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

Transplant Trial Watch April 2019 - Kidney Transplantation

Cote, J., Fortin, M.C. et al. (2018). Web-Based Tailored Intervention to Support Optimal Medication Adherence Among Kidney Transplant Recipients: Pilot Parallel-Group Randomized Controlled Trial. JMIR Formative Research 2(2): e14.
Aim:
This study aimed to evaluate the Transplant-TAVIE intervention’s acceptability, feasibility, and preliminary efficacy.
Interventions:
Kidney transplant patients on immunosuppressive medication were randomly assigned either to an experimental group (Transplant-TAVIE) (n=35) or to a control group (existing medication websites) (n=35).
Participants:
70 kidney transplant patients on immunosuppresive medication.
Outcomes:
The primary outcome of this trial was medication adherence. Secondary outcomes included self-efficacy, skills, medication, side-effects and self-perceived general state of health.
Follow Up:
6 months.
CETs Conclusions:
This pilot randomised controlled trial aimed to assess the feasibility, acceptability and preliminary efficacy of Transplant-TAVIE, a web-based tailored nursing intervention that was developed to support medical adherence among kidney transplant recipients. Transplant-TAVIE consisted of three interactive, web-based sessions hosted by a virtual nurse that aimed to gradually increase knowledge and abilities. The control group was invited to visit three conventional transplantation-related websites offering information. No sample size calculation was performed for this pilot study. The randomisation list was computer-generated and allocation was concealed by using numbered, opaque, sealed envelopes. Data entry was blinded. Analysis was based on intention to treat but missing data were not imputed. Seventy patients were randomised of which only 39 (23 (Transplant-TAVIE) versus 16 (control)) completed the six-month follow up questionnaire. The main reason for withdrawal was described as ‘Did not respond’ (n=24). Transplant-TAVIE was evaluated among 18 participants and was generally found to be acceptable and all participants would recommend the intervention to other transplant recipients. These pilot data found no differences between groups regarding the efficacy at any time point.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified intention to treat
Allocation Concealment 
Yes
Trial Registration:
Not reported
Funding Source:
Non-Industry funded
Pihlstrøm, H. K., Mjøen, G. et al. (2018). Genetic markers associated with long-term cardiovascular outcome in kidney transplant recipients. Am J Transplant; [record in progress].
Aim:
The study aimed to evaluate the predictive value of the risk score in renal transplant recipients (RTRs) in relation to cardiovascular risk levels.
Interventions:
This is a post-hoc analysis of the Assessment of Lescol in Renal Transplantation (ALERT) trial, which compared fluvastatin with placebo.
Participants:
1640 participants from the ALERT trial (Assessment of Lescol in Renal Transplantation).
Outcomes:
Primary outcome was assessed as time from study inclusion to incidence of first major cardiovascular event (MACE). Secondary endpoints included: time from inclusion to cardiac death, allcause death, and death‐censored graft loss.
Follow Up:
5.2 Years.
CETs Conclusions:
Data from the ALERT trial (Assessment of Lescol in Renal Transplantation), which compared fluvastatin with placebo in stable renal transplant recipients, were used to validate the genetic risk score in a transplant population. Of all 2039 patients included in the ALERT trial, 1640 were included who had DNA samples for genotyping and were genotyped for 27 single nucleotide polymorphisms (SNPs) that are included in the genetic risk score. Associations between genotype at each of the 27 loci and major cardiovascular events were tested in Cox regression analyses. Missing data for each SNP were imputed using the population mean (only in 1% of the population). The authors conclude further genetic studies are needed that use broader gene panels.
Reporting Quality:
Jadad Score 
4
Data Analysis 
Strict intention to treat
Allocation Concealment 
Yes
Trial Registration:
Not reported
Funding Source:
Industry funded

Transplant Trial Watch April 2019 - Liver Transplantation

Gomez Gavara, C., Esposito, F et al. (2019). Liver transplantation in elderly patients: a systematic review and first meta-analysis. HPB 21(1): 14-25.
Aim:
The aim of this study was to synthesize the available evidence on liver transplantation for elderly patients to assess graft and patient survival.
Interventions:
A literature search of the Medline, EMBASE, and Scopus databases was carried out from January 2000 to August 2018.
Participants:
22 studies were included involving a total of 242,487 patients.
Outcomes:
The primary outcomes assessed were patient mortality and graft loss rates. The secondary outcomes were perioperative morbidity and 90-day mortality.
CETs Conclusions:
This is an interesting systematic review and meta-analysis in liver transplantation that compares the outcomes for adults older than 65 years with those of adults under 65 years. The primary outcomes were 1- and 5-year patient and graft survival. The systematic review was prospectively registered, and searches were conducted in multiple databases, resulting in 22 included studies. Eight studies were registry analyses, 2 were comparative studies and 12 were retrospective single-centre databases, including in total over 240,000 patients. Articles were screened by two reviewers independently. Three quarters of the studies included were of low quality and the remaining quarter were of very low quality according to the review authors’ assessments. The definition of elderly in included studies ranged from over 63 years to over 75 years, so only 7 studies could be included in the meta-analysis with a threshold of 65 years. In this analysis there was moderate heterogeneity (I-squared = 48%) and older patients had a Hazard Ratio of 1.26 for survival although it was not statistically different in this reduced sample (HR range 0.97-1.63, p=0.09). Graft loss was not significantly different also, but studies did not clearly define how this was assessed. The key point is that it was not possible to know how each included study assessed patients as being suitable for transplantation, ie what is their physiological age? The older group did have a significantly lower MELD score in half the studies reporting this variable, so it may be that a more conservative approach was being taken with older recipients.
Reporting Quality:
Quality Notes 
Systematic review - Quality assessment not appropriate.
Trial Registration:
PROSPERO - CRD42017058261
Funding Source:
Not reported
Hanada, M., Soyama, A. et al. (2019). Effects of quadriceps muscle neuromuscular electrical stimulation in living donor liver transplant recipients: phase-II single-blinded randomized controlled trial. Clinical Rehabilitation [record in progress].
Aim:
To evaluate the efficacy of neuromuscular electrical stimulation on quadriceps muscle strength and thickness in liver transplantation patients.
Interventions:
The study group received bilateral quadriceps muscle electrical stimulation and the control group received bilateral tilialis anterior muscle stimulation. Neuromuscular electrical stimulation sessions were conducted for 30 minutes per session, once per day for five weekdays over four weeks by a physical therapist.
Participants:
45 liver transplantation patients randomly assigned to quads group (n = 23) or the control group (n = 22).
Outcomes:
Outcomes were assessed as quadriceps muscle strength, quadriceps muscle thickness and 6-minute walking distance.
Follow Up:
Up to 90 days.
CETs Conclusions:
This small single-centre study investigates the role of passive electrical stimulation of the quadriceps muscle post-transplant in liver recipients. The authors find a reduction in post-transplant quadriceps muscle loss (measured by muscle thickness) in the study group when compared to controls, but with no difference in strength or walking distance. The study design is robust, with blinded outcome assessment and allocation concealment. The control group received stimulation of the tibialis anterior muscle, which may have affected some outcomes (e.g. 6-minute walk test) and therefore reduced any effect size seen in these outcomes. Despite a small initial sample size (45 patients), over 30% patients were lost to final follow-up in each group, limiting the final power. Ultimately, larger studies will be required to see if the benefits seen here translate into any meaningful clinical effect.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict intention to treat
Allocation Concealment 
Yes
Trial Registration:
UMIN-CTR - UMIN000011655
Funding Source:
No funding
Sultan, A. M., Shehta, A. et al. (2019). Clamp-Crush Technique Versus Harmonic Scalpel for Hepatic Parenchymal Transection in Living Donor Hepatectomy: a Randomized Controlled Trial. J Gastrointest Surg; [record in progress].
Aim:
The aim of this study was to compare the safety, efficacy, and outcome of clamp-crush technique versus harmonic scalpel as a method of parenchymal transection in living-donor hepatectomy.
Interventions:
Cases were randomized into two groups: group (A) harmonic scalpel group and group (B) Clamp-crush group.
Participants:
72 patients undergoing right hemihepatectomy for adult living donor liver transplantation (LDLT).
Outcomes:
Primary outcomes of the study included blood loss (during parenchymal resection and total operative blood loss) and blood transfusion requirements. Secondary outcomes included parenchymal transection time, total operating time, necrosis at the cut margin of the remnant liver by pathological examination, perioperative morbidities (bleeding and bile leakage), postoperative biochemical markers (leucocytic count, platelets, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), international normalized ration (INR), CRP), and hospital stay.
CETs Conclusions:
This study randomised living liver donors to either harmonic scalpel or clamp-crush technique for parenchymal transection, the most invasive step of the right hepatectomy procedure. Randomisation was by “closed envelope” which, whilst we have to assume is random may not result in completely robust allocation concealment. The primary outcomes were blood loss and blood transfusion requirements, but no power calculation is provided. It is unclear if the analysis presented is per protocol or intention to treat. No significant difference was found in operative blood loss or blood transfusion requirement, however the overall range of operative blood loss is very wide (from 50 to 1750ml). Operative time was significantly longer with clamp-crush technique (440 minutes average versus 360 minutes average). The authors describe that more unexpected bleeding events were found with harmonic scalpel, but this is not defined (22% versus 3%). There was a larger margin of necrotic tissue at the cut edge with harmonic scalpel than with clamp-crush technique (0.5mm versus 0.3mm) but this does not seem clinically relevant. The study may be underpowered for clinically relevant differences in the primary outcomes and was not set up as either a superiority or non-inferiority trial. As with all surgical interventions, it can be difficult to assess the impact of a technique alone when the familiarity of the surgeon with the technique is of major importance.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict intention to treat
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT02853981
Funding Source:
Not reported
Yang, S. C., Lee, H. Y. et al. (2018). Eye Protection in Liver Transplantation Patients Under General Anesthesia. Transplantation Proceedings 50(9): 2651-2653.
Aim:
The aim of this current study is to compare the effectiveness of using Opsite in eye protection with either wet gauze alone or with wet gauze following application of eye ointment in patients undergoing living donor liver transplantation (LDLT).
Interventions:
One eye of each patient was protected with sterile gauze soaked with normal saline solution and covered with Opsite. Duratears ointment was applied to the other eye before covering it with sterile wet gauze and Opsite (ointment group).
Participants:
Total of 41 patients with 82 eyes undergoing liver transplantation were enrolled into this study.
Outcomes:
Outcomes were assessed as corneal epithelial defects and/or abrasion in patients undergoing LDLT.
CETs Conclusions:
This small study investigates the use of an opsite dressing over wet gauze, with or without ointment, to prevent corneal abrasion during liver transplant surgery. The investigators witnessed no corneal abrasions in either group during the study, leading them to claim that either method was 100% successful. It is unclear what the hypothesis being tested here is. The authors seem to suggest that the novel intervention is the use of an opsite dressing to create the equivalent of a moisture chamber over the eye, and yet the difference between the two groups is the use of eye ointment or not. No power calculation is provided, but the authors suggest in the introduction that the incidence of corneal epithelial defects during surgery with the use of eye protection is 2.1%. To power a study to detect a reduction to 1% would require a sample size of over 2,500 patients, far in excess of the 41 patients recruited!
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol
Allocation Concealment 
Yes
Trial Registration:
Not reported
Funding Source:
Not reported

