Transplant Trial Watch

Transplant Trial Watch

Keeping the transplantation community informed with a monthly overview of 10 new Randomised Controlled Trials and Systematic Reviews

The Transplant Trial Watch (TTW) lists 10 recently published randomized controlled trials (RCTs) and Systematic Reviews in organ transplantation. The TTW includes a brief description of each study, an assessment of the reporting of some methodological quality features and the main conclusions of the report written by the Peter Morris Centre for Evidence in Transplantation (CET). Studies are selected by the CET on the basis of quality or interest. Electronic publications ahead of print are listed as [record in progress]. For more information on the assessment of the methodological quality, click here.

For all published RCTs in organ transplantation go to the Transplant Library.

To view the previous issues of the Transplant Trial Watch go to the CET website or download the free Transplant Trial Watch app.

Transplant Trial Watch February 2019 – Kidney Transplantation

Aditianingsih D, Mochtar CA, et al. Comparison of Three-Quadrant Transversus Abdominis Plane Block and Continuous Epidural Block for Postoperative Analgesia After Transperitoneal Laparoscopic Nephrectomy. Anesth. 2018; 8(5):e80024.
Aim:
To compare the effect of TAP block analgesia with continuous epidural analgesia for pain management following transperitoneal laparoscopic living donor nephrectomy.
Interventions:
Three-quadrant TAP block using 0.25% bupivacaine with additional dexamethasone 8 mg versus continuous epidural block using 0.125% bupivacaine.
Participants:
50 adult patients under going transperitoneal laparoscopic living donor nephrectomy (TAP block, n=25; continuous epidural, n=25).
Outcomes:
Outcomes assessed in ITT population. The primary outcome was cumulative morphine consumption in the first 24 hours after surgery. The secondary outcomes were the numerical rating scale (NRS) assessment of pain, the first-time mobilization, and duration of urinary catheterization, postoperatively.
Follow Up:
24 hours post surgery
CETs Conclusions:
The primary outcome was morphine consumption in the first 24 hours after surgery. It is likely that this study was underpowered for this outcome and no power calculation is presented. There was no significant difference in the amount of morphine used post-operatively. There were no significant differences between the groups in terms of pain scores and time to mobilisation. There was a significantly longer duration of urinary catheterisation in the epidural group. Despite being described as a randomised study, there is no description of the method used, and we therefore cannot comment on its adequacy, or whether or not allocation concealment was possible. In its favour the study was strictly intention to treat analysis and there were no patients lost to follow up.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Intention to treat
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT03154436
Funding Source:
Non-Industry funded
Hamdy AF, Elhadedy MA, et al. Outcome of Sirolimus based Immunosuppression, Fifteen Years Post Live-Donor Kidney Transplantation: Single Center Experience. Clin Transplant. 2018; [record in progress].
Aim:
An observational extension study of an RCT to assess the long term effects of sirolimus based immunosuppression in live donor kidney transplant recipients on survival and graft function.
Interventions:
Live donor kidney transplant recipients were randomized to receive sirolimus primary immunosuppression in combination with either low dose tacrolimus (TAC group) or mycophenolate mofetil (MMF group).
Participants:
132 adult (TAC group, n=65; MMF group, n=67) patients with end-stage renal disease, who received a live donor kidney allo-transplant.
Outcomes:
Study outcomes were efficacy (patient and graft survival, biopsy-confirmed acute rejection, chronic allograft nephropathy episodes and graft function), safety and renal allograft pathology. Changes to immunosuppression doses and regimens were also assessed.
Follow Up:
15 years post transplantation.
CETs Conclusions:
This manuscript reports the 15-year follow-up of a randomized trial comparing two sirolimus-based regimens in living donor renal transplant recipients. Patients were randomized to sirolimus, steroids and either low-dose tacrolimus or MMF. This long-term follow-up demonstrates numerically higher mortality in the Tac arm (10.8% vs. 3%), along with significantly inferior graft function. There was no difference in graft survival, adverse events or tolerability between the arms. Perhaps as expected, avoiding tacrolimus does appear to offer some benefit in renal function in the long term, and the combination of MMF and sirolimus provides acceptable outcomes in this low-risk population. However, it should be noted that over 40% patients in both arms switched to a non-mTOR regimen during the course of follow-up, in keeping with previous evidence.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified intention to treat
Allocation Concealment 
Yes
Trial Registration:
Not reported
Funding Source:
Non-Industry funded
Park M, Katz R, et al. Urinary Markers of Fibrosis and Risk of Cardiovascular Events and Death in Kidney Transplant Recipients: The FAVORIT Trial. Am J Transplant. 2017;17(10):2640-9.
Aim:
