC of the University of Vienna, Austria. This study will be conducted in accordance with current local regulations and international applicable regulatory requirements according to the principles of the Declaration of Helsinki and ISO14155:2020. Main primary and secondary outcomes will be published on modified intention-to-treat population and per-protocol population.
Liver transplantation is the last therapeutic option for patients with end-stage liver disease. Postreperfusion syndrome (PRS), defined as a fall in mean arterial pressure of more than 30% within the first 5 minutes after reperfusion of at least 1 minute, can occur in liver transplantation as a deep hemodynamic instability with associated hyperfibrinolysis immediately after reperfusion of the new graft. Its incidence has remained unchanged since it was first described in 1987. PRS is related to ischemia-reperfusion (I/R) injury, whose pathophysiology involves the release of several mediators from both the donor and the recipient. The antioxidant effect of ascorbic acid has been studied in resuscitating patients with septic shock and burns. Even today, there are publications with conflicting results, and there is a need for further studies to confirm or rule out the usefulness of this drug in this group of patients. The addition of ascorbic acid to preservation solutions used in solid organ transplantation is under investigation to harness its antioxidant effect and mitigate I/R injury. Since PRS could be considered a manifestation of I/R injury, we believe that the possible beneficial effect of ascorbic acid on the occurrence of PRS should be investigated.
OBJECTIVE:
The aim of this randomized controlled trial is to assess the benefits of ascorbic acid over saline in the development of PRS in adult liver transplantation.
METHODS:
We plan to conduct a single-center randomized controlled trial at the Hospital Universitario Ramón y Cajal in Spain. A total of 70 participants aged 18 years or older undergoing liver transplantation will be randomized to receive either ascorbic acid or saline. The primary outcome will be the difference between groups in the incidence of PRS. The randomized controlled trial will be conducted under conditions of respect for fundamental human rights and ethical principles governing biomedical research involving human participants and in accordance with the international recommendations contained in the Declaration of Helsinki and its subsequent revisions.
RESULTS:
The enrollment process began in 2020. A total of 35 patients have been recruited so far. Data cleaning and analysis are expected to occur in the first months of 2024. Results are expected around the middle of 2024.
CONCLUSIONS:
We believe that this study could be particularly relevant because it will be the first to analyze the clinical effect of ascorbic acid in liver transplantation. Moreover, we believe that this study fills an important gap in the knowledge of the potential benefits of ascorbic acid in the field of liver transplantation, particularly in relation to PRS.
TRIAL REGISTRATION:
European Union Drug Regulating Authorities Clinical Trials Database 2020-000123-39; https://tinyurl.com/2cfzddw8; ClinicalTrials.gov NCT05754242; https://tinyurl.com/346vw7sm.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This well-written report details an analysis of perfusate samples collected during the COMPARE study, an RCT comparing oxygenated with non-oxygenated machine perfusion. Mass spectrometry was used to analyse the proteomic make up of the perfusate fluid. During hypothermic machine perfusion, proteins enter the perfusate system, increasing over time. The authors explored the relation between perfusate proteins and clinical outcomes, with some indication that outcomes such as acute rejection and kidney function at 12 months.
Aims:
The aim of this study was to provide mechanistic insight into biological alterations that occur in deceased donor kidneys during standard nonoxygenated versus oxygenated hypothermic machine perfusion (HMP), using perfusate samples collected in the COMPARE study.
Interventions:
In the COMPARE trial, pairs of kidneys donated following circulatory death were randomly assigned to receive either oxygenated HMP or nonoxygenated HMP.
Participants:
210 perfusate samples.
Outcomes:
The main outcome of this paper was to identify protein changes across durations of perfusion and in relation to 12-month estimated glomerular filtration rate (eGFR).