Transplant Trial Watch April 2019 - Lung Transplantation

Gottlieb, J., Neurohr, C. et al. (2019). A randomized trial of everolimus-based quadruple therapy versus standard triple therapy early after lung transplantation. American Journal of Transplantation [record in progress].
Aim:
The aim of the current study was to demonstrate that everolimus with low CNI exposure in a quadruple immunosuppression regimen is superior to a standard triple CNI regimen in terms of renal function, as assessed by eGFR, in patients with impaired kidney function early after lung transplantation.
Interventions:
Patients were randomized to either a quadruple low CNI regimen or to a standard triple CNI regimen.
Participants:
The study population comprised 232 adults (>18 years) who had received a lung transplant from a deceased donor 3‐18 months prior to study entry.
Outcomes:
The primary endpoint was renal function at 12 months, as assessed by estimated GFR. Secondary endpoints included: renal function at months 1, 3, 6, 9 and 12, incidence of acute rejection, incidence and time to progression of bronchiolitis obliterans syndrome (BOS), incidence of graft loss/retransplantation, incidence of death, exercise capacity (as assessed by the six-minute walk test) and quality of life, all at months 6 and 12 post-randomisation.
Follow Up:
12 months.
CETs Conclusions:
This is an interesting and well conducted study in lung transplantation. The primary aim was to see if the addition of everolimus to the immunosuppression regimen would permit reduction of CNI doses and hence improve eGFR at one year after randomisation. Reduced eGFR is also a surrogate marker, or predictor, for future cardiovascular events and mortality. The study was only conducted in patients at least 3 months after transplantation and with only mild to moderate renal impairment. The method of randomisation was adequate and allocation concealment was maintained, although the study had to be open-label to permit clinicians to monitor and adjust drug doses. The power calculation is presented and seems reasonable. Both intention to treat and per-protocol results are presented. At the end of the study 70% of the everolimus group were still on allocated treatment, compared to 90% in the standard treatment group. In both the ITT and per protocol analysis, patients in the everolimus arm had an improved eGFR at 12 months (65ml/min versus 55ml/min ITT). Patients in the standard treatment arm had on average a gradual fall in eGFR over the 12 months, whilst patients in the everolimus arm had on average a small increase. There was no significant difference in BPAR rates, which were equally low. Acne and peripheral oedema were significantly more common in the everolimus arm (18% versus 1% and 33% versus 16%). There was no significant difference in infectious complications. Despite being underpowered, this study demonstrated that a quadruple immunosuppression regimen including everolimus could improve eGFR in lung transplant recipients compared to standard triple immunosuppression. A significant proportion of patients will not tolerate this study regimen, but it did not result in an increase in serious adverse events.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict intention to treat
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT01404325
Funding Source:
Industry funded
Miura, K., Vail, A. et al. (2019). Omega-3 fatty acid supplement skin cancer prophylaxis in lung transplant recipients: A randomized, controlled pilot trial." Journal of Heart & Lung Transplantation; 38(1).
Aim:
To assess the feasibility and acceptability, and safety of daily supplementation with omega-3 fatty acids (FA) to prevent skin cancers in lung transplant recipients.
Interventions:
Participants were randomly allocated to daily supplements containing either 4g omega-3 FA (3.36g eicosapentaenoic acid (EPA) + docosahexaenoic acid) or placebo (4g olive oil) for 12 months.
Participants:
49 lung transplant recipients randomised into two groups (n=25 omega-3 FA intervention) (n=24 placebo group).
Outcomes:
Primary outcomes were assessed as rates of recruitment, retention, adherence (assessed by plasma omega-3 FA) and safety. Secondary outcomes were assessed as the incidence of skin cancers.
Follow Up:
12 months.
CETs Conclusions:
This pilot, double-blind randomised controlled trial investigated the feasibility, acceptability and safety of daily omega-3 fish oil to prevent skin cancers in adult lung transplant recipients who were at least 1 year post-transplant. Patients were randomised based on a computer-generated randomisation sequence to either omega-3 fish oil or placebo capsules that looked identical and were stored in identical containers. No sample size calculation was conducted and 49 patients were included. Six patients withdrew from the study and 86% completed the follow up. Groups were similar at baseline although there were more patients with skin prone to sunburn in the placebo group (71% versus 40%) and less patients in the placebo group that never applied sunscreen to the head/neck area (8% versus 32%). The study showed that the supplementation is feasible and safe. A sufficiently powered study will need to be conducted to evaluate the efficacy of omega-3 fish oil in reducing skin cancers.
Reporting Quality:
Jadad Score 
5
Data Analysis 
Available case analysis
Allocation Concealment 
Yes
Trial Registration:
ANZ Clinical Trial Registry - 12614000873628
Funding Source:
Industry funded, Non-Industry funded