The aim of the multicenter double-blind, randomized controlled FAVORIT trial was to determine if lowering homocysteine levels with vitamin therapy reduced CVD events in stable KTRs. This case-cohort substudy of the FAVORIT trial assessed whether higher urine concentrations of four markers are associated with risk of cardiovascular disease (CVD) events and death in stable kidney transplant recipients (KTRs) independent of chronic kidney disease (CKD) and CVD risk factors, baseline eGFR, and urine albumin-to-creatinine ratio (ACR). These markers were alpha 1 microglobulin (a1m), monocyte chemoattractant protein-1 (MCP-1), and procollagen amino-terminal pro-peptides of type I and type III collagen (PINP and PIIINP) and have been associated with severity of tubulointerstitial fibrosis.
Interventions:
Participants in the FAVORIT trial were randomized to either a standard multivitamin with high doses of folic acid, vitamin B6, and B12 or a multivitamin containing no folic acid and low doses of vitamin B6 and vitamin B12. For this study, urine markers of fibrosis (a1m, MCP-1, PINP, and PIIINP) were measured in duplicate in spot urine samples obtained at the FAVORIT baseline study visit.
Participants:
513 participants from the FAVORIT trial were included in the subcohort for this study. Members of the subcohort were selected at random irrespective of whether or not they experienced CVD or death during follow-up. Among these 513 subcohort participants, 23 had CVD events and 36 deaths occurred, with 31 participants experiencing both. Among the cases included in the study, there were 300 CVD cases and 371 deaths, with 143 cases of both CVD events and death.
Outcomes:
Outcomes assessed or utilized in this substudy were urine markers of fibrosis, urine injury biomarkers (urine NGAL, KIM-1, IL-18, and L-FABP), eGFR, urine ACR, CVD risk factors, CVD events (defined as a composite of CVD death, myocardial infarction, resuscitated sudden death, and stroke) and death. Statistical models were used to test associations between markers and events.
Follow Up:
Median 3.46 years follow-up.
CETs Conclusions:
This paper represents another ancillary analysis of the FAVORIT study, which we have previously assessed as a very good quality study with adequate randomisation, blinding and follow up. Four urinary proteins known to correlate with interstitial fibrosis were evaluated for their association with cardiovascular events and death. Higher levels of urinary alpha-1-microglobulin, MCP-1 and PINP were associated with significantly increased hazard ratio for cardiovascular events and death. The paper gives a thorough description of methods and analysis. The authors speculate on the mechanistic relationship between these markers and the primary outcome but this study itself does not help to explain this.
Reporting Quality:
Jadad Score 
5
Data Analysis 
Per protocol
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT00064753
Funding Source:
Non-Industry funded
Seeman T, Vondrak K, Dusek J. Effects of the strict control of blood pressure in pediatric renal transplant recipients-ESCORT trial. Pediatr Transplant. 2018; [record in progress].
Aim:
To determine the efficacy and safety of strict blood pressure (BP) control on the progression of allograft dysfunction in children after kidney transplantation (KTx).
Interventions:
Patients were randomised to either the standard BP group (STAND, target 24‐hour mean arterial pressure [MAP] 50‐95th percentile, n = 11) or the intensified BP group (INTENS, target 24‐hour MAP <50th percentile, n = 12).
Participants:
23 pediatric patients (age 3‐15.9 years, ≥1 year post KTx, no acute rejection in the previous 3 months, eGFR >15ml/min/1.73m2, 24‐hour MAP ≥50th percentile).
Outcomes:
The primary endpoint was the annual reduction in eGFR (mL/min/1.73 m2/y). Secondary endpoints were changes in 24‐hour MAP, proteinuria, graft and patient survival, and safety. BP was measured in the renal clinic using oscillometric BP monitor (Omron M6, Omron Healthcare), eGFR and proteinuria (protein/creatinine ratio) were tested every month, and ambulatory 24‐hour blood pressure monitoring was carried out every 6 months. Treatment of BP was managed according to 24‐hour MAP levels.
Follow Up:
3 years
CETs Conclusions:
The small ESCORT trial examined whether strict blood pressure control in paediatric kidney transplant recipients can slow down the progression of chronic allograft dysfunction. Patients who were at least 1 year posttransplant were randomised to standard blood pressure target (50th to 95th percentile of 24‐hour mean arterial pressure (MAP)) or an intensified blood pressure target (<50th percentile of 24‐hour MAP). No details of the randomisation were described and the authors stated that no power analysis was conducted as there are no previous studies on strict blood pressure control in paediatric or adult kidney transplant patients. Data were analysed according to intention to treat and all 23 participants were accounted for in the analysis. The annual reduction in eGFR did not differ significantly between groups in the intention to treat and per-protocol analyses. Of the secondary outcomes, only the change in 24-hour MAP was significantly different between groups.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Modified intention to treat
Allocation Concealment 
No
Trial Registration:
Not reported
Funding Source:
Non-Industry funded

