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  • Ferrer-Fàbrega J
  • Mesnard B
  • Messner F
  • Doppenberg JB
  • Drachenberg C
  • et al.
Transpl Int. 2023 Jul 19;36:11374 doi: 10.3389/ti.2023.11374.

The advent of Machine Perfusion (MP) as a superior form of preservation and assessment for cold storage of both high-risk kidney's and the liver presents opportunities in the field of beta-cell replacement. It is yet unknown whether such techniques, when applied to the pancreas, can increase the pool of suitable donor organs as well as ameliorating the effects of ischemia incurred during the retrieval process. Recent experimental models of pancreatic MP appear promising. Applications of MP to the pancreas, needs refinement regarding perfusion protocols and organ viability assessment criteria. To address the "Role of pancreas machine perfusion to increase the donor pool for beta cell replacement," the European Society for Organ Transplantation (ESOT) assembled a dedicated working group comprising of experts to review literature pertaining to the role of MP as a method of improving donor pancreas quality as well as quantity available for transplant, and to develop guidelines founded on evidence-based reviews in experimental and clinical settings. These were subsequently refined during the Consensus Conference when this took place in Prague.

  • Khajeh E
  • Ramouz A
  • Aminizadeh E
  • Sabetkish N
  • Golriz M
  • et al.
HPB (Oxford). 2023 Jul;25(7):732-746 doi: 10.1016/j.hpb.2023.02.017.
BACKGROUND:

In conventional orthotopic liver transplantation (OLT), the recipient's retrohepatic inferior vena cava (IVC) is completely clamped and replaced with the donor IVC. The piggyback technique has been used to preserve venous return, either via an end-to-side or standard piggyback (SPB), or via a side-to-side or modified piggyback (MPB) anastomosis, using a venous cuff from the recipient hepatic veins with partially clamping and preserves the recipient's inferior vena cava. However, whether these piggyback techniques improve the efficacy of OLT is unclear. To address the low quality of the available evidence, we performed a meta-analysis to compare the efficacy of conventional, MPB, and SPB techniques.

METHODS:

Literature was searched in Medline and Web of Science databases for relevant articles published until 2021 without any time restriction. A Bayesian network meta-analysis was performed to compare the intra- and postoperative outcomes of conventional OLT, MPB, and SPB techniques.

RESULTS:

Forty studies were included, comprising 10,238 patients. MPB and SPB had significantly shorter operation times and fewer transfusions of red blood cell and fresh frozen plasma than conventional techniques. However, there were no differences between MPB and SPB in operation time and blood product transfusion. There were also no differences in primary non-function, retransplantation, portal vein thrombosis, acute kidney injury, renal dysfunction, venous outflow complications, length of hospital and intensive care unit stay, 90-day mortality rate, and graft survival between the three techniques.

CONCLUSION:

MBP and SBP techniques reduce the operation time and need for blood transfusion compared with conventional OLT, but postoperative outcomes are similar. This indicates that all techniques can be implemented based on the experience and policy of the transplant center.

  • van de Leemkolk FEM
  • Lo Faro ML
  • Shaheed S
  • Mulvey JF
  • Huurman VAL
  • et al.
PLoS One. 2023 Jun 23;18(6):e0287713 doi: 10.1371/journal.pone.0287713.
CET Conclusion
Reviewer: 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.

  • Schroder JN
  • Patel CB
  • DeVore AD
  • Bryner BS
  • Casalinova S
  • et al.
N Engl J Med. 2023 Jun 8;388(23):2121-2131 doi: 10.1056/NEJMoa2212438.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This multicentre study randomised patients on the heart transplant waiting list to waiting for a standard, DBD organ; or to a DCD organ (assessed via ex-vivo perfusion) or DBD organ, whichever came first. 297 wait-listed patients were randomised, of whom 180 were transplanted in the study – 90 with DBD organs, and 90 with DCD organs. At 6 months post-transplant, there was no difference in risk-adjusted survival or other clinical outcomes between the two groups. This is a very well-designed study. Studies that alter with organ allocation are challenging as they must not disadvantage patients by reducing the chances of an organ offer. By allowing patients in the DCD arm to receive a DBD organ if allocated, the investigators overcome this. At least in the short term, outcomes from DCD hearts assessed ex-vivo appear equivalent, and have the potential to increase the rate of transplantation – within the study, 67% patients randomised to the DCD cohort were transplanted compared to 39% in the DBD cohort.
Aims: The aim of this study was to investigate posttransplant outcomes of hearts obtained from donation after circulatory death (DCD) versus donation after brain death (DBD) donors.
Interventions: Participants were randomised to receive a heart from either a DCD or DBD donor.
Participants: 297 adult candidates for heart transplantation were randomised, out of which 180 underwent transplantation.
Outcomes: The primary efficacy outcome was patient survival adjusted for prespecified donor and recipient risk factors. The secondary efficacy outcome was the donor-heart utilization rate.
Follow Up: 1 year posttransplantation
BACKGROUND:

Data showing the efficacy and safety of the transplantation of hearts obtained from donors after circulatory death as compared with hearts obtained from donors after brain death are limited.