Transplant Trial Watch April 2019 - Heart Transplantation

Dhar, R., Stahlschmidt, E. et al. (2019). A randomized trial comparing triiodothyronine (T3) with thyroxine (T4) for hemodynamically unstable brain-dead organ donors. Clinical Transplantation;33(3).
Aim:
To determine whether T3 infusion can improve cardiac performance, haemodynamic stability, and result in more hearts transplanted than standard T4 therapy in haemodynamically unstable heart‐eligible brain dead (BD) organ donors.
Interventions:
Donors underwent echocardiography, within 12 hours of brain death and were randomized to T3 or T4 infusion for 8 hours.
Participants:
37 BD donors were randomised (n=16 T3 vs n=21 T4).
Outcomes:
Primary outcomes were assessed as incidence of myocardial dysfunction, improvement in left ventricular ejection fraction (LVEF) after 8 hours of treatment and proportion of donors with abnormal LVEF who achieve recovery to normal LVEF. Secondary outcomes comprised proportion of hearts that could be successfully transplanted, improvement in haemodynamic parameters and the change in free T3 and free T4 levels between groups after infusion.
Follow Up:
8 hours.
CETs Conclusions:
This is a very interesting study comparing T3 with T4 infusions in brain dead donors prior to cardiac allograft retrieval. Whilst the randomisation process was fair and the allocation concealment maintained, the infusions were not blinded to the study clinicians. The study was not powered for the number of hearts transplanted, but for the proportion of hearts with normalised Left Ventricular Ejection Fraction (LVEF) after infusion. Based on previous cases, the authors assumed a normalisation rate of 85% versus 44% using data from different time-periods to power their study. However, during the study, both arms had a normalisation rate of approximately 50%. During this study baseline T3 and T4 levels were not low in donors prior to infusions starting. More hearts from donors receiving T3 were ultimately transplanted, however there were significant differences in the baseline characteristics of the groups that may explain this phenomenon: younger donors, less with left ventricular hypertrophy, more blood group O donors. Overall this study is likely to be underpowered to test the hypothesis, and cardiac stunning seemed to resolve regardless of free T3 levels after infusion.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict intention to treat
Allocation Concealment 
Yes
Trial Registration:
Not reported
Funding Source:
Not reported

Transplant Trial Watch April 2019 - Various Organ Transplantation

Leino, A. D., King, E. C. et al. (2018). Assessment of Tacrolimus Intra-patient Variability in Stable Adherent Transplant Recipients: Establishing Baseline Values. American Journal of Transplantation; [record in progress].
Aim:
To identify the intrapatient variability of tacrolimus in adherent transplant recipients.
Interventions:
Secondary, post-hoc analysis of 3 different formulations of tacrolimus, each for two 1‐week periods.
Participants:
42 individuals with a kidney and 40 with a liver transplant were consented and randomised to a treatment sequence.
Outcomes:
Outcomes were measured as tacrolimus adherence, tacrolimus trough levels (C0) and tacrolimus variability.
Follow Up:
6 weeks.
CETs Conclusions:
This manuscript reports the post-hoc analysis of a randomized controlled trial comparing different tacrolimus formulations, investigating baseline tacrolimus intrapatient variability (IPV). The authors find a median IPV of 15.2% in this very adherent population, with no differences seen between formulation or transplant organ. They also demonstrate feasibility of home tacrolimus monitoring using dried blood spot technology. These data set a useful baseline for IPV in an adherent population. As adherence was over 99% in all groups, the effect of poor adherence on IPV could not be ascertained. It should be noted that IPV measurements were taken from daily samples over a 7-day dosing period, which is not typical of the longer-periods over which measurements would be taken in a real-world clinical setting.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified intention to treat
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT01889758
Funding Source:
Non-Industry funded

Transplant Trial Watch May 2019 – Kidney Transplantation

Afriansyah, A., Rasyid, N. et al. (2019). Laparoscopic procurement of single versus multiple artery kidney allografts: Meta-analysis of comparative studies. Asian Journal of Surgery 42(1): 61-70.
Aim:
The objective of this systematic review was to examine the outcomes in both donors and recipients of multiple arteries allograft kidneys compared with single renal artery kidneys.
Interventions:
The PubMed, Cochrane CENTRAL, Science Direct, and CINAHL database engines were searched in this study for articles that compared safety and efficacy using kidney donors with multiple renal arteries (published between January 1970 and October 2016).
Participants:
358 records were retrieved with 24 studies included in meta-analysis of this study.
Outcomes:
Outcomes were distinguished as donor and recepient. Donor outcomes were assessed as operative time, hospital stay, first warm ischaemic time, blood loss and donor complications. Recipient outcomes include second warm ischaemic time, cold ischaemic time, vascular complications, ureteral complication, delayed graft function and one year graft loss.
Follow Up:
N/A (no statement/follow-up not adequate)
CETs Conclusions:
The meta-analysis aimed to evaluate the donor and recipient outcomes of multiple arteries kidney grafts compared to single artery grafts procured by laparoscopy. The bibliographic searched was performed in several databases. Study selection, data extraction and risk of bias assessment was done by independent reviewers. Twenty-four comparative studies of adult, living kidney donors using laparoscopic techniques for kidney extraction were included in the meta-analysis. The Newcastle Ottawa scale was used to assess the study quality. All studies were of good quality regarding the selection items and most studies showed good quality on comparability (67%) and outcome (79%) items. Meta-analyses were conducted for several donor and recipient outcomes. For donor outcomes, the operative time was longer for multiple artery grafts and for recipient outcomes there was a higher rate of graft loss, vascular complications and ureteral complications, and loner cold ischemic time for multiple artery grafts but no differences for other outcomes. The heterogeneity was quite significant for some pooled analyses however the authors did not attempt to explore this further.
Reporting Quality:
Quality Notes 
Meta analysis - QA not necessary.
Trial Registration:
Not reported
Funding Source:
Not reported
Aquil, S. et al. (2019). The impact of a muscle pump activator on incisional wound healing compared to standard stockings and compression devices in kidney and kidney-pancreas transplant recipients: A randomized controlled trial. Can Urol Assoc J; 26:26.
Aim:
The study aimed to evaluate the impact of thrombo-embolic-deterrent + intermittent pneumatic compression (TED + IPC) vs. muscle pump activator (MPA) on incisional wound healing in kidney and simultaneous pancreas- kidney (SPK) transplant recipients.
Interventions:
Patients were randomised to wear TED and IPC or MPA for the first six days post-transplant surgery.
Participants:
104 kidney and simultaneous pancreas-kidney transplant patients (kidney n=94; SPK, n=10).
Outcomes:
Outcomes were assessed as length of hospital stay and percentage of wound infection and wound healing on postoperative days 3, 5, and 30, which were assessed using the Southampton Wound Care Score.
Follow Up:
30 days.
CETs Conclusions:
The muscle pump activator (MPA) used in this study is the Geko Plus device that delivers neuro-muscular stimulation via low voltage stimulus of the skin over the common peroneal nerve. It thereby activates the calf and foot muscles. Other trans-cutaneous direct muscular stimulation devices using high voltage intensity have not been widely adopted, due to discomfort. Wound healing was assessed at days 3,5 and 30. There was a significant reduction in superficial wound infections in the MPA arm (13% versus 29%) and wound scores on days 3 and 5. This outcome measure was not blinded and was subjective to the assessor. By day 30 the wound scores were not different between the two arms. Patients were also significantly more likely to report that the MPA device was more comfortable and related to less wound swelling, another subjective judgement, this time by the patients. The funding source is not described.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Strict intention to treat (sITT)
Allocation Concealment 
No
Trial Registration:
Not reported
Funding Source:
Not reported
Gustavsen, M. T., Midtvedt, K. et al. (2019). Evaluation of tools for annual capture of adherence to immunosuppressive medications after renal transplantation. Transplant International 15: 15.
Aim:
The objective of this study was to evaluate tools suitable for annual routine capture of adherence data in renal transplant recipients.
Interventions:
Patients were randomised to receive intensive or single point adherence assessment in the early phase and 1-year post-surgery period, respectively.
Participants:
Participants were divided into two groups: A and B. Group A comprised 200 renal transplant patients were included 4 weeks post-transplant, and randomized to either an intensive follow-up (group A1) or a single assessment follow up (group A2). Group B included 100 previously renal transplant patients returning to the transplant centre for their 1-year routine investigation and evaluated for adherence at that visit, as well as after 2 and 4 weeks.
Outcomes:
Outcomes up to 1 year were assessed as biopsy-proven AR (BPAR) rates, graft loss and overall mortality. Returning patients (>1 year) were assessed by both de novo donor-specific antibodies (dnDSA) and measured glomerular filtration rate (mGFR, 2-point iohexol plasma clearance) levels.
Follow Up:
1 year.
CETs Conclusions:
This study investigates the use of different adherence assessment tools in kidney transplant recipients early and at one year after transplant (BAASIS questionnaire, tacrolimus variability, clinician-reported adherence and pill-counting). The aim was to identify adherence assessment tools suitable for use in a national registry. The authors find that different tools result in different estimates of non-adherence, with little overlap between the tools. Adherence measured on the BAASIS survey shows strong correlation with development of de-novo DSA. The authors conclude that combinations of tools should be used to capture non-compliance. The idea is interesting and there are certainly a lot of useful data presented. The study is hampered by lack of a gold standard, as the pill-counting arm failed due to insufficient returns. The data are very different to interpret when you do not know which patients had “true” non-compliance – different tools likely capture different non-adherent populations.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol
Allocation Concealment 
Yes
Trial Registration:
Not reported
Funding Source:
Not reported
Patel, S. J., Knight, R. J. et al. (2019). Ciprofloxacin for BK Viremia Prophylaxis in Kidney Transplant Recipients: Results of a Prospective, Double-Blind, Randomized, Placebo-controlled Trial. American Journal of Transplantation 27: 27.
Aim:
This study aimed to evaluate the safety and efficacy of ciprofloxacin for prevention of BK viremia in kidney transplant recipients.
Interventions:
Participants were randomized to a 3‐month course of ciprofloxacin or placebo for the prevention of BK viremia.
Participants:
200 kidney transplant recipients.
Outcomes:
Primary outcomes were assessed as the difference in proportion of patients developing BK viremia (defined as ≥300 copies/mL on 2 occasions) within 6 months. Secondary outcomes include adverse events associated with treatment, 6‐month rates of urinary tract infections, bloodstream infections, and Clostridium difficile infection, as well as, 12‐month rates of acute rejection, graft loss, or death.
Follow Up:
12 months.
CETs Conclusions:
The randomised, double-blinded, controlled trial aimed to evaluate the safety and efficacy of ciprofloxacin to prevent BK viremia. The sample size calculation showed that based on the primary endpoint BK viremia at 6 months 180 kidney transplant recipients were needed. To account for dropouts 200 patients were randomised in a 2:1 ratio to ciprofloxacin or placebo. Patients were randomised according to a computer-generated list and the pharmacy services supplied identical looking drug bottles. A small number of patients discontinued from the trial (6.8% versus 6% for ciprofloxacin and placebo, respectively). The intention to treat analysis showed that BK viremia at 6 months were significantly higher in the ciprofloxacin group (18.8%) versus the control group (7.5%). There were no differences for the secondary outcomes acute rejection, graft loss or death at 1 year.
Reporting Quality:
Jadad Score 
5
Data Analysis 
Strict intention to treat (sITT)
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT01789203
Funding Source:
Non-Industry funded
Tedesco-Silva, H., Pascual, J. et al. (2019).Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study. Transplantation [record in progress].
Aim:
This study aimed to evaluate the one-year safety outcomes of the study, with a focus on the adverse events of interest.
Interventions:
De novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI or mycophenolic acid (MPA) with standard-exposure CNI, both with induction and corticosteroids.
Participants:
2026 de novo kidney transplant patients; (everolimus with reduced-exposure CNI; n=1014 or mycophenolic acid (MPA) with standard-exposure CNI; n=1012).
Outcomes:
Outcomes were assessed as adverse effects, serious adverse effects, infection rates and wound healing complicatons one year post-transplant.
Follow Up:
12 months.
CETs Conclusions:
This manuscript reports a detailed safety analysis from the TRANSFORM study, comparing everolimus and reduced CNI with standard CNI and MPA in renal transplant recipients. All patients received steroids and induction therapy. Overall adverse event rates were similar between the arms, although discontinuation of the study drug was twice as likely with everolimus. The findings are in keeping with previous trials and meta-analyses, demonstrating increased incidence of hyperlipidaemia, interstitial lung disease, oedema, proteinuria, ulceration and would healing complications in the everolimus arm, and increased incidence of leukopenia, diarrhoea, nausea, vomiting and tremor in the MPA arm. Perhaps the most striking finding is the size of the reduction in viral infection with everolimus, including CMV and BKV infection. The size of the study, along with use of a contemporary baseline immunosuppression regimen, make these very useful data in guiding baseline immunosuppression in this population.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict intention to treat (sITT)
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov - NCT01950819
Funding Source:
Industry funded