Transplant Trial Watch February 2019 – Liver Transplantation

Ghinolfi D, Rreka E, et al. Pilot, open, randomized, prospective trial for normothermic machine perfusion evaluation in liver transplantation from older donors. Liver Transpl. 2018; [record in progress].
Aim:
To determine whether ex-situ normothermic machine perfusion (NMP) might minimize ischemia/reperfusion injury (IRI) of liver grafts.
Interventions:
Patients randomized (1:1) to NMP or cold storage.
Participants:
20 adult primary whole-size liver transplant recipients of older liver grafts (≥70 years) from brain death donors.
Outcomes:
The primary study endpoint was graft and patient survival at 6 months post transplantation. The secondary endpoints were to IRI (by means of peak transaminases within 7 days after surgery), incidence of biliary complications at Month 6, and evaluation of liver and bile duct histology.
Follow Up:
6 months post transplantation.
CETs Conclusions:
This small pilot study investigates the use of post SCS normothermic perfusion in livers from elderly (>70 years) donors. Whilst the study finds no difference in clinical outcomes, there was a reduction in histological markers of ischaemia-reperfusion injury in the NMP preserved livers. The lack of improvement in clinical outcomes differs from the recent, larger multicentre COPE study, which found improved early biochemical markers and a reduction in reperfusion instability with longer periods of NMP. The authors postulate that this may be due to the older donor population, which is possible, although it should also be noted that these were all DBD (no DCD) livers, and the perfusion device used is different. Ultimately, this study is underpowered to demonstrate differences in clinical efficacy with just 10 patients per arm.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per protocol
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT02940600
Funding Source:
Non-Industry funded
Gupta S, Pollack T, et al. Hyperglycemia in the Posttransplant Period: NODAT vs Posttransplant Diabetes Mellitus. Journal of the Endocrine Society. 2018; 2(11):1314-9.
Aim:
To characterize the types of hyperglycemia that occur up to 1 year following liver transplant, and clarify the nomenclature for posttransplant hyperglycemia.
Interventions:
Liver transplant recipients enrolled in an RCT comparing moderate (target glucose ~180 mg/dL [10 mmol/L] group) to intensive (target glucose ~140 mg/dL [7.8 mmol/L] group) insulin therapy to determine if patients had preexisting known diabetes, transient hyperglycemia, persistent hyperglycemia, or new-onset diabetes after transplantation (NODAT).
Participants:
65 patients with hyperglycemic episodes following initial hospital discharge and up to 1 year following transplant were included in this retrospective study. These patients were divided into three groups (transient hyperglycemia, n=48; NODAT, n=4; persistent hyperglycemia, n=13).
Outcomes:
Analysis of 1-year post transplant glycemic follow-up data in these three groups of patients. Data included fasting glucose levels, random glucose levels, and hemoglobin A1c levels that were obtained at routine posttransplant visits.
Follow Up:
1 year post transplantation
CETs Conclusions:
This post-hoc analysis used data from a randomised controlled trial, comparing moderate insulin with intensive insulin in 164 liver transplant recipients to clarify the nomenclature of posttransplant hyperglycemia and to analyse the most common causes of transient hyperglycemia. There were 65 patients who had hyperglycemic episodes following discharge and up to 1 year posttransplant. Of these, 48 patients had transient posttransplant hyperglycemia, 13 patients had persistent hyperglycemia posttransplant up to 1 year and three patients met the criteria for diabetes. Of the 48 patients who had transient posttransplant hyperglycemia, this resolved between 30 days and 1 year posttransplant in 32 patients. Hyperglycemia for these 32 patients was found to be linked to higher than maintenance steroid doses, high tacrolimus doses, infections and rejection. The RCT was previously appraised and includes an expert commentary in the Transplant Library: http://www.transplantlibrary.com/article/27875061?term=wallia
Reporting Quality:
Jadad Score 
3
Data Analysis 
Available case analysis
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov - NCT01211730
Funding Source:
Non-Industry funded
Leon Diaz FJ, Fernandez Aguilar JL, et al. Combined Flush With Histidine-Tryptophan-Ketoglutarate and University of Wisconsin Solutions in Liver Transplantation: Preliminary Results. Transplantation Proceedings. 2018; 50(2):539-42.
Aim:
To compare ischemia reperfusion injury (IRI0, early allograft dysfunction (EAD), and primary allograft failure (PAF) in liver transplantation in a cohort of patients perfused with histidine-tryptophan ketoglutarate (HTK) solution and University of Wisconsin (UW) solution versus HTK alone.
Interventions:
80 patients were randomized (1:1) to receive perfusion with either HTK + UW or to HTK alone (n=40 in each group). This paper presents data for the first 20 patients assigned to each group.
Participants:
40 liver transplant patients randomized to HTK + UW (n=20) or to HTK (n=20).
Outcomes:
Primary endpoints included IRI, EAD, PAF, re-intervention, acute cellular rejection, retransplantation, arterial complications, and biliary complications at postoperative Day 90.
Follow Up:
Post-operative Day 90.
CETs Conclusions:
The scientific rationale for mixing preservation fluids is not clearly explained in this study, other than in an attempt to reduce ischaemia-reperfusion injury. Perhaps comparing HTK with UW directly would have been a better comparison. This study is probably too small to be adequately powered for any of the multiple primary endpoints listed. Serum levels of glutamic oxaloacetic transaminase and glutamic pyruvic transaminase were higher in the HTK group. The study was not blinded, and there is no thorough description of withdrawals and dropouts. This study does not give strong evidence to support the mixing of preservation fluids, a process that may have unintended consequences.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Per protocol