Follow Up:
12 months
OBJECTIVE:
To provide mechanistic insight into key biological alterations in donation after circulatory death kidneys during continuous pefusion we performed mass spectrometry profiling of perfusate samples collected during a phase 3 randomized double-blind paired clinical trial of hypothermic machine perfusion with and without oxygen (COMPARE).
BACKGROUND:
Despite the clinical benefits of novel perfusion technologies aiming to better preserve donor organs, biological processes that may be altered during perfusion have remained largely unexplored. The collection of serial perfusate samples during the COMPARE clinical trial provided a unique resource to study perfusate proteomic profiles, with the hypothesis that in-depth profiling may reveal biologically meaningful information on how donor kidneys benefit from this intervention.
METHODS:
Multiplexed liquid chromatography-tandem mass spectrometry was used to obtain a proteome profile of 210 perfusate samples. Partial least squares discriminant analysis and multivariate analysis involving clinical and perfusion parameters were used to identify associations between profiles and clinical outcomes.
RESULTS:
Identification and quantitation of 1716 proteins indicated that proteins released during perfusion originate from the kidney tissue and blood, with blood-based proteins being the majority. Data show that the overall hypothermic machine perfusion duration is associated with increasing levels of a subgroup of proteins. Notably, high-density lipoprotein and complement cascade proteins are associated with 12-month outcomes, and blood-derived proteins are enriched in the perfusate of kidneys that developed acute rejection.
CONCLUSIONS:
Perfusate profiling by mass spectrometry was informative and revealed proteomic changes that are biologically meaningful and, in part, explain the clinical observations of the COMPARE trial.
Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This small, randomised control trial looked at early post-transplant outcomes after dHOPE compared with SCS in an undifferentiated group of DBD livers. They found no significant difference in their primary outcome of MEAF score between the two groups. They also found no difference in all grades of complications, mortality, post-reperfusion syndrome rates, comprehensive complications index (CCI), L-GrAFT7, or the other non-prespecified secondary outcomes, ITU stay, PNF, EAD and EASE score. The lack of significant benefits were similar to that seen in Schlegal et al’s recent larger multicentre randomised trial who used CCI as their primary outcome. In this study, only 26 livers were in the intervention group and they were hoping to detect a MEAF score reduction of 1.5, a delta in primary outcome of no specific significance. The small number and lack of power calculation has meant there is significant risk of falsely negative findings. They performed a sub-group analysis, dividing the livers arbitrarily by DRI, with a cut-off of >1.7 as becoming ‘high-risk’, within this group dHOPE caused a significant reduction in MEAF score (4.92 vs 6.31, p=0.037) and in CCI (p=0.05). This led the authors to conclude that routine use of dHOPE is not recommended in DBD livers, only for those deemed ‘high-risk’. Again, caution is needed with the conclusion that there is no benefit in lower risk livers, given only 12 and 14 livers were in the DRI ≤1.70 and DRI >1.70 respectively. The trial is appropriately randomised, but was not blinded due to logistical reasons, which with a device trial of this nature is challenging. There is no information given regarding drop-outs or protocol breaches. The area of investigation is interesting and a valid research question, however, this trial is not sufficiently powered to be relied upon as a negative study. They have highlighted a potential difference in benefit, or lack there of depending on the quality of donor, and future studies should consider this and power specifically for sub-group analysis.
Aims:
To assess if dual hypothermic oxygenated perfusion (dHOPE) prior to transplantation improves the Model for Early Allograft Function (MEAF) score during the 72 hours following transplant compared with static cold storage (SCS).
Interventions:
The intervention group received at least 2 hours of dHOPE prior to transplantation, and the control group underwent standard SCS.
Participants:
104 adult whole liver transplant recipients from donation after brainstem death.
Outcomes:
The primary outcome was MEAF score during the 72 hours post transplant. Secondary outcomes were complications over 90-days, 7-day liver graft assessment following transplantation (L-GrAFT7), post-reperfusion syndrome rate, comprehensive complication index (CCI) and mortality.