Transplant Trial Watch May 2019 – Lung Transplantation

Tarrant, B. J., Snell, G. et al. (2019). Dornase alfa during lower respiratory tract infection post lung transplantation: a randomized controlled trial. Transplant International [record in progress].
Aim:
This trial aimed to explore the safety and efficacy of nebulized dornase alfa during lower respiratory tract infection (LRTI) following lung transplantation (LTx).
Interventions:
Participants were nebulized and received 5ml isotonic saline, or 2.5ml dornase alfa for one month.
Participants:
32 patients with LRTI participated in this study.
Outcomes:
Primary outcome was assessed as lung clearance index (LCI2%). Secondary outcomes included spirometry; quality of life; readmission; length of stay; self-reported exacerbations and adverse events at baseline, 1 and 3 months.
Follow Up:
3 months.
CETs Conclusions:
Lung transplant recipients with LRTI were randomised to receive nebulised dornase alpha (mucoactive agent) or placebo (saline). This is a well written and well conducted study in which blinded assessors used a widely accepted lung clearance index as the primary outcome. Only 32 patients were recruited, but according to the authors’ power calculations, this was enough for 80% power. There were no significant differences in the primary outcome between groups at any follow up time point, nor in any of the secondary outcomes. There was a low rate of adverse events in both groups, so dornase alpha appears safe, however given its high cost, its use in this setting is not recommended by the results of this study.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict intention to treat (sITT)
Allocation Concealment 
Yes
Trial Registration:
Not reported
Funding Source:
Not reported

Transplant Trial Watch May 2019 – Heart Transplantation

Choi, D. H., Kobayashi, Y. et al. (2018). Change in lymphocyte to neutrophil ratio predicts acute rejection after heart transplantation. International Journal of Cardiology 251: 58-64.
Aim:
This study evaluated whether a change in the lymphocyte to neutrophil ratio (LNR) is related to acute rejection following cardiac transplantation.
Interventions:
Peripheral blood lymphocyte and neutrophil counts were measured at baseline, three, six and twelve months after heart transplantation.
Participants:
74 cardiac transplant recipients.
Outcomes:
The primary outcome was measured as clinically significant acute rejection (defined as ISHLT grade >= 2R acute rejection or non-cellular rejection resulting in haemodynamic compromise; requiring augmentation of immunosuppression).
Follow Up:
3 months.
CETs Conclusions:
This small, post-hoc analysis of data from an RCT investigates the role of the change in lymphocyte to neutrophil ratio (LNR) in peripheral blood in the 3-months following cardiac transplantation and the risk of acute rejection. The authors find a smaller change in LNR early post-transplant who subsequently went on to develop cellular rejection, leading to the suggestion that this could be used as a biomarker to identify at-risk patients. These findings are interesting, but require validation in a larger, prospective cohort. The clinical utility of the test is also uncertain – results are not available until 3-monhts post-transplant, and the predictive accuracy of the test (using the threshold as defined) is limited with a ROC AUC of just 0.565. Sensitivity and specificity at this threshold are not reported.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol
Allocation Concealment 
No
Trial Registration:
Not reported
Funding Source:
Industry funded, Non-Industry funded
Nytrøen, K., Rolid, K. et al. (2019). Effect of High-Intensity Interval Training in De Novo Heart Transplant Recipients in Scandinavia: 1-Year Follow-Up of the HITTS Randomized, Controlled Study. Circulation 18: 18.
Aim:
To evaluate the effects of high intensity interval training (HIIT) on patients exercise capacity and health-related quality of life (HRQoL), after a heart transplant (HTx), in comparison to moderate intensity training.
Interventions:
All patients were provided with general advice on lifestyle changes and then randomized into a high intensity intervention training or moderate intensity (n=39), continuous training group (n=42).
Participants:
81 heart transplant recipients.
Outcomes:
The primary outcome was assessed as the change in VO2peak from baseline to follow-up. Secondary outcomes included muscular capacity; chronotropic responses; right heart catheterization hemodynamics; lung function; cardiac dimension and function;; arteriovenous oxygen difference (a-v O2 diff); endothelial function; HRQoL;tolerability; safety; and exercise-related adverse events.
Follow Up:
12 months.
CETs Conclusions:
This is a good quality, multicentre RCT that is clearly reported. Both arms of the study received physical training sessions post-transplant, but the only difference was the intensity of the exercise. High intensity interval training initiated 11 weeks after heart transplant was safe. It showed a larger improvement in VO2 peak compared to moderate intensity training, although the treatment group started at a lower baseline on average. High intensity training also showed significantly larger increases in anaerobic threshold and muscular strength. There was no serious, exercise-related adverse event in either group. Adherence was monitored throughout, and across both groups was 81% completion of intended exercise sessions. The performance of unsupervised exercise would be a useful addition to the study.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Per Protocol
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov - NCT01796379
Funding Source:
Industry funded, Non-Industry funded