Allocation Concealment 
No
Trial Registration:
Not reported
Funding Source:
Not reported
Saliba F, Fischer L, et al. Association Between Renal Dysfunction and Major Adverse Cardiac Events After Liver Transplantation: Evidence from an International Randomized Trial of Everolimus-Based Immunosuppression. Ann Transplant. 2018; 23:751-7
Aim:
A post hoc analysis of data from an RCT of de novo liver transplant recipients examining the association between the evolution of renal function and the incidence of major adverse cardiac events over the first 2 years post-transplantation.
Interventions:
Patients were randomized at 30 days post-transplant to receive: (i) everolimus [EVR] and reduced tacrolimus [EVR/rTAC], (ii) EVR with tacrolimus discontinued [TAC Elimination], or (iii) standard tacrolimus [TAC Control].
Participants:
719 patients were randomized and formed the ITT population (EVR/rTAC, n=245, TAC Elimination, n=231, TAC Controls, n=243).
Outcomes:
Trends in renal function from randomization to Month 24 were evaluated using eGFR values documented at each study visit (Months 1, 2, 3, 4, 5, 6, 9, 12, 18, and 24) to calculate the area under the curve (AUC). Information on major cardiac events was collected as part of adverse event reporting procedures at each study visit. The association between eGFR AUC and treatment group, and eGFR AUC as a continuous variable and the occurrence of first major cardiac event was assessed. All analyses were based on the ITT population.
Follow Up:
24 months post randomization.
CETs Conclusions:
This post-hoc analysis investigated whether there is a relationship between renal dysfunction and the incidence of major cardiac events in de novo liver transplant recipients. Data were used from an RCT comparing everolimus/reduced tacrolimus versus everolimus/tacrolimus discontinuation versus standard tacrolimus. Major cardiac events were defined as ischemic heart diseases, cardiac failure, ischemic stroke, and sudden death. The evolution of renal function was determined according to the area under the curve (AUC) of the estimated glomerular filtration rate (eGFR) from baseline to 2 years posttransplant. The analysis included 716 patients for whom data on major cardiac events were available. It was shown that renal function was inversely related to the incidence of major cardiac events in the first 2 years posttransplant.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Intention to treat
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT00622869
Funding Source:
Industry funded
Shaked A, DesMarais MR, et al. Outcomes of immunosuppression minimization and withdrawal early after liver transplantation. Am J Transplant. 2018; [record in progress].
Aim:
To determine the outcomes of immunosuppression minimization and withdrawal starting within 2 years after liver transplantation in recipients with hepatitis C (HCV) or nonimmune nonviral (NINV) causes of liver failure.
Interventions:
Eligible patients receiving immunosuppression with corticosteroids and a calcineurin inhibitor and/or antimetabolite following transplantation were randomized (4:1) to either immunosuppression withdrawal or to immunosuppression maintenance at 1 and 2 years post transplantation. Patients assigned to immunosuppression maintenance were assessed for 2 years. Patients assigned to immunosuppression withdrawal were assessed for 2 years after immunosuppression withdrawal concluded. Biopsies were obtained on the day of transplant, at evaluation of randomization eligibility (12-24 months post-transplant) and at 24 and 36 months post-transplant. Additional protocol biopsies were obtained for HCV patients at 6 and 12 months post-transplant. Liver biopsies were also planned when allograft dysfunction was detected or as clinically indicated.
Participants:
95 patients were randomized 4:1 to immunosuppression withdrawal (n=77) or maintenance (n=18). Randomization was stratified by HCV or NINV status.
Outcomes:
The primary composite endpoint was defined as the occurrence of death or graft loss, grade 4 secondary malignancy, grade 4 opportunistic infection, stage 3 or higher fibrosis, or a decrease in renal function. All outcomes were assessed at 2 years post randomization except renal function that was assessed at 24 months to 36 months post randomization. Secondary endpoints were eligibility for random assignment, immunosuppression withdrawal completion, immunosuppression-free duration, hepatitis C viral load, fibrosis and graft loss or death.
Follow Up:
Up to 3 years post transplantation.
CETs Conclusions:
This interesting study investigated attempted immunosuppression withdrawal in highly selected liver transplant recipients with HCV or non-immune causes of failure. Of the 275 recipients enrolled, 95 eligible patients were randomized in a 4:1 ratio to attempted minimization/withdrawal or maintenance. Immunosuppression was successfully withdrawn in 10 patients, with 52 reduced to <50% baseline dose. No difference was seen in the primary composite outcome (death, graft loss, malignancy/infection, 25% fall in GFR, fibrosis). This study provides some useful insights into immunosuppression withdrawal and operational tolerance in this patient group. Only a small proportion of enrolled patients were able to achieve complete withdrawal, although minimization was successful in a larger number. Of note, 23% of enrolled patients withdrew consent post-transplant before randomization, suggesting that many patients do not have the appetite for taking risk when clinically stable. The initial sample size calculation over-estimated the number of patients who would be eligible for randomization, and so the study is ultimately underpowered to demonstrate non-inferiority of this strategy compared to immunosuppression maintenance.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Per protocol
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT00135694
Funding Source:
Non-Industry funded

