Transplant Trial Watch

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

Participants 432 adult kidney transplant recipients receiving ABO-compatible organs with low immunological risk scores, from living or deceased donors.

Outcomes
Primary efficacy outcome was the combined endpoint of BPAR, graft failure and death within 6 months.Secondary endpoints were renal function, delayed graft function.Chronic ABMR, DSAs, PTDM, infective incidence.

CET Conclusion by John Fallon
This large multi-centre European open-label RCT demonstrated non-inferiority of a slow and low tacrolimus regimen with regards their composite end-point of BPAR, graft failure and death over a period of 6 months.However, one should be cautious in the interpretation.It is important to note that the study was conducted in immunologically low risk recipients, clearly recipients with a negative CDC cross- match, but also no history of rejection in previous allografts, no DSAs, PRA <20% and no DCD organs, which in a wider context does limit the impact of the regimen's presented non-inferiority.When scrutinising the results more closely, the combined primary end-point occurred in 20.3% of slow and low and 18.8% of the standard care, risk difference and two-sided 90% confidence interval 1.5% (−6.0%; 9.0%; one-sided test of equivalence with a noninferiority margin of 12.5% p = 0.008), but in this context a noninferiority margin of 12.5% could be considered too large, but if reduced to margins closer to 5%, which one might consider more appropriate in this context, significance would likely not be reached.This combined with the finding that there was a statistically higher percentage of BANFF IA-III, i.e., above borderline, in the slow and low regimen compared with standard (11.6% vs. 5.2%, p = 0.027) could be a concern.The assessment on the impact of these is limited by the duration of follow-up being only 6 months, given these subtle event changes are impactful on the ultimate lifespan of a graft rather than necessarily acute losses.We must then consider conceptually the overall reason for interest in a slow and low regimen, which is the effects of early high trough levels.Slow and low avoided concerningly high trough levels within the first week, and by week 4 the levels in standard and slow and low are equilibrated, with acceptable therapeutic levels for nearly all patients throughout.However, despite this no difference was observed in secondary outcome parameter such as AE, SAE, kidney function, neurotoxicity, PTDM, or DGF (the study duration being too limited to consider implication to cardiovascular risk factors).While standardising early tacrolimus use is attractive for its clinical ease and its potential non-inferiority to standard care, the fact remains that variations in tacrolimus metabolism exist, and the present study is insufficient to confidently demonstrate the non-inferiority or reasoning behind a slow and low regimen.

Data Analysis
Modified intention-to-treat analysis.

Allocation Concealment
Yes.

Funding Source
Industry funded.

Aims
The aim of this study was to investigate the role of intraoperative dexmedetomidine infusion on the incidence of acute kidney injury (AKI) in living donor liver transplant patients.

Interventions
Participants were randomised to receive either an infusion of dexmedetomidine or 0.9% saline.
Participants 214 living donor liver transplant patients.

Outcomes
The primary endpoint was the incidence of AKI.The secondary endpoints were levels of serial lactate during surgery, overall mortality, graft failure, early allograft dysfunction, major adverse cardiovascular events, chronic kidney disease, duration of mechanical ventilation, intensive care unit (ICU) and hospital length of stay.

CET Conclusion by Simon Knight
This interesting paper from a single centre in South Korea investigated the use of dexmedetomidine (an alpha-2 agonist with anti-inflammatory and anti-oxidant properties) as a renoprotective agent during living-donor liver transplantation.205 recipients were randomised to dexmedetomidine or control (saline) infusion during surgery.The authors report a significant reduction in risk of acute kidney injury in the dexmedetomidine group (35% vs. 50%), with lower postreperfusion lactate levels, although no difference in incidence of post-reperfusion syndrome.The study appears well designed, with adequate randomisation, allocation concealment and double-blinding.The exact method by which the clinical team were blinded to intervention is unclear-placebo was used, but how this was masked was not described.Given the evidence available from this study and others in cardiac surgery, it certainly warrants further investigation in more mixed multicentre cohorts.

Data Analysis
Per protocol analysis.

Allocation Concealment
Yes.

RANDOMISED CONTROLLED TRIAL 2
Effect of Dexmedetomidine on the Incidence of Postoperative Acute Kidney Injury in Living Donor Liver Transplantation Recipients: A Randomized Controlled Trial.by Kwon, H. M., et al.International Journal of Surgery 2024 [record in progress].
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.Fixed Low Dose Versus Concentration-Controlled Initial Tacrolimus Dosing With Reduced Target Levels in the Course After Kidney Transplantation: Results From A Prospective Randomized Controlled Non-Inferiority Trial (Slow and Low study).