Follow Up:
Not reported
OBJECTIVE:
To assess whether end-ischemic hypothermic oxygenated machine perfusion (HOPE) is superior to static cold storage (SCS) in preserving livers procured from donors after brain death (DBD).
BACKGROUND:
There is increasing evidence of the benefits of HOPE in liver transplantation, but predominantly in the setting of high-risk donors.
METHODS:
In this randomized clinical trial, livers procured from DBDs were randomly assigned to either end-ischemic dual HOPE for at least 2 hours or SCS (1:3 allocation ratio). The Model for Early Allograft Function (MEAF) was the primary outcome measure. The secondary outcome measure was 90-day morbidity (ClinicalTrials. gov, NCT04812054).
RESULTS:
Of the 104 liver transplantations included in the study, 26 were assigned to HOPE and 78 to SCS. Mean MEAF was 4.94 and 5.49 in the HOPE and SCS groups ( P =0.24), respectively, with the corresponding rates of MEAF >8 of 3.8% (1/26) and 15.4% (12/78; P =0.18). Median Comprehensive Complication Index was 20.9 after transplantations with HOPE and 21.8 after transplantations with SCS ( P =0.19). Transaminase activity, bilirubin concentration, and international normalized ratio were similar in both groups. In the case of donor risk index >1.70, HOPE was associated with significantly lower mean MEAF (4.92 vs 6.31; P =0.037) and lower median Comprehensive Complication Index (4.35 vs 22.6; P =0.050). No significant differences between HOPE and SCS were observed for lower donor risk index values.
CONCLUSION:
Routine use of HOPE in DBD liver transplantations does not seem justified as the clinical benefits are limited to high-risk donors.
Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This unblinded randomised trial compared the outcomes of liver transplantation following either normothermic machine perfusion (NMP) or static cold storage (SCS). The study employed a ‘device-to-donor’ methodology where the Organox metra device is transported to the site of organ retrieval, which the authors highlight is logistically more challenging. 266 livers were included in the analysis. The primary endpoint was early allograft dysfunction (EAD), defined as abnormal liver parameters 7 days after transplantation. There was no significant difference in EAD between the 2 groups. Although the difference in EAD was numerically greater when using an as treated or sub-group analysis of higher risk groups (high DRI, DCD donor), this to failed to reach statistical significance. The authors reached conclusions similar to that of previous European trials – NMP is a safe modality and shows potential to improve outcomes in marginal organs.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
3
Review:
The use of machine preservation technologies in liver transplantation has been gaining pace over recent years, with centres using a mixture of normothermic machine perfusion (NMP), hypothermic oxygenated machine perfusion (HOPE) and normothermic regional perfusion (NRP). Machine preservation has the potential to resuscitate the liver, reverse retrieval-related injury, allow longer safe preservation times and enable viability assessment prior to implant. In particular, NMP allows functional assessment of the liver with well-defined parameters predicting early allograft function (1). The first multicentre randomised controlled trial (RCT) of normothermic machine perfusion in Europe was published in 2018, and demonstrated a significant (50%) reduction in the incidence of early allograft dysfunction (EAD) in machine perfused livers, despite longer preservation times (2). These results were replicated in a US study (using a different NMP device), which also demonstrated a significant reduction in the incidence of EAD with NMP (3). Whilst not specifically designed to demonstrate differences in organ utilisation, both studies also showed a reduction in organ discard rates, particularly for donation after cardiac death (DCD) livers. In a recent publication in the Annals of Surgery, Chapman and colleagues report the results of the large multicentre US experience of NMP (4). They used a protocol very similar to that followed in the European RCT. Livers were randomised to either conventional static cold storage (SCS) or NMP, with perfusion initiated at the donor hospital and the liver transported on