Transplant Trial Watch February 2019 – Various Organ Transplantation

Rajapakse S, Weeratunga P, et al. Prophylaxis of human toxoplasmosis: a systematic review. Pathog Glob Health. 2017; 111(7):333-42.
Aim:
This review aims to describe the modalities for prophylaxis of toxoplasmosis in susceptible populations including transplant recipients.
Interventions:
A search was carried out in PUBMED and EMBASE using broad search terms. The search included all articles published from 1985 to 2017 with no restriction of language. Bibliographies of cited literature were also searched. Three authors systematically assessed the search results and selected manuscripts for inclusion by consensus. There is no assessment of study quality or bias.
Participants:
1618 papers were identified during the database search and 68 papers were evaluated for relevant data. Data from 42 papers were included in the synthesia (reviews, meta-analyses, randomized controlled trials, observational studies, case control studies and cohort studies). Of these, 29 manuscripts (12570 susceptible patients) included qualitative data on pharmacological prophylaxis for human toxoplasmosis (2 meta-analyses, 9 RCTs and 18 non-RCTs). The majority of studies were from the USA or Europe.
Outcomes:
A narrative synthesis of data on prophylaxis for toxiplasmosis. For solid organ tranplantation, data was only available for heart or heart/lung transplant recipients, was drawn from five observational studies and assessed prophylaxis with spiramycin or trimethoprim plus sulphamethoxazole.
Follow Up:
Literature published from 1985 to 2017
CETs Conclusions:
This systematic review has a wide remit, covering the prophylaxis of toxoplasmosis in various at-risk groups (congenital transmission, HIV positive patients and transplant recipients). A broad search was conducted with papers assessed by 3 authors. It is not clear if the protocol was registered in advance. The review included 9 RCTs, 2 meta-analyses and 18 non-randomised studies and no quality assessment of included studies is presented. Most of the information relating to transplantation in this review is in the field of heart transplantation, and these studies are actually very limited in their impact.
Reporting Quality:
Quality Notes 
Systematic review – QA not appropriate
Trial Registration:
Not reported
Funding Source:
Not reported