Transplant Trial Watch May 2019 – Various Organ Transplantation

Almasri, J., Tello, M. et al. (2019). A systematic review for variables to be collected in a transplant database for improving risk prediction. Transplantation 06: 06.
Aim:
The systematic review aimed to determine new variables associated with transplant outcomes that are not currently collected by the Organ Procurement and Transplantation Network (OPTN).
Interventions:
The Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, and Scopus were searched . Grey literature and conference abstracts were also searched.
Participants:
81 studies were included in the systematic review which evaluated recipient-related risk factors (donor and recipient factors, patient-level and system-level factors, only pre-operative factors, organs: kidney, pancreas, pancreas and kidney, liver, liver and kidney, heart, lung, and heart and lung) and donor-related risk factors (studies in which patients were eligible for organ transplant, were waitlisted for deceased donor transplant, or underwent deceased donor/living donor transplant). Randomized controlled trials and observational studies were included, with no time or study location restriction.
Outcomes:
Outcomes of interest were death on the waiting list, all-cause mortality, graft failure, death-censored graft loss, and waitlist mortality (death/delisting due to being too sick to undergo transplant). Risk factors for each organ transplant failure outcome were reported with odds ratio, hazard ratio, and relative risk, which were extracted and were all referred to as relative effect.
Follow Up:
N/A
CETs Conclusions:
This systematic review evaluated published multi-variate analyses of pretransplant risk factors that predict outcomes, focussing on kidney, pancreas, liver, heart and lung transplantation and including multi-organ transplants. A comprehensive, bibliographic search consisting of controlled vocabulary terms with keywords was designed by an information specialist. To be included the study had to evaluate risk factors and a minimum, organ-specific study sample size was required to exclude studies that were likely to be underpowered. Study selection and data extraction was done by pairs of independent reviewers. Eighty-one studies were included. Risk of bias was low to moderate for most factors. The review identified 108 additional risk factors that are currently not included in the OPTN database, of which most were related to the recipient (n=104).
Reporting Quality:
Quality Notes 
Systematic review - Quality assessment not necessary.
Trial Registration:
Not reported
Funding Source:
Non-Industry funded
Rogers, W., Robertson, M. P. et al. (2019). Compliance with ethical standards in the reporting of donor sources and ethics review in peer-reviewed publications involving organ transplantation in China: a scoping review. BMJ Open 9(2): e024473.
Aim:
This review aims to investigate whether papers reporting research on Chinese transplant recipients comply with international professional standards.
Interventions:
Medline, Scopus and Embase were searched from January 2000 to April 2017 for studies published in peer-reviewed English -language journals reporting on outcomes of research involving solid organ transplant recipients from mainland China.
Participants:
445 studies were included.
Outcomes:
Publications were assessed for statements regarding(1) use of any biological material from executed prisoners; (2) Institutional Review Board (IRB) approval and (3) consent of donors.
Follow Up:
N/A
CETs Conclusions:
This interesting review examines the transplant literature from China over a 17-year period, investigating the ethical statements and donor sources reported in the published studies. Specifically, the authors were attempting to identify presence of IRB approval and explicit statements as to the consent of donors and use of organs from executed prisoners. Whilst a relatively high proportion of studies reported IRB approval, very few explicitly stated that prisoners were not used as a source of organs. In those that did, many recruited transplants performed during a time period in which voluntary donation was not occurring, making it unlikely that the statement was true. These results are concerning to the transplant community, and clearly we are some way from full transparency in this area. There are some limitations to the review. It only captures statements in the manuscript, and it is possible that further assurances were captured by the journal during the editorial process that were not included in the published paper. Chinese language publications were excluded, which means that these results are unlikely to capture the full extent of the problem in Chinese transplantation research. In the interests of balance, it is likely that a similar proportion of manuscripts from other countries fail to report IRB approval in the manuscript, and few will explicitly state consent arrangements for donors even though these are implied.
Reporting Quality:
Quality Notes 
Review - Quality assessment not necessary.
Trial Registration:
Not reported
Funding Source:
No funding