the device to the implanting centre. In contrast to the European study, the trial did not meet its primary endpoint of demonstrating an overall reduction in EAD. Per-protocol analysis showed similar trends to the prior European and US studies, with greater reduction in EAD rates seen with NMP in DCD and high donor-risk index (DRI) subgroups. Interestingly, there was evidence of a learning curve, with a reduction in EAD rates in the NMP arm following enhanced training during the study. Unlike the previous two RCTs, there was no difference in transplant rate between the arms. One important point to note is that all three RCTs used NMP in a “device-to-donor” configuration, with initiation of NMP at the donor hospital and transport on the device. This has significant logistical challenges, particularly in countries like the US where travel distances are longer and travel by plane is more common. In reality, most centres using NMP routinely in the UK and Europe are using NMP in a “back-to-base” configuration, with transport of the liver under SCS and initiation of perfusion in the recipient centre. Whilst small studies suggest that this does not compromise outcomes for the majority of livers (5), there is no large-scale RCT evidence to support the back-to-base NMP perfusion strategy that many centres are employing. Overall, whilst this study demonstrates a smaller effect size than previous RCTs, it does confirm that the technology is safe and that the main benefit of this technology appears to be for more marginal (high DRI and DCD) livers. References 1. Watson CJE, Gaurav R, Fear C et al. Predicting Early Allograft Function After Normothermic Machine Perfusion. Transplantation 2022; 106: 2391. 2. Nasralla D, Coussios CC, Mergental H et al. A randomized trial of normothermic preservation in liver transplantation. Nature 2018; 557: 50. 3. Markmann JF, Abouljoud MS, Ghobrial RM et al. Impact of Portable Normothermic Blood-Based Machine Perfusion on Outcomes of Liver Transplant: The OCS Liver PROTECT Randomized Clinical Trial. JAMA Surgery 2022; 157: 189. 4. Chapman WC, Barbas AS, D’Alessandro AM et al. Normothermic Machine Perfusion of Donor Livers for Transplantation in the United States - A Randomized Controlled Trial. Annals of Surgery 2023; 5. Ceresa CDL, Nasralla D, Watson CJE et al. Transient Cold Storage Prior to Normothermic Liver Perfusion May Facilitate Adoption of a Novel Technology. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2019; 25: 1503.
Aims:
The aim of this study was to investigate the effectiveness of normothermic machine preservation (NMP) versus static cold storage (SCS) in the prevention of preservation-related graft injury.
Interventions:
Donor livers were randomised to undergo either NMP or SCS.
Participants:
383 donor livers were randomised out of which 266 donor livers were transplanted.
Outcomes:
The primary endpoint was early allograft dysfunction (EAD). Secondary endpoints included graft survival, patient survival, incidence of postreperfusion syndrome, biochemical liver function, biliary complications, histological evidence of ischemia-reperfusion injury, feasibility and safety, health economics and organ utilization.
Follow Up:
12 months
OBJECTIVE:
To compare conventional low-temperature storage of transplant donor livers [static cold storage (SCS)] with storage of the organs at physiological body temperature [normothermic machine perfusion (NMP)].
BACKGROUND:
The high success rate of liver transplantation is constrained by the shortage of transplantable organs (eg, waiting list mortality >20% in many centers). NMP maintains the liver in a functioning state to improve preservation quality and enable testing of the organ before transplantation. This is of greatest potential value with organs from brain-dead donor organs (DBD) with risk factors (age and comorbidities), and those from donors declared dead by cardiovascular criteria (donation after circulatory death).
METHODS:
Three hundred eighty-three donor organs were randomized by 15 US liver transplant centers to undergo NMP (n = 192) or SCS (n = 191). Two hundred sixty-six donor livers proceeded to transplantation (NMP: n = 136; SCS: n = 130). The primary endpoint of the study was "early allograft dysfunction" (EAD), a marker of early posttransplant liver injury and function.