Transplant Trial Watch March 2019 - Kidney Transplantation

Buttigieg, J., Ali, H. et al. (2018). Positive Luminex and negative flow cytometry in kidney transplantation: a systematic review and meta-analysis. Nephrology Dialysis Transplantation [record in progress].
Aim:
To assess graft function, acute rejection (AR) rates, graft survival and patient survival in positive Luminex and negative flow cytometry (PLNF) compared with donor-specific antibody (DSA)-negative transplants.
Interventions:
The PubMed, Ovid MEDLINE and Scopus database were searched in this study (01 January 2000 and 31 December 2016). Transplant characteristics such as Luminex cut-off intensity, FCXM cut-off, desensitization techniques, induction and maintenance immunosuppression, and outcomes such as graft function, AR episodes, graft survival and patient survival were utilised to generate a pooled analysis. Articles were only included if published in the English language. Publication bias was estimated using funnel plots.
Participants:
1124 records were identified by the database search. After screening and eligibility assessment, 7 studies were included in the final content analysis (429 PLNF transplants and 10677 DSA-negative transplants).
Outcomes:
Outcomes compared incidence of AR at 1 year, graft failure and patient mortality at 1 and 5 years between PLNF and DSA-negative transplants.
Follow Up:
5 Years
CETs Conclusions:
The systematic review aimed to compare glomerular filtration rate (GFR), acute rejection, and graft and patient survival for positive Luminex and negative flow (PLNF) cytometry transplants with donor-specific antibodies (DSA)-negative transplants. The bibliographic search identified 496 unique references of which seven studies met the inclusion criteria. Full text screening and data extraction was done by two independent reviewers. The methodological quality was assessed using the Newcastle-Ottawa scale although it was not described whether the quality assessment was done by two independent reviewers. Six out of seven studies were considered to be of good quality. Data were summarised by narrative review or, where possible, by calculating the risk ratios using a random effects model. Data allowed pooling of studies for acute rejection, and patient and graft survival and found no significant differences between PLNF and DSA-negative transplants for any of the outcomes. It should be noted that the pooled analyses only included two, three or four studies. Four studies reported GFR data and narrative review of the studies did not show a clear trend favouring PLNF or DSA-negative transplants.
Reporting Quality:
Quality Notes 
Systematic review – QA not appropriate
Trial Registration:
Not reported
Funding Source:
Not reported
Campsen, J., Call, T. et al. (2018). Prospective, double blind, randomized clinical trial comparing an ERAS pathway with ketorolac and pregabalin versus standard of care plus placebo during live donor nephrectomy for kidney transplant. Am J Transplant.
Aim:
To determine whether, in donor nephrectomies, the use of a non-opioid analgesic for the Enhanced Recovery After Surgery (ERAS) protocol could decrease narcotics used, without increasing the complications of a patient.
Interventions:
Participants were randomized to either the ERAS group, receiving ketorolac and pregabalin (n=33) or the control group, receiving standard treatement and placebo (n=29).
Participants:
62 patients, undergoing nephrectomy for live donor kidney transplantation (>18 years).
Outcomes:
Primary outcomes were assessed as renal function alongisde secondary outcomes. Secondary endpoints included length of stay, operative time, hematocrit (Hct) levels and 30‐day postoperative mortality.
Follow Up:
48 Hours
CETs Conclusions:
This small single-centre study investigates the use of an enhanced recovery (ERAS) pathway following living kidney donation. Patients were randomized to receive either standard of care (mainly opiate-based analgesia), or standard of care plus pre-operative pregabalin and post-operative ketorolac. The authors demonstrate equivalent creatinine change, a reduction in opiate use in the ERAS group, with a reduction in length of hospital stay. The study is well designed, with use of placebo and double blinding. The clinical significance of the reduction in hospital stay (6 hours) is questionable, but the reduction in opiate use is likely to be clinically significant. The authors do not look at opioid-related side effects (e.g. constipation) or outcomes following hospital discharge. It would be interesting in future studies to look at longer-term outcomes such as opiate use following discharge, return to normal function and return to work.
Reporting Quality:
Jadad Score 
5
Data Analysis 
Per Protocol
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT03669081
Funding Source:
Not reported
Cockfield, S. M., Wilson, S. et al. (2018). Comparison of the Effects of Standard Versus Low-dose Prolonged-release Tacrolimus with or without ACEi/ARB on the Histology and Function of Renal Allografts. Am J Transplant;[record in progress].
Aim:
To assess the effects of IF/TA prevalence using a reduced tacrolimus dosing strategy and RAS-blocking AHTs.
Interventions:
At randomization, patients were assigned to one of four possible treatments; standard-dose, prolonged-release tacrolimus, plus, either an ACE inhibitor or angiotensin II receptor blocker (n=71), or other antihypretensive therapy (n=69), or low- dose prolonged-release tacrolimus, plus, either an ACE inhibitor or angiotensin II receptor blocker (n=71), or other antihypretensive therapy (n=68), corresponding to two tacrolimus interventions (low vs standard) and two AHT interventions (ACEi/ARB vs OAHT).
Participants:
281 adult renal transplant recepients. Of these, 235 completed the study.
Outcomes:
This study had two co-primary outcomes: the prevalence of IF/TA at Month 6 and at Month 24. Secondary endpoints included the progression of IF/TA post-transplant, and assessment of renal function, blood pressure and use of antihypertensive agents throughout the study period.
Follow Up:
Up to 24 months
CETs Conclusions:
This interesting multicenter open-label study investigated the interaction between low- and high-dose tacrolimus and use of ACE inhibitors on the development of IF/TA following renal transplantation. The investigators used a 2x2 randomised design to compare low- versus high-dose prolonged release tacrolimus and ACEi/ARB versus other antihypertensive use. Protocol biopsies were taken at baseline, 6 months and 24 months. The largest reduction in 24-month IF/TA came from the use of low-dose tacrolimus, although there was some interaction between the two treatments with the lowest rate of IF/TA seen in the ACEi and low-dose Tac group. Use of ACEi/ARB in conjunction with low-dose tacrolimus also appears to reduce the rejection risk associated with low-dose tac use. Interestingly, post-hoc analysis also demonstrated a significant reduction in the risk of IF/TA with inflammatory infiltrate associated with ACEi/ARB use. Taken together, these results suggest that addition of ACEi/ARB to low-dose tacrolimus early after transplantation is safe and may confer some benefit in the progression of IF/TA and risk of T-cell mediated rejection. It is not clear whether the histopathologists involved in this study were blinded to treatment assignment, raising the risk of measurement bias. Longer-term follow-up will determine whether the early benefits seen translate to differences in graft function and survival.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified intention to treat
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT00933231
Funding Source:
Not reported
Nieuwenhuijs-Moeke, G. J., van den Berg, T. A. J. et al. (2018). Preemptively and non-preemptively transplanted patients show a comparable hypercoagulable state prior to kidney transplantation compared to living kidney donors. PLoS ONE;13(7):e0200537.
Aim:
To determine whether there is a difference in haemostatic state between pre-emptively and non-pre-emptively transplanted patients.
Interventions:
None – this is a post-hoc observational analysis of patients in the VAPOR-1 study.
