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  • Mulvey JF
  • Shaheed SU
  • Charles PD
  • Snashall C
  • Lo Faro ML
  • et al.
Ann Surg. 2023 Nov 1;278(5):676-682 doi: 10.1097/SLA.0000000000006046.
CET Conclusion
Reviewer: 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.

  • Grąt M
  • Morawski M
  • Zhylko A
  • Rykowski P
  • Krasnodębski M
  • et al.
Ann Surg. 2023 Nov 1;278(5):662-668 doi: 10.1097/SLA.0000000000006055.
CET Conclusion
Reviewer: 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.

  • Chapman WC
  • Barbas AS
  • D'Alessandro AM
  • Vianna R
  • Kubal CA
  • et al.
Ann Surg. 2023 Nov 1;278(5):e912-e921 doi: 10.1097/SLA.0000000000005934.
CET Conclusion
Reviewer: 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.

  • Liang A
  • Cheng W
  • Cao P
  • Cai S
  • Zhang L
  • et al.
Int J Surg. 2023 Nov 1;109(11):3617-3630 doi: 10.1097/JS9.0000000000000661.
BACKGROUND:

The increasing use of extended criteria donors (ECD) sets higher requirements for graft preservation. Machine perfusion (MP) improves orthotopic liver transplantation (OLT) outcomes, but its effects on different donor types remains unclear. The authors' aim was to assess the effects of hypothermic machine perfusion (HMP), normothermic machine perfusion (NMP), or normothermic regional perfusion (NRP) versus static cold storage (SCS) on different donor types.

MATERIALS AND METHODS:

A literature search comparing the efficacy of MP versus SCS in PubMed, Cochrane, and EMBASE database was conducted. A meta-analysis was performed to obtain pooled effects of MP on ECD, donation after circulatory death (DCD), and donor after brainstem death.

RESULTS:

Thirty nine studies were included (nine randomized controlled trials and 30 cohort studies). Compared with SCS, HMP significantly reduced the risk of non-anastomotic biliary stricture (NAS) [odds ratio (OR) 0.43, 95% confidence interval (CI) 0.26-0.72], major complications (OR 0.55, 95% CI 0.39-0.78), and early allograft dysfunction (EAD) (OR 0.46, 95% CI 0.32-0.65) and improved 1-year graft survival (OR 2.36, 95% CI 1.55-3.62) in ECD-OLT. HMP also reduced primary non-function (PNF) (OR 0.40, 95% CI 0.18-0.92) and acute rejection (OR 0.62, 95% CI 0.40-0.97). NMP only reduced major complications in ECD-OLT (OR 0.56, 95% CI 0.34-0.94), without favorable effects on other complications and survival. NRP lowered the overall risk of NAS (OR 0.27, 95% CI 0.11-0.68), PNF (OR 0.43, 95% CI 0.22-0.85), and EAD (OR 0.58, 95% CI 0.42-0.80) and meanwhile improved 1-year graft survival (OR 2.40, 95% CI 1.65-3.49) in control DCD-OLT.

CONCLUSIONS:

HMP might currently be considered for marginal livers as it comprehensively improves ECD-OLT outcomes. NMP assists some outcomes in ECD-OLT, but more evidence regarding NMP-ECD is warranted. NRP significantly improves DCD-OLT outcomes and is recommended where longer non-touch periods exist.

  • Giulioni C
  • Palantrani V
  • De Stefano V
  • Cicconofri A
  • Antezza A
  • et al.
J Endourol. 2023 Oct;37(10):1129-1138 doi: 10.1089/end.2023.0224.

Background: Patients who have undergone renal transplant may have a concomitant benign prostatic hyperplasia (BPH), a condition that can potentially hinder the recovery of the renal graft and necessitate surgical intervention. However, endoscopic treatment of BPH should be performed carefully because of the associated perioperative risks. We aimed to systematically assess the factors affecting surgical indications and perioperative outcomes of BPH surgical treatment in renal transplantation (RT) recipients. Methods: A systematic literature search was performed on January 28, 2023, using Scopus, PubMed, and EMBASE with no date limit. Preclinical and animal studies, reviews, letters to the editor, case reports, and meeting abstracts were excluded. Results: Eighteen articles were accepted and included. Clinical BPH has a high incidence rate after RT, particularly in elderly men. Secondary events associated with BPH, such as acute urinary retention and urinary tract infections, can lead to a gradual decline of renal graft function and patient survival. BPH procedure can prevent these events and guarantee improvements in serum creatinine levels, voiding parameters, and lower urinary tract symptoms. When the urine culture is negative, the endoscopic procedure of the prostate may be performed within 1 month of the initial procedure, particularly in older patients, more prone to develop voiding dysfunction. Alternatively, a transurethral incision of the prostate may be recommended for patients with smaller prostates who wish to preserve ejaculatory function. Data on comparative BPH surgical procedures are lacking. Conclusions: BPH procedure should be offered in RT recipients who develop bladder outlet obstruction owing to BPH. Endoscopic treatment should be performed after a few weeks from RT to avoid further graft deterioration.