METHODS:

We conducted a randomized, noninferiority trial in which adult candidates for heart transplantation were assigned in a 3:1 ratio to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group). The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation.

RESULTS:

A total of 180 patients underwent transplantation; 90 (assigned to the circulatory-death group) received a heart donated after circulatory death and 90 (regardless of group assignment) received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor). The risk-adjusted 6-month survival in the as-treated population was 94% (95% confidence interval [CI], 88 to 99) among recipients of a heart from a circulatory-death donor, as compared with 90% (95% CI, 84 to 97) among recipients of a heart from a brain-death donor (least-squares mean difference, -3 percentage points; 90% CI, -10 to 3; P<0.001 for noninferiority [margin, 20 percentage points]). There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation.

CONCLUSIONS:

In this trial, risk-adjusted survival at 6 months after transplantation with a donor heart that had been reanimated and assessed with the use of extracorporeal nonischemic perfusion after circulatory death was not inferior to that after standard-care transplantation with a donor heart that had been preserved with the use of cold storage after brain death. (Funded by TransMedics; ClinicalTrials.gov number, NCT03831048.).

  • Pradat P
  • Pantel S
  • Maynard M
  • Lalande L
  • Thevenon S
  • et al.
Trials. 2023 Jun 6;24(1):379 doi: 10.1186/s13063-023-07402-0.
CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This paper documents in detail the study protocol for a trial of end-ischaemic hypothermic oxygenated machine perfusion (HOPE) in extended criteria donor livers. There is a pragmatic element to the design, as livers will be preserved by static cold storage and then in the study group will receive 1-4 hours of HOPE. By concentrating on ECD livers, the study is more likely to find a significant impact on the primary outcome of early allograft dysfunction. The study is powered (80%) for a reduction in early allograft dysfunction from 30% to 15%, accounting for 10% dropout rate. Randomization will occur after allocation of the liver graft to a recipient. Allocation concealment is maintained, but there is no blinding of the surgical team nor patient. Data analysts will be blinded to group allocation. Interestingly the trial commenced in 2019 and is ongoing. This paper is published in order to “prevent biased analysis of trial outcomes and improve transparency of the trial results”. The study is funded by the French Ministry of Health and is being conducted at 8 transplant centres in France.
Aims: This is a protocol for a randomised controlled trial that aims to determine the efficacy of hypothermic oxygenated machine perfusion (HOPE) when used prior to transplantation of extended criteria donor (ECD) liver grafts obtained from brain-dead donors, for reduction of early allograft dysfunction (EAD) post-operation in comparison to simple cold static storage.
Interventions: ECD liver grafts will be randomly assigned to receive either HOPE or static cold storage.
Participants: Adult patients (≥ 18 years) transplanted with a liver graft harvested from a brain-dead ECD.
Outcomes: The primary outcomes are early allograft dysfunction (EAD) and primary non-function (PNF). The secondary outcomes include quality of conservation; ischemia–reperfusion injuries, intra-operative events; 90-day morbidity and mortality; duration of intermediate care unit stay and total hospital stay; actuarial graft and patient’s survival rates; and costs of liver transplantation with ECD grafts using HOPE or not and incremental cost-effectiveness ratio.
Follow Up: 12 months (± 30 days) following transplantation (36 months maximum).
BACKGROUND:

Given the scarce donor supply, an increasing number of so-called marginal or extended criteria donor (ECD) organs are used for liver transplantation. These ECD liver grafts are however known to be associated with a higher rate of early allograft dysfunction and primary non-function because of a greater vulnerability to ischemia-reperfusion injury. The end-ischemic hypothermic oxygenated machine perfusion (HOPE) technique may improve outcomes of liver transplantation with ECD grafts by decreasing reperfusion injury.