RESULTS:
The difference in the incidence of EAD did not achieve significance, with 20.6% (NMP) versus 23.7% (SCS). Using exploratory, "as-treated" rather than "intent-to-treat," subgroup analyses, there was a greater effect size in donation after circulatory death donor livers (22.8% NMP vs 44.6% SCS) and in organs in the highest risk quartile by donor risk (19.2% NMP vs 33.3% SCS). The incidence of acute cardiovascular decompensation at organ reperfusion, "postreperfusion syndrome," as a secondary outcome was reduced in the NMP arm (5.9% vs 14.6%).
CONCLUSIONS:
NMP did not lower EAD, perhaps related to the inclusion of lower-risk liver donors, as higher-risk donor livers seemed to benefit more. The technology is safe in standard organ recovery and seems to have the greatest benefit for marginal donors.
Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This small unblinded randomised trial was conducted in a single high volume transplant centre in China by the group who have been pioneering the ischaemia-free liver transplant technique since its fist publication in 2018. Images and videos of their technique have been included in their 3 publications on their reports and protocols. The IFLT cohort was n=32 and the CLT n=33, of these 2 (6%) in the IFLT experience EAD and 8 (24%) in the CLT (p=0.044) which was the primary endpoint. In some of the secondary endpoints they found significant improvement with IFLT: peak ALT and ASK at 7 days, total bilirubin, post-op lactate positive perfusate microbial culture and non-anastomotic strictures at 12 months. When scrutinising these strictures, there were 2 in IFLT (one mild and one moderate) and 9 in CLT (five mild and four moderate) none of which required intervention. The marked reduction in post-reperfusion syndrome is important 3 (9%) in IFLT and 21 (64%) in CLT given the risk of post-reperfusion cardiac arrest. They found no significant differences in primary non-function, over-all hospital stay, anastomotic stenosis (though the rate was higher in IFLT) and, graft and patient survival. They present an impressive success given the complexity of the procedure, however this is its key limitation. Despite the improvement in EAD, strictures and post-reperfusion syndrome there was no measurable benefit in patient or graft survival within the first year and none of the strictures require intervention. It was done in a set of low risk DBD donors, a cohort in which similar benefits have been seen with NMP alone. There are technical limitations, it was performed with a liver assist device which is not transportable, thus donor and recipient must be in the same location. The technique is of interest and a great technical achievement, but a study of larger numbers with a wider range of DBD donors and longer-term follow-up is required.
Expert Review
Reviewer:
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Review:
This is a very interesting randomised controlled trial in liver transplantation that has the potential to significantly change practice and improve transplant outcomes. 68 liver transplant recipients from donation after brain death were randomised to standard treatment or for an “Ischemia-Free Liver Transplant” (IFLT). The trial was conducted at a single hospital in China. The study was adequately randomised, but the clinical team could not be blinded to the intervention, understandably. For the intervention group, the Liver Assist device (Organ assist, The Netherlands) was used to establish in situ normothermic perfusion. The liver was then procured and moved to the reservoir of the Liver Assist for ex situ normothermic machine perfusion and moved to the recipient locality for transplant. For the liver implantation to the recipient, the anastomoses of the inferior vena cava, portal vein, and hepatic artery were performed under continuous in situ normothermic machine perfusion. Machine perfusion was discontinued after the donor liver had been revascularized. Then the biliary tract was reconstructed. There was therefore zero cold ischemic time for the IFLT group. Mean cold ischaemic time in the standard care group was approximately 7 hours, and mean normothermic perfusion time in the IFLT group was approximately 7 hours. The primary outcome was Early Allograft Dysfunction (EAD) and this was significantly reduced by IFLT (6% versus 24%), as were peak ALT, AST and bilirubin levels. Post-reperfusion syndrome was dramatically reduced, from 64% to 9%. Non-anastomotic biliary strictures were also significantly reduced (8% versus 36%), although this was recorded as seen on protocol MRCP. This clinical trial has shown a dramatic reduction in the ischemia reperfusion injury of transplant livers through the novel use of technology to remove the cold ischemic phase of the organ preservation period. The donor liver is kept warm and perfused all through the process of procurement from the donor body, preservation outside the body, and during the implant into the recipient up until the moment of reperfusion with the recipient’s blood. The technique clearly improved early transplant function. The reduction in non-anastomotic strictures was largely asymptomatic, so it remains to be seen if this technique can significantly reduce the risk of symptomatic strictures in higher risk livers.