Transplant Trial Watch June 2019 – Kidney Transplantation

Bonani, M., Frey, D. et al. (2019). Effect of denosumab on trabecular bone score in de novo kidney transplant recipients.Nephrology Dialysis Transplantation;[record in progress].
Aim:
To identify the trabecular bone score (TBS) in the POSTOP study population at baseline and after 12months, and to explore the effect of TBS changes with lumbar spine and total hip BMD changes, and changes in HRpQCT parameters, in both denosumab-treated and control patients.
Interventions:
Patients were randomised to denosumab (60 mg subcutaneously at baseline and after 6months) or no treatment.
Participants:
90 kidney transplant recipients.
Outcomes:
Outcomes were assessed as relationship between TBS and total hip areal bone mineral density, relationship between TBS and peripheral bone microarchitecture and strength at baseline and effect of denosumab on TBS changes.
Follow Up:
6.6 Years
CETs Conclusions:
This manuscript reports a post-hoc analysis of an RCT of the RANKL inhibitor denosumab in kidney transplant recipients. The authors retrospectively assessed trabecular bone score (TBS) in a subset of 44 patients from the original 90. They report that baseline TBS is low in renal transplant recipients, and that it improves with treatment although the changes do not reach statistical significance. Assessment of TBS was blinded, but risk of selection bias remains with only half of the originally randomized patients included in this study. It remains to be seen whether the changes in TBS are sustained, and whether they translate into a real reduction in fracture incidence over time.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict intention to treat (sITT)
Allocation Concealment 
Yes
Trial Registration:
Clinical.Trials.gov - NCT01377467
Funding Source:
Non-Industry funded
Defendi, F., Malvezzi, P. et al. (2019). Effects of immunoadsorption combined with membrane filtration on complement markers - Results of a randomized, controlled, crossover study. Transplant International: 22:22.
Aim:
To investigate whether adding a membrane filtration (MF) to a circuit during semi-selective immunoadsorption (IA) can enhance the elimination of ABO reactivity to remove additional macromolecular complement components, such as mannose-binding lectin (MBL) and properdin.
Interventions:
Patients were randomized into two intervention sequences : a single session of IA combined with MF (IA+MF) followed by a single session of IA alone, or vice versa.
Participants:
14 kidney transplant recipients.
Outcomes:
Outcomes included impact of apheresis on complement activation, effect of IA+MF versus IA on properdin and MBL concentration.
Follow Up:
7 days.
CETs Conclusions:
Antibody depletion prior to ABO or HLA incompatible transplantation has been used to facilitate transplantation in these patient groups. This good quality RCT was previously reported and the new paper describes the effect on complement depletion of combined immunoadsorption (IA) + membrane filtration (MF), compared to IA. The trial was open label, but the results presented are very objective. Levels of C5b-9b, the terminal complex of the complement cascade, were used as a marker of complement system activation. There was no significant difference in C5b-9 levels between groups pre- or post-intervention and nor was there a significant change in levels in either group. The combination of IA+MF significantly reduced levels of properdin and mannose-binding lectin compared to IA alone. Conversely, levels of properdin and mannose-binding lectin returned to pre-treatment levels at day 7 in the IA+MF group, but not in the IA alone group. This is difficult to explain and the exact mechanisms of clearance and recovery are unclear. The authors acknowledge that the carry-over effect from cross-over treatments may be the cause; the clinical implications are uncertain.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov number - NCT01698736
Funding Source:
No funding
Mansell, H., Rosaasen, N. et al. (2019).Randomised controlled trial of a video intervention and behaviour contract to improve medication adherence after renal transplantation: the VECTOR study protocol. BMJ Open 9(3): e025495.
Aim:
To determine the effectiveness of an electronically delivered video series and adherence behaviour contract on improving medication adherence to immunosuppressant medications.
Interventions:
Participants will be randomised to either the intervention group where they will receive standard education along with the home-based video education plus a behaviour contract or usual care alone.
Participants:
Patients who have received a de novo kidney transplant.
Outcomes:
Primary outcome will be measured as medication adherence. Secondary outcomes include the difference in change in knowledge score between the intervention and control groups, and differences between the intervention and control in the following measures: self-efficacy, beliefs about medications, quality of life, satisfaction with education, adherence to appointments and days in hospital.
Follow Up:
12 months.
CETs Conclusions:
This is a trial protocol paper of the VECTOR trial, which aims to test the effectiveness of a video intervention plus adherence contract versus usual care to improve medication adherence among de novo kidney transplant patients. The multicenter trial will be conducted in four transplant centres across North America. The video intervention describes the kidney transplant process and was developed for and with patients, and patient stakeholders. The videos will supplement routine post-transplant education care and the adherence contract will be completed around 1 month after transplantation. Randomisation will be done centrally and study sites will receive sequentially numbered survey participant links ensuring concealed allocation. The study team will be blinded and participants will be asked not to share the details of the intervention with the study team. The primary outcome adherence at 12 months will be assessed by using an electronic self-report assessment tool. The power calculation based on the primary outcome shows that the 268 patients are needed for 80% power, which accounts for a drop-out rate of 25%.
Trial Registration:
ClinicalTrials.gov - NCT03540121
Funding Source:
Non-Industry funded
Nielsen, M. B., Krogstrup, N. V. et al. (2019). P-NGAL Day 1 predicts early but not one year graft function following deceased donor kidney transplantation – The CONTEXT study. PLoS ONE [Electronic Resource] 14(2): e0212676.
Aim:
This study aimed to evaluate the levels and changes in: U- and P-NGAL, U-L-FABP, U-cystatin C, and U-YKL-40 following deceased donor kidney transplantation and to correlate these biomarkers with DGF, early graft function, including measured GFR and estimated GFR.
Interventions:
This is a sub study of the CONTEXT trial, which explored the effect of remote ischaemic conditioning on renal transplantation.
Participants:
225 patients undergoing deceased donor kidney transplantation from the CONTEXT trial.
Outcomes:
Outcomes were assessed as reperfusion time, levels of U- and P-NGAL, U-L-FABP, U-cystatin C, and U-YKL-40, urine output and graft function.
Follow Up:
1 year.
CETs Conclusions:
This paper reports one year follow up from a previously reported, good quality study. The results are from the large, multicentre CONTEXT trial. The prediction of DGF early on may help to optimise clinical management of the patient, and therefore biomarkers to pre-empt this outcome are eagerly sought. In this study several potential biomarkers were assessed and analysed for relationships with clinical outcomes. Whilst plasma NGAL on day 1 after transplantation was associated with DGF, it was less predictive than urine output and did not correlate with 12-month measured GFR. The level of plasma NGAL was related to the dialysis status of the patient pre-operatively, being higher in those on dialysis than pre-dialysis, and this needs to be taken into account. Also, 40% of dialysis patients had DGF, but only 5% of pre-dialysis patients. The paper describes a multivariate analysis but it is not explicitly declared that this important confounder was dealt with. 200 of the patients received DBD kidneys and only 22 DCD, which raises the question of how the biomarker may relate to outcomes of DCD kidneys, which were under-represented in this study and which may have a different mechanism of DGF compared to DBD. None of the biomarkers assessed in this study correlated well with graft function at 3 and 12 months.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT01395719
Funding Source:
Non-Industry funded
Marks, W. H. et al. (2019). Safety and efficacy of eculizumab in the prevention of antibody-mediated rejection in living-donor kidney transplant recipients requiring desensitization therapy: a randomized trial. American Journal of Transplantation 19:19.
Aim:
To evaluate the safety and efficacy of eculizumab in preventing acute antibody-mediated rejection (AMR) in kidney transplant recipients who require desensitization.
Interventions:
Patients were randomised into standard post transplantation care or eculizumab for 9 weeks from the day of transplantation.
Participants:
102 patients who required a kidney transplant and required pretransplantation desensitization.
Outcomes:
Primary outcome was assessed as treatment failure, which included the occurrence of: biopsy-proven AMR (Banff 2007 grades II or III); graft loss; patient death; or loss to follow-up.
Follow Up:
36 months.
CETs Conclusions:
This phase II industry-led multicenter study investigated the role of eculizumab as part of a desensitization protocol in living donor renal transplantation. 102 patients were randomized, and the study found no difference in the composite primary efficacy outcome of antibody mediated rejection, graft loss and death. All biopsies were reassessed centrally, and a beneficial effect of eculizumab was only found in post-hoc analysis when grade I AMR was included in efficacy failure. The study was open-label, although the central pathologists were blinded to study allocation. Treatment failure rates were significantly lower in the standard-care arm than expected, which ultimately resulted in an underpowered study. It is therefore unlikely that eculizumab will become part of standard care on the basis of these results, especially given the costs involved and the increasing success of paired-exchange programs.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol
Allocation Concealment 
Yes
Trial Registration:
Clinicaltrials.gov - NCT01399593 and EudraCT number - 2010-019630-28
Funding Source:
Industry funded