  • Sica GS
  • Sensi B
  • Siragusa L
  • Blasi F
  • Crispino B
  • et al.
Eur J Surg Oncol. 2023 Oct;49(10):106922 doi: 10.1016/j.ejso.2023.04.021.
INTRODUCTION:

Colon cancer in ulcerative colitis patients with liver transplant (UCCOLT) due to primary sclerosing cholangitis carries significant treatment challenges. Aim of this literature search is to review management strategies and provide a framework to facilitate the decisional process in this clinical setting.

METHODS:

PRISMA-compliant systematic search was followed by critical expert commentary of the results and development of a surgical management algorithm. Endpoints included surgical management, operative strategies, functional and survival outcomes. Technical and strategics aspects with particular regard to the choice of reconstruction were evaluated to tentatively develop an integrated algorithm.

RESULTS:

Ten studies reporting treatment of 20 UCCOLT patients were identified after screening. Nine patients underwent proctocolectomy and end-ileostomy (PC) and eleven had restorative ileal pouch-anal anastomosis (IPAA). Reported results for perioperative outcomes, oncological outcomes, and graft loss were comparable for both procedures. There were no reports of subtotal colectomies and ileo-rectal anastomosis (IRA).

CONCLUSIONS:

Literature in the field is scarce and decision-making is particularly complex. PC and IPAA have been reported with good results. Nevertheless, IRA may also be considered in UCCOLT patients in selected cases, reducing the risks of sepsis, OLT and pouch failure; furthermore, in young patients, it has the advantage of preserving fertility or sexual function. The proposed treatment algorithm may represent a valuable support in guiding surgical strategy.

  • Tingle SJ
  • Dobbins JJ
  • Thompson ER
  • Figueiredo RS
  • Mahendran B
  • et al.
Cochrane Database Syst Rev. 2023 Sep 12;9(9):CD014685 doi: 10.1002/14651858.CD014685.pub2.
BACKGROUND:

Liver transplantation is the only chance of cure for people with end-stage liver disease and some people with advanced liver cancers or acute liver failure. The increasing prevalence of these conditions drives demand and necessitates the increasing use of donated livers which have traditionally been considered suboptimal. Several novel machine perfusion preservation technologies have been developed, which attempt to ameliorate some of the deleterious effects of ischaemia reperfusion injury. Machine perfusion technology aims to improve organ quality, thereby improving outcomes in recipients of suboptimal livers when compared to traditional static cold storage (SCS; ice box).

OBJECTIVES:

To evaluate the effects of different methods of machine perfusion (including hypothermic oxygenated machine perfusion (HOPE), normothermic machine perfusion (NMP), controlled oxygenated rewarming, and normothermic regional perfusion) versus each other or versus static cold storage (SCS) in people undergoing liver transplantation.

SEARCH METHODS:

We used standard, extensive Cochrane search methods. The latest search date was 10 January 2023.

SELECTION CRITERIA:

We included randomised clinical trials which compared different methods of machine perfusion, either with each other or with SCS. Studies comparing HOPE via both hepatic artery and portal vein, or via portal vein only, were grouped. The protocol detailed that we also planned to include quasi-randomised studies to assess treatment harms.

DATA COLLECTION AND ANALYSIS:

We used standard Cochrane methods. Our primary outcomes were 1. overall participant survival, 2. quality of life, and 3. serious adverse events. Secondary outcomes were 4. graft survival, 5. ischaemic biliary complications, 6. primary non-function of the graft, 7. early allograft function, 8. non-serious adverse events, 9. transplant utilisation, and 10. transaminase release during the first week post-transplant. We assessed bias using Cochrane's RoB 2 tool and used GRADE to assess certainty of evidence.