METHODS:

HOPExt trial is a comparative open-label, multicenter, national, prospective, randomized, controlled study, in two parallel groups, using static cold storage, the gold standard procedure, as control. The trial will enroll adult patients on the transplant waiting list for liver failure or liver cirrhosis and/or liver malignancy requiring liver transplantation and receiving an ECD liver graft from a brain-dead donor. In the experimental group, ECD liver grafts will first undergo a classical static cold (4 °C) storage followed by a hypothermic oxygenated perfusion (HOPE) for a period of 1 to 4 h. The control group will consist of the classic static cold storage which is the gold standard procedure in liver transplantation. The primary objective of this trial is to study the efficacy of HOPE used before transplantation of ECD liver grafts from brain-dead donors in reducing postoperative early allograft dysfunction within the first 7 postoperative days compared to simple cold static storage.

DISCUSSION:

We present in this protocol all study procedures in regard to the achievement of the HOPExt trial, to prevent biased analysis of trial outcomes and improve the transparency of the trial results. Enrollment of patients in the HOPExt trial has started on September 10, 2019, and is ongoing.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT03929523. Registered on April 29, 2019, before the start of inclusion.

  • Ghoneima AS
  • Sousa Da Silva RX
  • Gosteli MA
  • Barlow AD
  • Kron P
J Clin Med. 2023 Jun 6;12(12) doi: 10.3390/jcm12123871.

The high demand for organs in kidney transplantation and the expansion of the donor pool have led to the widespread implementation of machine perfusion technologies. In this study, we aim to provide an up-to-date systematic review of the developments in this expanding field over the past 10 years, with the aim of answering the question: "which perfusion technique is the most promising technique in kidney transplantation?" A systematic review of the literature related to machine perfusion in kidney transplantation was performed. The primary outcome measure was delayed graft function (DGF), and secondary outcomes included rates of rejection, graft survival, and patient survival rates after 1 year. Based on the available data, a meta-analysis was performed. The results were compared with data from static cold storage, which is still the standard of care in many centers worldwide. A total of 56 studies conducted in humans were included, and 43 studies reported outcomes of hypothermic machine perfusion (HMP), with a DGF rate of 26.4%. A meta-analysis of 16 studies showed significantly lower DGF rates in the HMP group compared to those of static cold storage (SCS). Five studies reported outcomes of hypothermic machine perfusion + O2, with an overall DGF rate of 29.7%. Two studies explored normothermic machine perfusion (NMP). These were pilot studies, designed to assess the feasibility of this perfusion approach in the clinical setting. Six studies reported outcomes of normothermic regional perfusion (NRP). The overall incidence of DGF was 71.5%, as it was primarily used in uncontrolled DCD (Maastricht category I-II). Three studies comparing NRP to in situ cold perfusion showed a significantly lower rate of DGF with NRP. The systematic review and meta-analysis provide evidence that dynamic preservation strategies can improve outcomes following kidney transplantation. More recent approaches such as normothermic machine perfusion and hypothermic machine perfusion + O2 do show promising results but need further results from the clinical setting. This study shows that the implementation of perfusion strategies could play an important role in safely expanding the donor pool.

  • Hosgood SA
  • Callaghan CJ
  • Wilson CH
  • Smith L
  • Mullings J
  • et al.
Nat Med. 2023 Jun;29(6):1511-1519 doi: 10.1038/s41591-023-02376-7.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This multicentre study randomised kidneys from controlled DCD donors to static cold storage (SCS) or to normothermic machine perfusion (NMP) with oxygenated blood for one hour prior to transplant. 338 kidneys were randomised. Primary endpoint was delayed graft function (DGF), defined by requirement for dialysis during the first 7 days post-transplant. Although NMP was feasible and safe, no difference in clinical endpoints were seen. The study is well-designed and reported and would appear to confirm that a short period of NMP prior to transplant does not confer clinical benefit. It is worth noting that the choice of primary endpoint can lead to challenges, as patients that are transplanted pre-emptively are less likely to reach the primary endpoint (DGF determined by dialysis need). As there was an imbalance between the proportions of pre-emptive patients in the control arm and study arm (22% versus 11%) this may impact the results. However, all secondary measures of graft function including functional DGF, DGF duration and creatinine reduction ratio were equivalent between the arms.
Aims: The aim of this study was to compare the posttransplant outcomes of conventional static cold storage (SCS) alone or SCS combined with 1 hour of normothermic machine perfusion (NMP) in donation after circulatory death (DCD) kidney transplant patients.
Interventions: Participants were randomised to either SCS plus 1-hour NMP or SCS alone.
Participants: 338 adult (≥18 years) kidney transplant patients that received a kidney from adult (≥ 18 years) DCD donors.
Outcomes: The primary endpoint was delayed graft function (DGF). The secondary endpoints included the incidence of primary nonfunction (PNF), duration of DGF, functional DGF, duration of hospital stay, estimated glomerular filtration rate (eGFR) or serum creatinine, and patient and allograft survival.
Follow Up: 12 months posttransplantation.