Aims:
To compare outcomes in the novel technique of ischaemia-free liver transplantation (IFLT) to conventional liver transplantation (CLT).
Interventions:
The technique being tested is IFLT compared with CLT. IFLT is a complex technique in which during DBD donation the perfusion cannulas of a Liver Assist can be placed in the donor liver prior to cessation of donor circulation. The arterial canula placed via the splenic artery, portal vein via and vein graft and the outflow canula into the infra-hepatic cava. The perfusion can then seamlessly be transferred from donor circulation to NMP, the liver is then procured and continued NMP until implantation. The supra-hepatic caval (piggyback), portal vein and hepatic arterial anastomoses are then performed in the recipient while NMP continues, and once completed the NMP cannulas are removed, and hepatic perfusion transferred from NMP to recipient without interruption of perfusion.
Participants:
65 adult whole liver-only transplant recipients.
Outcomes:
The primary endpoint was early allograft dysfunction (EAD) within 7 days as defined by the Olthoff criteria. The secondary endpoints included primary non-function, post-reperfusion syndrome, biliary complications, post-reperfusion lactate, post-transplant LFTs, patient and graft survival at 1,6, & 12 months, ITU stay and overall hospital stay.
Follow Up:
12 months
BACKGROUND & AIMS:
Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ availability. Ischemia-free organ transplantation is a novel approach designed to avoid IRI, with the potential to improve outcomes.
METHODS:
In this randomized-controlled clinical trial, recipients of livers from donors after brain death were randomly assigned to receive either an ischemia-free or a 'conventional' transplant. The primary endpoint was the incidence of early allograft dysfunction. Secondary endpoints included complications related to graft IRI.
RESULTS:
Out of 68 randomized patients, 65 underwent transplants and were included in the analysis. 32 patients received ischemia-free liver transplantation (IFLT), and 33 received conventional liver transplantation (CLT). Early allograft dysfunction occurred in two recipients (6%) randomized to IFLT and in eight (24%) randomized to CLT (difference -18%; 95% CI -35% to -1%; p = 0.044). Post-reperfusion syndrome occurred in three recipients (9%) randomized to IFLT and in 21 (64%) randomized to CLT (difference -54%; 95% CI -74% to -35%; p <0.001). Non-anastomotic biliary strictures diagnosed with protocol magnetic resonance cholangiopancreatography at 12 months were observed in two recipients (8%) randomized to IFLT and in nine (36%) randomized to CLT (difference, -28%; 95% CI -50% to -7%; p = 0.014). The comprehensive complication index at 1 year after transplantation was 30.48 (95% CI 23.25-37.71) in the IFLT group vs. 42.14 (95% CI 35.01-49.26) in the CLT group (difference -11.66; 95% CI -21.81 to -1.51; p = 0.025).
CONCLUSIONS:
Among patients with end-stage liver disease, IFLT significantly reduced complications related to IRI compared to a conventional approach.
CLINICAL TRIAL REGISTRATION:
chictr.org. ChiCTR1900021158.