Transplant Trial Watch June 2019 – Liver Transplantation

Garoufalia, Z., Prodromidou, A. et al. (2019). Liver Transplantation for Wilson's Disease in Non-adult Patients: A Systematic Review. Transplantation Proceedings 51(2): 443-445.
Aim:
This study reviews the outcomes of paediatric Wilson Disease (WD) patients after liver transplantation and to study the role of liver transplantation in WD patients.
Interventions:
PubMed was searched for all articles published from inception-October 2017 on presenting cases of paediatric liver transplant patients as a result of Wilson’s Disease.
Participants:
Six articles with a total of 290 paediatric patients were included in this systematic review.
Outcomes:
Outcomes were assessed as chronic liver failure, fulminant liver failure, average 1-year and 5-year survival rate and retransplantation.
Follow Up:
5 years.
CETs Conclusions:
This short paper reports a systematic review of liver transplantation in paediatric patients with Wilson’s Disease. Only pubmed was searched, neglecting other potential sources of papers and studies were excluded for quite a variety of reasons. It is not clear if the searches and paper selection was done in duplicate or by one author alone. The included papers were retrospective case series, which can make quality assessment less straightforward, however the authors have not presented any quality indicators for their included studies or assessed for risk of bias. There is also no in-depth discussion of differences between the included series. The paper therefore does not add much more to the literature on this topic beyond the case series already published. In the included series the 5-year graft survival ranged from 83.9-96.6%.
Trial Registration:
Not reported
Funding Source:
Not reported
Prodromidou, A., Kostakis, I. D. et al. (2019). Pregnancy Outcomes After Liver Transplantation: A Systematic Review. Transplantation Proceedings 51(2): 446-449.
Aim:
To explore the evidence surrounding pregnancy outcomes in liver transplant (LT) patients.
Interventions:
Literature search for articles referring to pregnancy outcomes following liver transplantation between 1963 to September 2017. Inclusion criteria comprised trials that recruited >10 patients presenting with at least one obstetric and/or maternal outcome with prior LT.
Participants:
A total of 19 retrospective studies, including 1290 pregnancies in 885 female LT recipients were included in the review.
Outcomes:
Outcomes were assessed as pregnancy related complications, which included: preterm birth, spontaneous abortion and preeclampsia and graft-related complications.
Follow Up:
N/A
CETs Conclusions:
This review aims to identify all studies reporting outcomes from pregnancies following liver transplantation. The authors identify 19 studies describing 1290 patients, and report on risks of preterm birth, spontaneous abortion, pre-eclampsia and graft-related complications. The brevity of the report means that it is difficult to assess the methodology used fully. The study is limited by potential overlap – many of the patients described in smaller studies are likely duplicated in the larger registry studies. Nonetheless, this paper acts as a good summary and starting-point for discussion of the potential risks of pregnancy with liver transplant patients.
Trial Registration:
Not reported
Funding Source:
Not reported
Shaji Mathew, J., Kumar, K. Y. S. et al. (2019). Antegrade hepatic artery and portal vein perfusion versus portal vein perfusion alone in live donor liver transplantation: a randomized trial. Liver Transplantation 25: 25.
Aim:
This study aimed to determine the effects of antegrade hepatic artery perfusion during live donor liver transplantation (LDLT).
Interventions:
Donor hepatectomy patients were randomised to receive graft perfusion of Histidine-tryptophan-ketoglutarate (HTK) solution either through dual perfusion using both the hepatic artery and portal vein, or standard perfusion, only through the portal vein.
Participants:
123 live donor liver transplant patients (>18 years; LDLT from Nov 2015-March 2017).
Outcomes:
Primary outcomes were assessed as Biliary stricture and Biliary Leak. These outcomes were measured as biliary obstruction on MR cholangiography, biliary obstruction on endoscopic retrograde cholangiography or percutaneous transhepatic cholangiography, or intrahepatic biliary radical dilatation on ultrasonography. Secondary outcomes included hepatic artery thrombosis, portal vein and hepatic venous vascular issues, such as thrombosis/stenosis, intra-operative parameters, such as mean arterial pressure, post-operative hospital stay, graft and patient survival rates and liver function tests immediately post-transplant, and 1, 3, 7 and 14 days post-operation.
Follow Up:
30.2 months.
CETs Conclusions:
This is a good quality RCT in live donor liver transplantation comparing two methods of perfusion: Dual (hepatic artery and portal vein) or single (portal vein only) perfusion. There was a significant reduction in biliary stricture in the study group from approximately 20% to 6% (p=0.04). There was no significant difference in hepatic artery thrombosis or biliary leak. The study was not powered to see a difference in hepatic artery thrombosis, which was a safety concern for the arterial perfusion, however, HAT was actually numerically less in the study group than control group. The 3-year graft survival was significantly better in the dual perfusion group than the single portal perfusion group (approximately 95% versus 77%, p=0.003). A soft catheter was used for arterial perfusion, a 14F paediatric aortic root cannula to minimise any potential trauma to the intima.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict intention to treat (sITT)
Allocation Concealment 
Yes
Trial Registration:
Clinical Trials Registry of India - CTRI/2015/11/006398
Funding Source:
No funding
van Rijn, R., van den Berg, A. P. et al. (2019). BMC Gastroenterology 19(1): 40.
Aim:
To determine the efficacy of end-ischaemic dual hypothermic oxygenated machine perfusion (DHOPE) in reducing the incidence of non-anastomotic biliary strictures (NAS) after donation after circulatory death (DCD) liver transplantation.
Interventions:
Liver grafts will either be preserved with static cold storage (SCS) followed by 2 hours of DHOPE (intervention group) or SCS alone without any further intervention (control group).
Participants:
156 patients undergoing DCD liver transplantation (>18 years).
Outcomes:
Primary outcome will be measured as symptomatic NAS. Secondary outcomes will be measured as incidence of asymptomatic NAS, severity of NAS, graft and recipient survival, liver failure requiring retransplantation or leading to death, initial poor function based on a modification of the Olthoff criteria, graft function and ischaemia-reperfusion injury measured by alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AlkP), gamma-glutamyl transferase (γGT), and total bilirubin at postoperative day 0–7 and 1, 3, and 6months, ICU and hospital stay following liver transplantation, postoperative complications and renal function and haemodynamic status (blood pressure, heart rate and vasopressor dosage) at 5 min before reperfusion, as well as 10 and 20 min after reperfusion. The DHOP group will have further secondary outcomes assessed, including: flow, pressure and resistance at every fifteen minutes, the perfusate at the start and end of DHOPE procedure, and every half hour in between will be analyzed for pH, ions and proteins that lead to tissue and/or mitochondrial injury and health-related quality of life.
Follow Up:
6 months.
CETs Conclusions:
This is the study protocol for the DHOPE-DCD trial, a multicentre, inferiority, randomized controlled trial which will compare cold storage plus two hours of dual, end-ischemic hypothermic oxygenated machine perfusion versus cold storage alone in donation after circulatory death liver transplantation. The power calculation is based the primary outcome non-anastomotic biliary strictures (NAS) at 6 months and showed that 154 are needed plus 1 patient in each arm to allow for dropouts for 80% power. The procurement surgeon and the patients will be blinded to group assignment and the primary outcome NAS will be assessed by a blinded adjudication committee. Randomisation will be done using a web-based tool and patients will not be randomised until a liver is deemed suitable for transplantation. Data will be analysed according to the intention to treat principle.
Trial Registration:
ClinialTrials.gov - NCT02584283
Funding Source:
Non-Industry funded

Transplant Trial Watch June 2019 – Heart Transplantation

Barten, M.(2019).Comparing everolimus-based immunosuppression with reduction or withdrawal of calcineurin inhibitor reduction from six months after heart transplantation: the randomized MANDELA study.American Journal of Transplantation[record in progress]
Aim:
This study aimed to compare everolimus-based immunosuppression with reduction or withdrawal of calcineurin inhibitor (CNI) reduction from six months after heart transplantation.
Interventions:
Patients were randomised 6 months after transplant to either (1) convert to CNI-free immunosuppression with everolimus and mycophenolic acid (MPA) or (2) to continue reduced-exposure CNI with concomitant everolimus.
Participants:
162 patients that were 6 months post-heart transplantation (18-70 years; eGFR >30-<100). Patients were only eligible if between 3 and 6 months post-transplantation were receiving tacrolimus at a trough concentration of 5–10 ng/mL or cyclosporine (CsA) with tacrolimus in the range 100–200 ng/mL, with either everolimus (C05–10 ng/mL) or MPA, and corticosteroids.
Outcomes:
Primary outcomes were assessed as eGFR at month 18 post-transplant based on the MDRD formula. Secondary outcomes was renal function, assessed as creatinine clearance, serum creatinine and creatinine slope, occurrence of treatment failure, acute rejection associated with haemodynamic compromise, graft loss or retransplantation, death or loss to follow-up, the incidence of major adverse cardiac events (MACE), myocardial infarction or coronary artery bypass grafting);and safety and tolerability parameters including incidence of adverse events, serious adverse events, adverse events leading to study discontinuation.
Follow Up:
18 months.
CETs Conclusions:
The MANDELA trial compared two renal-sparing regimens, i.e. everolimus plus mycophenolic acid (calcineurin-inhibitor (CNI) free) versus reduced exposure CNI and everolimus (reduced CNI) in heart transplant patients randomised at 6 months posttransplant. Patients were eligible if the eGFR was >30 mL/min/1.73m2, had not undergone changes to the immunosuppressive regimen due to immunologic reasons, and did not have severe rejection or intractable immunosuppression-related complications or side effects. Patients were randomised by an automated, central system hence allocation was concealed. The sample size calculation was based on the primary endpoint eGFR at 18 months and showed that 172 patients were needed for 90% power. The analysis was based on intention to treat (ITT) using the last observation carried forward method for missing data. 162 patients were randomised and 145 patients were included in the ITT analysis. eGFR at baseline was similar between groups but at 18 months eGFR was significantly higher in the CNI-free group (difference 11.3 mL/min/1.73m2).
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict intention to treat (sITT)
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT00862979
Funding Source:
Industry funded