MAIN RESULTS:

We included seven randomised trials (1024 transplant recipients from 1301 randomised/included livers). All trials were parallel two-group trials; four compared HOPE versus SCS, and three compared NMP versus SCS. No trials used normothermic regional perfusion. When compared with SCS, it was uncertain whether overall participant survival was improved with either HOPE (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.42 to 1.98; P = 0.81, I2 = 0%; 4 trials, 482 recipients; low-certainty evidence due to imprecision because of low number of events) or NMP (HR 1.08, 95% CI 0.31 to 3.80; P = 0.90; 1 trial, 222 recipients; very low-certainty evidence due to imprecision and risk of bias). No trials reported quality of life. When compared with SCS alone, HOPE was associated with improvement in the following clinically relevant outcomes: graft survival (HR 0.45, 95% CI 0.23 to 0.87; P = 0.02, I2 = 0%; 4 trials, 482 recipients; high-certainty evidence), serious adverse events in extended criteria DBD liver transplants (OR 0.45, 95% CI 0.22 to 0.91; P = 0.03, I2 = 0%; 2 trials, 156 participants; moderate-certainty evidence) and clinically significant ischaemic cholangiopathy in recipients of DCD livers (OR 0.31, 95% CI 0.11 to 0.92; P = 0.03; 1 trial, 156 recipients; high-certainty evidence). In contrast, NMP was not associated with improvement in any of these clinically relevant outcomes. NMP was associated with improved utilisation compared with SCS (one trial found a 50% lower rate of organ discard; P = 0.008), but the reasons underlying this effect are unknown. We identified 11 ongoing studies investigating machine perfusion technologies.

AUTHORS' CONCLUSIONS:

In situations where the decision has been made to transplant a liver donated after circulatory death or donated following brain death, end-ischaemic HOPE will provide superior clinically relevant outcomes compared with SCS alone. Specifically, graft survival is improved (high-certainty evidence), serious adverse events are reduced (moderate-certainty evidence), and in donors after circulatory death, clinically relevant ischaemic biliary complications are reduced (high-certainty evidence). There is no good evidence that NMP has the same benefits over SCS in terms of these clinically relevant outcomes. NMP does appear to improve utilisation of grafts that would otherwise be discarded with SCS; however, the reasons for this, and whether this effect is specific to NMP, is not clear. Further studies into NMP viability criteria and utilisation, as well as head-to-head trials with other perfusion technologies are needed. In the setting of donation following circulatory death transplantation, further trials are needed to assess the effect of these ex situ machine perfusion methods against, or in combination with, normothermic regional perfusion.

  • Maspero M
  • Ali K
  • Cazzaniga B
  • Yilmaz S
  • Raj R
  • et al.
Hepatology. 2023 Sep 1;78(3):835-846 doi: 10.1097/HEP.0000000000000363.
BACKGROUND AND AIMS:

Acute cellular rejection (ACR) is a frequent complication after liver transplantation. By reducing ischemia and graft damage, dynamic preservation techniques may diminish ACR. We performed a systematic review to assess the effect of currently tested organ perfusion (OP) approaches versus static cold storage (SCS) on post-transplant ACR-rates.

APPROACH AND RESULTS:

A systematic search of Medline, Embase, Cochrane Library, and Web of Science was conducted. Studies reporting ACR-rates between OP and SCS and comprising at least 10 liver transplants performed with either hypothermic oxygenated perfusion (HOPE), normothermic machine perfusion, or normothermic regional perfusion were included. Studies with mixed perfusion approaches were excluded. Eight studies were identified (226 patients in OP and 330 in SCS). Six studies were on HOPE, one on normothermic machine perfusion, and one on normothermic regional perfusion. At meta-analysis, OP was associated with a reduction in ACR compared with SCS [OR: 0.55 (95% CI, 0.33-0.91), p =0.02]. This effect remained significant when considering HOPE alone [OR: 0.54 (95% CI, 0.29-1), p =0.05], in a subgroup analysis of studies including only grafts from donation after cardiac death [OR: 0.43 (0.20-0.91) p =0.03], and in HOPE studies with only donation after cardiac death grafts [OR: 0.37 (0.14-1), p =0.05].

CONCLUSIONS:

Dynamic OP techniques are associated with a reduction in ACR after liver transplantation compared with SCS. PROSPERO registration: CRD42022348356.

  • Czigany Z
  • Michalski CW
J Hepatol. 2023 Sep;79(3):e114-e116 doi: 10.1016/j.jhep.2023.03.009.
  • Guo Z
  • Zhao Q
  • Jia Z
  • Huang C
  • Wang D
  • et al.
J Hepatol. 2023 Aug;79(2):394-402 doi: 10.1016/j.jhep.2023.04.010.
CET Conclusion
Reviewer: 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.