Kidney transplantation is the optimal treatment for end-stage renal disease, but it is still severely limited by a lack of suitable organ donors. Kidneys from donation after circulatory death (DCD) donors have been used to increase transplant rates, but these organs are susceptible to cold ischemic injury in the storage period before transplantation, the clinical consequence of which is high rates of delayed graft function (DGF). Normothermic machine perfusion (NMP) is an emerging technique that circulates a warmed, oxygenated red-cell-based perfusate through the kidney to maintain near-physiological conditions. We conducted a randomized controlled trial to compare the outcome of DCD kidney transplants after conventional static cold storage (SCS) alone or SCS plus 1-h NMP. A total of 338 kidneys were randomly allocated to SCS (n = 168) or NMP (n = 170), and 277 kidneys were included in the final intention-to-treat analysis. The primary endpoint was DGF, defined as the requirement for dialysis in the first 7 d after transplant. The rate of DGF was 82 of 135 (60.7%) in NMP kidneys versus 83 of 142 (58.5%) in SCS kidneys (adjusted odds ratio (95% confidence interval) 1.13 (0.69-1.84); P = 0.624). NMP was not associated with any increase in transplant thrombosis, infectious complications or any other adverse events. A 1-h period of NMP at the end of SCS did not reduce the rate of DGF in DCD kidneys. NMP was demonstrated to be feasible, safe and suitable for clinical application. Trial registration number: ISRCTN15821205 .

  • Risbey CWG
  • Pulitano C
J Clin Med. 2023 May 28;12(11) doi: 10.3390/jcm12113718.
BACKGROUND:

Liver transplantation is a lifesaving procedure for patients with end-stage liver disease (ESLD). However, many patients never receive a transplant due to insufficient donor supply. Historically, organs have been preserved using static cold storage (SCS). However, recently, ex vivo normothermic machine perfusion (NMP) has emerged as an alternative technique. This paper aims to investigate the clinical progress of NMP in humans.

METHODS:

Papers evaluating the clinical outcomes of NMP for liver transplantation in humans were included. Lab-based studies, case reports, and papers utilizing animal models were excluded. Literature searches of MEDLINE and SCOPUS were conducted. The revised Cochrane risk-of-bias tool for randomised trials (RoB 2) and the risk of bias in nonrandomised studies for interventions (ROBINS-I) tools were used. Due to the heterogeneity of the included papers, a meta-analysis was unable to be completed.

RESULTS:

In total, 606 records were identified, with 25 meeting the inclusion criteria; 16 papers evaluated early allograft dysfunction (EAD) with some evidence for lower rates using NMP compared to SCS; 19 papers evaluated patient or graft survival, with no evidence to suggest superior outcomes with either NMP or SCS; 10 papers evaluated utilization of marginal and donor after circulatory death (DCD) grafts, with good evidence to suggest NMP is superior to SCS.

CONCLUSIONS:

There is good evidence to suggest that NMP is safe and that it likely affords clinical advantages to SCS. The weight of evidence supporting NMP is growing, and this review found the strongest evidence in support of NMP to be its capacity to increase the utilization rates of marginal and DCD allografts.

  • Le Meur Y
  • Nowak E
  • Barrou B
  • Thierry A
  • Badet L
  • et al.
Trials. 2023 May 1;24(1):302 doi: 10.1186/s13063-023-07302-3.
BACKGROUND:

Preventing ischemia‒reperfusion injury (IRI) is a major issue in kidney transplantation, particularly for transplant recipients receiving a kidney from extended criteria donors (ECD). The main consequence of IRI is delayed graft function (DGF). Hypoxia is one of the key factors in IRI, suggesting that the use of an oxygen carrier as an additive to preservation solution may be useful. In the OxyOp trial, we showed that the organs preserved using the oxygen carrier HEMO2life® displayed significantly less DGF. In the OxyOp2 trial, we aim to definitively test and quantify the efficacy of HEMO2life® for organ preservation in a large population of kidney grafts.

METHODS:

OxyOp2 is a prospective, multicenter, randomized, comparative, single-blinded, parallel-group study versus standard of care in renal transplantation. After the selection of a suitable donor according to the inclusion/exclusion criteria, both kidneys will be used in the study. Depending on the characteristics of the donor, both kidneys will be preserved either in static cold storage (standard donors) or on machine perfusion (for ECD and deceased-after-cardiac-death donors (DCD)). The kidneys resulting from one donor will be randomized: one to the standard-of-care arm (organ preserved in preservation solution routinely used according to the local practice) and the other to the active treatment arm (HEMO2life® on top of routinely used preservation solution). HEMO2life® will be used for ex vivo graft preservation at a dose of 1 g/l preservation solution. The primary outcome is the occurrence of DGF, defined as the need for renal replacement therapy during the first week after transplantation.