Participants:
57 kidney donor recipients from the VAPOR-1 trial. Of these, 28 were transplanted pre-emptively and 29 were transplanted non-preemptively.
Outcomes:
The main outcome being measured in this study was haemostatic state of transplant patients by measuring coagulation and platlet activation. Aside from this, the levels of thrombin, von-Willebrand factor, clot lysis and reperfusion pathology were measured to assess the haemostatic state of preemptive and non-preemptive patients.
Follow Up:
2 years
CETs Conclusions:
In many renal transplant centres, anti-coagulation protocols differ between pre-emptive and dialysing recipients in the belief that pre-emptive recipients have an increased risk of thrombosis compared to those on dialysis. The authors of this manuscript investigate this assumption using a retrospective analysis of samples from the VAPOR-1 study. They find that both pre-emptive and non-preemptive recipients have a hypercoagulable pre-transplant state compared to healthy living donors, with no difference between the two groups. These results suggest that there is no rationale for differential treatment of recipients depending on dialysis status at the time of transplantation. Whether the use of a single dose of unfractionated heparin prior to vessel clamping, as used in many centres, has a significant impact on thrombosis risk would require further prospective study.
Reporting Quality:
Jadad Score 
4
Data Analysis 
Per Protocol
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT01248871
Funding Source:
Non-Industry funded
Reindl-Schwaighofer, R. et al. (2019). Steroid pretreatment of organ donors does not impact on early rejection and long-term kidney allograft survival: Results from a multicenter randomized, controlled trial. Am J Transplant;[record in progress].
Aim:
To determine the long-term effects of anti-inflammatory treatment of organ donors on kidney allograft and patient outcomes.
Interventions:
Patients received either 1000mg of methylprednisolone or placebo prior to their organ procurement.
Participants:
306 deceased donors and 455 renal transplant recipients from three different transplantation centers in Europe. Of these, 238 patients received an organ from a steroid (methylprednisolone) pretreated donor and 217 patients received an organ from a donor treated with placebo.
Outcomes:
The primary outcome was the rate of delayed graft function at one-week. Further primary outcomes included the incidence of acute rejection episodes within the first three months and death censored graft survival at five years. Secondary outcomes measured actual graft survival at five years as well as allograft function over time using the estimated glomerular filtration rate (GFR).
Follow Up:
Up to 5 years
CETs Conclusions:
Steroid pre-treatment of donors has been used to reduce inflammation in donated organs with some supporting evidence from older, non-randomised studies. This report is of a high quality, multi-centre RCT that is well written. The previously reported short-term outcomes from this study found no difference in DGF between the arms, and the study had been powered for that outcome. The authors do present the calculated power for the long-term outcome of graft survival at 5 years, and it is reasonable. The study report shows excellent follow up maintenance at 5 years. The report shows that there was no significant difference in acute rejection at 3 months (10% versus 12%), 5-year graft survival (84% versus 82%), or hazard ratio for graft loss. The use of high-dose systemic steroids prior to organ retrieval is therefore not supported by this study.
Reporting Quality:
Jadad Score 
5
Data Analysis 
Per Protocol
Allocation Concealment 
Yes
Trial Registration:
ISRCTN78828338
Funding Source:
Industry funded
Tedesco Silva, H., Jr., Evans, R. W. et al. (2018). A Cost-Effectiveness Analysis of Organ Preservation Methods for Deceased Donor Kidneys at High Risk for Delayed Graft Function in Brazil. Transplant Proc;50(10):3121-7.
Aim:
This analysis aims to consider the cost-effectiveness of machine perfusion, relative to static cold storage, based on clinical data from patients in the Brazilian multi center clinical trial.
Interventions:
Comparison of cost effectiveness between machine perfusion and static cold storage in the Brazilian cohort.
Participants:
A decision tree model that simulates the 1000 kidney transplant recipients from data derived from the Brazilian multi center clinical trial cohort.
Outcomes:
The decision tree model aimed to measure three possible graft outcomes following 1 year post-transplantation: graft success, graft failure or delayed graft function. Alongside this, quality of life of machine perfusion relative to static cold storage was assessed.
Follow Up:
1 year
CETs Conclusions:
This was a cost-effectiveness analysis of a randomised controlled trial (RCT) that compared machine perfusion with static cold storage in 80 pairs of deceased donor kidneys. The RCT found that the incidence of delayed graft function (DGF) was significantly lower following machine perfusion compared to static cold storage (45% versus 61%). A decision tree model was developed based on the Brazilian National Health System and accounted for the possible outcomes DGF, an immediately functioning kidney and primary non-function requiring return to dialysis. Cost-effectiveness was reported as the incremental cost-effectiveness ratio (ICER). Quality of life was included in the model as health utility but as the outcome was not collected in the trial, assumptions for health utility values were based on the published literature. At 1-year post-transplant machine perfusion was cost-effective compared to static cold storage. The authors concluded that machine perfusion leads to more functioning kidneys and better quality of life compared to static cold storage.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol
Allocation Concealment 
Yes
Trial Registration:
Not reported
Funding Source:
Industry funded
Tsujita, M., Kosugi, T. et al. (2018). The effect of maintaining high hemoglobin levels on long-term kidney function in kidney transplant recipients: a randomized controlled trial. Nephrol Dial Transplant;[record in progress].
Aim:
To determine the effect of low and high Hb target levels on kidney function of kidney transplant recipients.
Interventions:
Patients were randomized into a high Hb group (n=64) and a low Hb group (n=63).
Participants:
127 enrolled patients (20-70 years of age; KTx performed within the last 12 months; stable kidney function for preceding 3 months prior to registration; Hb levels 9.0-11.5 g/dL).
Outcomes:
The primary endpoint was the difference in the rate of decline of Cr-based eGFR (eGFRcre) between the initiation point and the 36-month follow-up assessment. Secondary outcomes measured the number of patients who progressed to end-stage renal disease (ESRD), occurrence of AR and cardiovascular events during the follow-up period.
Follow Up:
Up to 36 months
CETs Conclusions:
The randomised controlled trial tested the hypothesis that sustained maintenance of target haemoglobin concentrations at high target levels (12.5-13.5 g/dL) with erythropoiesis-stimulating agents would limit deterioration of kidney function compared with low target levels (10.5-11.5 g/dL) in kidney transplant recipients. The randomisation order was computer-generated but there was no description of concealed allocation. The power calculation showed that a total of 100 patients were needed for a power of 80% with a significance level of 5%. The study randomised 127 patients of which 19 patients were excluded. The per-protocol analysis of the primary outcome (the difference in the rate of decline of creatinine-based eGFR between baseline and 36 months posttransplant) showed a significantly greater decline in eGFR for the low target group versus the high target group (-5.1±9.5 versus -1.0±8.4 mL/min/1.73m2).
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol
Allocation Concealment 
No
Trial Registration:
University Hospital Medical Information Network - UMIN 000009594
Funding Source:
Non-Industry funded