IMPACT AND IMPLICATIONS:
Ischemia-reperfusion injury has thus far been considered as an inevitable event in organ transplantation, compromising outcomes and limiting organ availability. Ischemia-free liver transplantation is a novel approach of transplanting donor livers without interruption of blood supply. We showed that in patients with end-stage liver disease, ischemia-free liver transplantation, compared with a conventional approach, led to reduced complications related to ischemia-reperfusion injury in this randomized trial. This new approach is expected to change the current practice in organ transplantation, improving transplant outcomes, increasing organ utilization, while providing a clinical model to delineate the impact of organ injury on alloimmunity.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This paper reports on a biomarker study conducted alongside the Consortium for Organ Preservation in Europe (COPE) study that compared Oxygenated HMP with standard HMP prior to kidney transplantation. The clinical results have been published previously (Jochmans et al 2020). Flavin Mononucleotide (FMN) is a cofactor for the mitochondrial membrane complex-I, which dissociates from the complex following ischaemia-reperfusion injury. It was therefore speculated that release of FMN in the perfusate whilst on machine perfusion may be an indicator for ischaemic injury, with some evidence in liver transplantation that correlates with poor lactate clearance and early graft loss. Analysis was done by fluorescence spectroscopy and liquid chromatography mass spectrometry. The primary analysis was to correlate FMN levels in machine perfusate immediately prior to transplantation with early and late post-transplant outcomes. Fluorescence in the FMN region was found to significantly increase during the preservation period in kidneys preserved with both oxygenated and standard HMP. As these profiles were similar, results from both groups were combined for the further analysis to increase sensitivity. Despite this approach, FMN was not found to be a clinically relevant biomarker to predict early or late graft function. The authors conducted a validation process, which suggested that the increase in fluorescence during perfusion may not be specifically related to FMN and therefore it may not be reliable perfusate biomarker in kidney transplantation.
Aims:
This study aimed to investigate the ability of flavin mononucleotide (FMN) to predict the quality of kidney grafts during hypothermic machine perfusion (HMP) with oxygenation (HMPO2).
Interventions:
Kidneys were randomised to receive either HMPO2 or HMP.
Participants:
197 kidney pairs (n=394) were randomised, out of which 220 were transplanted.
Outcomes:
The primary outcome was the association between end of perfusion (P3) and early transplant outcomes (immediate graft function, DGF, primary non-function (PNF) and serum creatinine (SCr)) and late post-transplant outcomes (estimated creatinine clearance, graft failure and biopsy proven rejection). The secondary outcomes were associations for the P1 and P2 timepoints (beginning and during perfusion) and the delta perfusion (ΔP) with early and late posttransplant outcomes.
Follow Up:
12 months posttransplantation.
Hypothermic machine perfusion (HMP) provides preservation superior to cold storage and may allow for organ assessment prior to transplantation. Since flavin mononucleotide (FMN) in perfusate has been proposed as a biomarker of organ quality during HMP of donor livers, the aim of this study was to validate FMN as a biomarker for organ quality in the context of HMP preserved kidneys. Perfusate samples (n = 422) from the paired randomised controlled COPE-COMPARE-trial, comparing HMP with oxygenation (HMPO2) versus standard HMP in kidneys, were used. Fluorescence intensity (FI) was assessed using fluorescence spectroscopy (excitation 450nm; emission 500-600nm) and validated by fluorospectrophotometer and targeted liquid chromatography mass spectrometry (LC-MS/MS). Fluorescence intensity (FI)(ex450;em500-600) increased over time during machine perfusion in both groups (p<0.0001). This increase was similar for both groups (p = 0.83). No correlation, however, was found between FI(ex450;em500-600) and post-transplant outcomes, including day 5 or 7 serum creatinine (p = 0.11; p = 0.16), immediate graft function (p = 0.91), creatinine clearance and biopsy-proven rejection at one year (p = 0.14; p = 0.59). LC-MS/MS validation experiments of samples detected FMN in only one perfusate sample, whilst the majority of samples with the highest fluorescence (n = 37/38, 97.4%) remained negative. In the context of clinical kidney HMP, fluorescence spectroscopy unfortunately appears to be not specific and probably unsuitable for FMN. This study shows that FMN does not classify as a clinically relevant predictive biomarker of kidney graft function after transplantation.
CET Conclusion