DISCUSSION:

The use of HEMO2life® in preservation solutions is a novel approach allowing, for the first time, the delivery of oxygen to organs. Improving graft survival by limiting ischemic lesions is a major public-health goal in the field of organ transplantation.

TRIAL REGISTRATION:

ClinicalTrials.gov, ID: NCT04181710 . registered on November 29, 2019.

  • Schlegel A
  • Mueller M
  • Muller X
  • Eden J
  • Panconesi R
  • et al.
J Hepatol. 2023 Apr;78(4):783-793 doi: 10.1016/j.jhep.2022.12.030.
CET Conclusion
Reviewer: Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: Hypothermic oxygenated perfusion (HOPE) liver perfusion has shown promising results in preclinical studies but has yet to demonstrate consistent benefit for clinically relevant endpoints. This multicentre RCT compared the complication rate following DBD liver transplant (LT) between conventional cold storage versus treatment with HOPE prior to implantation. The study showed no significant difference in the rate of Clavien score > 3 between the two groups. A post hoc analysis compared the rate of liver-related graft loss, but the rationale for this analysis is not clear and the difference reported was not statistically significant. This study thus did not demonstrate any benefit to utilising HOPE in DBD liver transplantation.
Aims: This study aimed to investigate the role of hypothermic oxygenated perfusion (HOPE) on morbidity within 1 year following liver transplantation.
Interventions: Livers were randomised to either conventionally cold stored (control group), or cold stored followed by 1-2 hours HOPE treatment before implantation (HOPE group).
Participants: Patients listed for liver only transplantation (18 years of age).
Outcomes: The primary outcome was the occurrence of one or more major post-transplant complication. Secondary outcomes were comprehensive complication index (CCI), graft survival, patient survival, laboratory parameters, duration of hospital and intensive care unit stay, and biliary complications.
Follow Up: 12 months
BACKGROUND & AIMS:

Machine perfusion is a novel method intended to optimize livers before transplantation. However, its effect on morbidity within a 1-year period after transplantation has remained unclear.

METHODS:

In this multicenter controlled trial, we randomly assigned livers donated after brain death (DBD) for liver transplantation (LT). Livers were either conventionally cold stored (control group), or cold stored and subsequently treated by 1-2 h hypothermic oxygenated perfusion (HOPE) before implantation (HOPE group). The primary endpoint was the occurrence of at least one post-transplant complication per patient, graded by the Clavien score of ≥III, within 1-year after LT. The comprehensive complication index (CCI), laboratory parameters, as well as duration of hospital and intensive care unit stay, graft survival, patient survival, and biliary complications served as secondary endpoints.

RESULTS:

Between April 2015 and August 2019, we randomized 177 livers, resulting in 170 liver transplantations (85 in the HOPE group and 85 in the control group). The number of patients with at least one Clavien ≥III complication was 46/85 (54.1%) in the control group and 44/85 (51.8%) in the HOPE group (odds ratio 0.91; 95% CI 0.50-1.66; p = 0.76). Secondary endpoints were also not significantly different between groups. A post hoc analysis revealed that liver-related Clavien ≥IIIb complications occurred less frequently in the HOPE group compared to the control group (risk ratio 0.26; 95% CI 0.07-0.77; p = 0.027). Likewise, graft failure due to liver-related complications did not occur in the HOPE group, but occurred in 7% (6 of 85) of the control group (log-rank test, p = 0.004, Gray test, p = 0.015).

CONCLUSIONS:

HOPE after cold storage of DBD livers resulted in similar proportions of patients with at least one Clavien ≥III complication compared to controls. Exploratory findings suggest that HOPE decreases the risk of severe liver graft-related events.

IMPACT AND IMPLICATIONS:

This randomized controlled phase III trial is the first to investigate the impact of hypothermic oxygenated perfusion (HOPE) on cumulative complications within a 12-month period after liver transplantation. Compared to conventional cold storage, HOPE did not have a significant effect on the number of patients with at least one Clavien ≥III complication. However, we believe that HOPE may have a beneficial effect on the quantity of complications per patient, based on its application leading to fewer severe liver graft-related complications, and to a lower risk of liver-related graft loss. The HOPE approach can be applied easily after organ transport during recipient hepatectomy. This appears fundamental for wide acceptance since concurring perfusion technologies need either perfusion at donor sites or continuous perfusion during organ transport, which are much costlier and more laborious. We conclude therefore that the post hoc findings of this trial should be further validated in future studies.