Transplant Trial Watch March 2019 - Liver Transplantation

Bekheit, M. et al. (2018). The role of graft reperfusion sequence in the development of non-anastomotic biliary strictures following orthotopic liver transplantation: A meta-analysis. Hepatobiliary & Pancreatic Diseases International;[record in progress].
Aim:
This study aimed to compare the incidence of non-anastomotic biliary stricture and other surgical complications in initial portal reperfusion (sequential) compared to simultaneous or initial artery reperfusion.
Interventions:
Meta-analysis of published studies comparing outcomes in initial portal reperfusion versus simultaneous artery reperfusion. Studies were identified under the guidance of the Cochrane guidelines for systematic reviews and meta-analysis.
Participants:
Analysis included 7 studies and 685 patients.
Outcomes:
The primary outcomes of this study included prevalence of non-anastomotic biliary strictures and reperfusion injury or damage to the transplanted liver. Secondary outcomes included, hospital stay, operative time and cold ischemia.
Follow Up:
Up to 18 months
CETs Conclusions:
This systematic review searched a wide variety of databases and used specific search strategies for each, and data extraction was done in duplicate. There were only 7 studies included, and these were a mixture of RCTs and other comparative study types. The authors found no evidence for a difference in non-anastomotic biliary strictures when comparing different strategies for hepatic allograft reperfusion. The most significant weakness is the lack of information on the delay time between portal and arterial reperfusion in the delayed group.
Reporting Quality:
Quality Notes 
Systematic review – QA not required.
Trial Registration:
Not reported
Funding Source:
No funding
Cillo, U., Saracino, L. et al. (2018). Very early introduction of everolimus in de novo liver transplantation: results of a multicenter, prospective, randomized trial (EPOCAL). Liver Transpl;[record in progress].
Aim:
To determine the efficacy and safety of an early (postoperative day 7) everolimus initiation and minimized tacrolimus compared with the standard tacrolimus regimen after lung transplantation.
Interventions:
Following one week after transplantation, patients were randomized (2:1) to receive everolimus and to gradually minimize or withdraw tacrolimus when everolimus was stable at >5 ng/mL, or to continue tacrolimus at 6‐12 ng/mL.
Participants:
140 participants were enrolled into this study (18-70 years): 93 randomized in the EVR group and 47 in the control group.
Outcomes:
The primary endpoint was the number of patients who did not show a treated biopsy-proven acute rejection (tBPAR) after 3 months from transplantation. Secondary outcomes included, composite efficacy failure rate at 3, 12 and 24 months post-transplantation and renal function (assessed by eGFR) at 1, 6, 12 and 24 months.
Follow Up:
Up to 24 months
CETs Conclusions:
This multi-centre RCT was conducted in early, stable liver transplant recipients in an effort to minimise the complications of calcineurin inhibitors. The exact method of randomisation is not described and the study was not blinded due to having to dose-adjust the medications. The power calculation was conducted on the basis of randomising patients in a 2:1 ratio and with assumed inactivity cutoff for the treatment of <60% and activity cutoff of >75%. As it happens, the rate of treated-BPAR was 12.9% in the everolimus group and 4.3% in the control group. This was reported as not a statistically significant difference (p=0.09), but if this difference in acute rejection were real, then this represents a clinically significant difference that this study was underpowered to see. A significant number of patients (17, 12.1%) were withdrawn during the first 3 months. 20 of the patients in the everolimus arm minimised tacrolimus doses before reaching their target everolimus dose and therefore were potentially under-immunosuppressed. Graft and patient survival was similar at 12 months. Conversion to everolimus was associated with a much higher rate of incisional hernia (25.8% versus 6.3%), wound complications (18.2% versus 0%) and higher rate of hypercholesterolaemia (15% versus 6.3%), but with much improved GFR over follow up, fewer neurological disorders (13.9% versus 31.9%) and serious infections (11.8% versus 27.6%).
Reporting Quality:
Jadad Score 
2
Data Analysis 
Strict intention to treat
Allocation Concealment 
No
Trial Registration:
Clinicaltrials.gov - NCT01423708
Funding Source:
Not reported

Transplant Trial Watch March 2019 - Heart Transplantation

Rabus, M. B. et al. (2018). Intraoperative Tissue-Immunosuppressive Therapy Reduces Rejection Episodes in Heart Transplant Recipients. Experimental & Clinical Transplantation: Experimental & Clinical Transplantation;[record in progress].
Aim:
To identify the effects of intraoperative antithymocyte globulin administration on donor hearts following cardiocirculatory death.
Interventions:
Patients were randomized to receive retrograde antithymocyte globulin infusion via coronary sinus intraoperatively and immediately after organ procurement or traditional antithymocyte globulin infusion after implantation.
Participants:
30 patients with orthotropic heart transplants.
Outcomes:
Allograft rejection and graft function.
Follow Up:
30 days
CETs Conclusions:
This small single-centre study investigated the role of intraoperative ATG injected directly to the coronary sinus during cardiac transplantation. Patients in both groups also received postoperative ATG infusion, to achieve the same total dose in both groups. The authors claim a significant reduction in the risk of acute rejection in the intraoperative ATG group, as well as a reduction in echocardiographic abnormalities and need of inotropic therapy. Whilst on the face of it, this sounds like a promising intervention, there are significant deficiencies in the methodology and reporting of this study. This study is described as randomised, but from the description in the manuscript it appears to be a sequential cohort study with all intraoperative ATG patients recruited at the end of the study. No power calculation is presented, and there is a real risk of type I error in the acute rejection results. I was unable to replicate the claim of a statistically significant increase in acute rejection – with 2/15 control and 0/15 study patients experiencing rejection, a Fisher exact test gives a p-value of 0.48, rather than the <0.05 reported in the manuscript. The claims of reduced inotrope use and improved echocardiographic function are not backed up with any data. In short, the data presented in the manuscript does not support the conclusion of the authors.
Reporting Quality:
Data Analysis 
Per Protocol
Allocation Concealment 
No
Trial Registration:
Not reported
Funding Source:
No funding