Simon R. Knight
John Fallon1,2- 1Oxford Transplant Centre, Churchill Hospital, Oxford, United Kingdom
- 2Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
- 3University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
To keep the transplantation community informed about recently published level 1 evidence in organ transplantation ESOT and the Centre for Evidence in Transplantation have developed the Transplant Trial Watch. The Transplant Trial Watch is a monthly overview of 10 new randomised controlled trials (RCTs) and systematic reviews. This page of Transplant International offers commentaries on methodological issues and clinical implications on two articles of particular interest from the CET Transplant Trial Watch monthly selection. For all high quality evidence in solid organ transplantation, visit the Transplant Library: www.transplantlibrary.com.
RANDOMISED CONTROLLED TRIAL 1
Balanced Crystalloid Solution Versus Saline in Deceased Donor Kidney Transplantation (BEST-Fluids): A Pragmatic, Double-Blind, Randomised, Controlled Trial.
by Collins, M. G., et al. Lancet 2023; 402(10396): 105–117.
Aims
To assess if use of balanced crystalloid vs. saline reduces rates of delayed graft function.
Interventions
The intervention group received a balanced crystalloid in the form of Plasma-Lyte 148 intra- and post-operatively for intravenous volume replacement vs. standard care who received 0.9% sodium chloride.
Participants
808 participants, adults and children receiving kidney only transplant.
Outcomes
The primary outcome was DGF, which they defined as need for dialysis within the first 7 days. Secondary outcomes included: number of dialysis treatments, duration of dialysis in days, ranked composite of DGF and day 2 creatinine reduction ratio, post-op hyperkalaemia, peak potassium, fluid overload, urine output, use of inotropes, acute rejection, number of biopsies, mortality, graft survival, graft function and hospital stay.
Follow-Up
52 weeks.
CET Conclusion
This large, multi-centre, double-blinded, randomised control trial found a reduction in DGF rate with the use of balanced crystalloid (30%) compared with normal saline (40%), a RR of 0.74 (p < 0.0001). The trial was well designed, with exceptional blinding, the Plasma-Lyte and saline were packaged in custom identical bags only identifiable by serial numbers, so all parties were blinded for the duration of the trial. The trial was conducted across 16 sites, with a representative trial cohort of deceased donor kidneys (DBD:DCD of 3:1), containing only 16 (2%) of pre-emptive recipients and 20 (2%) kidneys that received HMP as preservation, which is crucial given their primary outcome. This reduction in DGF equated to 190 fewer dialysis sessions in the balanced crystalloid group and a number needed to treat of 10 to prevent 1 case of DGF. Their hypothesised effect of the fluid on post-transplant biochemistry, with reduced chloride burden, increase bicarbonate and pH with minimal effect on potassium was demonstrated and thus reduced tubular acidosis and improve blood flow leading to lower rates of DGF is sound. The trial has few limitations, laboratory data was not collected beyond post-operative day 2 and other minor data points such as blood pressure and surgical anastomosis time, however given the trial size and randomisation strategy limiting centre effect, this is likely of no consequence. It is important to note that the effect is not necessarily generalisable to other balanced crystalloids such as Hartman’s, given that contains more chloride as well as lactate and further work would be needed to assess their benefit. This trial provides robust evidence sufficient to warrant consideration of changing practice, Plasma-Lyte is readily available, relatively inexpensive and in the context of renal transplant providing likely reduction in DGF.
Jadad Score
5.
Data Analysis
Modified intention-to-treat analysis.
Allocation Concealment
Yes.
Trial Registration
ACTRN12617000358347; ClinicalTrials.gov—NCT03829488.
Funding Source
Non-industry funded.
RANDOMISED CONTROLLED TRIAL 2
Normothermic Machine Perfusion of Donor Livers for Transplantation in the United States—A Randomized Controlled Trial.
by Chapman, W. C., et al. Annals of Surgery 2023 [record in progress].
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.
CET 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 two 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.
Jadad Score
3.
Data Analysis
Strict intention-to-treat analysis.
Allocation Concealment
Yes.
Trial Registration
ClinicalTrials.gov—NCT02478151.
Funding Source
Industry funded.
Clinical Impact Summary
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 et al. 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.
Clinical Impact
3/5.
Author Contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of Interest
SK has received past consultancy income from OrganOx Ltd. for assistance in the design of clinical trials.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1. Watson, CJE, Gaurav, R, Fear, C, Swift, L, Selves, L, Ceresa, CDL, et al. Predicting Early Allograft Function After Normothermic Machine Perfusion. Transplantation (2022) 106:2391–8. doi:10.1097/TP.0000000000004263
2. Nasralla, D, Coussios, CC, Mergental, H, Akhtar, MZ, Butler, AJ, Ceresa, CDL, et al. A Randomized Trial of Normothermic Preservation in Liver Transplantation. Nature (2018) 557:50–6. doi:10.1038/s41586-018-0047-9
3. Markmann, JF, Abouljoud, MS, Ghobrial, RM, Bhati, CS, Pelletier, SJ, Lu, AD, et al. Impact of Portable Normothermic Blood-Based Machine Perfusion on Outcomes of Liver Transplant: The OCS Liver PROTECT Randomized Clinical Trial. JAMA Surg (2022) 157:189–98. doi:10.1001/jamasurg.2021.6781
4. Chapman, WC, Barbas, AS, D’Alessandro, AM, Vianna, R, Kubal, CA, Abt, P, et al. Normothermic Machine Perfusion of Donor Livers for Transplantation in the United States - A Randomized Controlled Trial. Ann Surg (2023). doi:10.1097/SLA.0000000000005934
Keywords: delayed graft function, deceased donor kidney transplantation, randomised controlled trial, liver transplant, normothermic machine perfusion
Citation: Knight SR, Fallon J and Mentor K (2023) Transplant Trial Watch. Transpl Int 36:12039. doi: 10.3389/ti.2023.12039
Received: 12 September 2023; Accepted: 19 September 2023;
Published: 24 October 2023.
Copyright © 2023 Knight, Fallon and Mentor. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Simon R. Knight, simon.knight@nds.ox.ac.uk