Transplant Trial Watch July 2019 – Kidney Transplantation

Anutrakulchai, S. et al. (2019). Therapeutic concentration achievement and allograft survival comparing usage of conventional tacrolimus doses and CYP3A5 genotype-guided doses in renal transplantation patients. BJCP; [record in progress].
Aim:
This study aimed to compare the therapeutic ranges and clinical outcomes between conventional tacrolimus (TAC) and genotype-guided tacrolimus doses.
Interventions:
64 patients were randomized to the control group (tacrolimus with a loading dose of 0.1mg/kg/day) and 62 patients were assigned to the genotype-guided group, where initial dose was stratified by CYP3A5 genotype.
Participants:
126 de novo renal transplantation patients.
Outcomes:
Primary outcome was measured as the proportion of patients achieving the TAC concentration within the therapeutic range at the 3rd day post-transplantation. Secondary outcomes included the time taken to achieve the therapeutic range, TAC levels, incidence of delayed graft function, GFR levels, proteinuria, graft and patient survival.
Follow Up:
37 months.
CETs Conclusions:
This interesting study randomized de novo kidney transplant recipients to standard or genotype-guided tacrolimus dosing. Dosing guided by CYP3A5 genotype resulted in a greater proportion of patients achieving therapeutic doses by day 3 post-transplant. Of note, genotype-guided dosing resulted in higher rates of DGF, particularly in those patients requiring high doses of tacrolimus, despite trough levels in the therapeutic range. This may be as a result of higher peak concentrations from an immediate release formulation in this patient subgroup. Overall the study is well designed – investigators were blinded to genotype in the control cohort, and analysis was by intent-to-treat. These findings will require validation in a non-Asian population, and the impact of modified release preparations on the increased risk of DGF should be explored.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified Intent to Treat (mITT)
Allocation Concealment 
Yes
Trial Registration:
Clinicaltrials.gov - NCT03173820
Funding Source:
Industry funded
Halden, T. A. S., Kvitne, K. E. et al. (2019). Efficacy and Safety of Empagliflozin in Renal Transplant Recipients With Posttransplant Diabetes Mellitus. Diabetes Care 12: 12.
Aim:
The aim of this study was to investigate the safety and efficacy of empagliflozin in renal transplant recipients with post-transplant diabetes mellitus (PTDM).
Interventions:
Patients were randomized to receive either 10mg empagliflozin or placebo (lactose monohydrate).
Participants:
44 renal transplant recipients.
Outcomes:
Outcomes included glycated haemoglobin HbA1c levels, GFR, body weight, adverse events, immunosuppressive drug levels and eGFR.
Follow Up:
24 weeks.
CETs Conclusions:
Overall, this is a well-conducted RCT that was adequately randomised and double-blinded with identical capsules for the study drug and placebo. Strangely a “technical error” meant that the primary outcome of the study (change in weighted mean glucose estimated with continuous glucose monitoring) could not be analysed, only the secondary outcomes. There is simply no adequate explanation for this within the report as published. Empagliflozin was associated with a statistically significant reduction in HbA1C compared to placebo of -0.2%, which may not be clinically significant. This effect was increased in patients with higher eGFR. Most striking is the impact on bodyweight, with an average 2.5kg loss in the treatment group and 1kg gain in the control group. The study was small, so evaluating adverse events is difficult, as was secondary outcomes. There was no difference in fasting plasma glucose, fasting plasma insulin, c-peptide or 2- hour insulin between the groups. However, 2-hour c-peptide increased in the empagliflozin group compared with a reduction in the placebo group. This study was supported indirectly by an unrestricted grant from Boehringer Ingelheim, who produce Jardiance (Empagliflozin).
Reporting Quality:
Jadad Score 
5
Data Analysis 
Per Protocol (PP)
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT0315741
Funding Source:
Industry funded
Pourfakhr, P. et al. (2019). Half Saline-Bicarbonate Solution as Intraoperative Fluid Replacement Therapy Leads to Less Acidosis and Better Early Renal Function During Deceased-Donor Transplant. Experimental & Clinical Transplantation: 17: 17.
Aim:
The aim of this study was to determine the effects of a combination of half saline and bicarbonate versus normal saline as a routine solution.
Interventions:
Patients were divided into either those who received normal saline, or those who received half saline and bicarbonate infusion as fluid replacement therapy during renal transplant.
Participants:
100 adult patients undergoing kidney transplantation.
Outcomes:
Primary outcome was measured as serial creatinine concentration at days 1, 2, 3, and 7 after transplantation. Secondary outcome were measured as urine output at recovery, 6 hours and 24 hours after transplant. Additonally, chloride, and sodium levels were analyzed before operation and at 6 hours posttransplant.
Follow Up:
N/A
CETs Conclusions:
This is a well-written and well-conducted RCT in renal transplantation. It was computer randomised and attempt was made at double-blinding, although this may not have been completely effective; the two solutions were made up by the hospital pharmacy in “the same-shape containers and with similar labels”. Sealed envelopes were used, which is not a fully satisfactory method to ensure allocation concealment. In this study the intra-operative administration of half saline-bicarbonate was associated with less hyperchloremic metabolic acidosis, improved urine output, and quicker fall in creatinine post-operatively. A previous Cochrane review concluded that low-chloride fluids were beneficial in renal transplantation for the prevention of metabolic acidosis, although with no proven effect on transplant outcomes (Wan et al 2016). This study finds a significant early benefit, but longer-term outcomes were not reported here. Rather than mandating the fluid used, perhaps a tight control of intra-operative acid-base balance is the important factor, as has previously been shown; this can then be applied to the population of patients that were excluded from this study (high potassium, intra-operative transfusion and low perioperative base excess or bicarbonate levels).
Reporting Quality:
Jadad Score 
4
Data Analysis 
Strict Intention To Treat (sITT)
Allocation Concealment 
Yes
Trial Registration:
Iranian Registry of Clinical Trials - IRCT2017080535510N1
Funding Source:
Not reported
Rao, N. N., Stokes, M. B. et al. (2019). Effects of Arteriovenous Fistula Ligation on Cardiac Structure and Function in Kidney Transplant Recipients. Circulation [record in progress].
Aim:
The study aimed to evaluate the effect of AVF ligation on cardiac structure and function in stable kidney transplant recipients.
Interventions:
Recipients were randomized to either AVF ligation or no intervention.
Participants:
64 kidney transplant recipients.
Outcomes:
The primary outcome was the change in left ventricular (LV) mass. Secondary outcomes included changes in LV volumes, left and right atrial areas, LV ejection fraction, N-Terminal pro-BNP levels (NT pro-BNP), cardiac output/index, brachial flows (ipsilateral to AVF) and pulmonary artery velocity.
Follow Up:
6 months.
CETs Conclusions:
This small single-centre study investigates whether the ligation of an AV fistula following successful transplantation can reduce cardiac risk. Recipients with stable function were randomized to ligation or maintenance of the AV fistula. Ligation resulted in a reduction in left ventricular mass, left ventricular end diastolic volume and end-systolic volumes compared to controls. There were no differences in LVEF, blood pressure or graft function. The study is well designed and described. Ultimately, larger studies with longer follow-up will be required to see if the changes in cardiac MRI observed in this study translate to a reduction in cardiac morbidity or mortality. Also, it is unclear whether ligation is beneficial in all recipients, or whether it would be better targeted to those with higher flow or existing cardiac dysfunction.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol (PP)
Allocation Concealment 
No
Trial Registration:
Australian and New Zealand Clinical Trials Registry - ACTRN12613001302741
Funding Source:
Industry funded
Sommerer, C. et al. (2019). An open-label, randomized trial indicates that everolimus with tacrolimus or cyclosporine is comparable to standard immunosuppression in de novo kidney transplant patients. Kidney International; [record in progress].
Aim:
The objective was to demonstrate the efficacy of everolimus with tacrolimus (EVR/TAC) versus everolimus with cyclosporine (EVR/CsA) versus mycophenolic acid (MPA) and tacrolimus (MPA/TAC) on renal function.
Interventions:
Everolimus with tacrolimus (EVR/TAC), everolimus with CsA (EVR/CsA) or MPA with tacrolimus (MPA/TAC), with similar tacrolimus exposure in both groups.
Participants:
De novo kidney transplant recipients.
Outcomes:
The primary outcome being assessed was renal function via eGFR measurement at month 12. Secondary endpoints were measured as treatment failure, defined as a composite of BPAR, graft loss, or death, at month 12 posttransplant and outcomes for infections, with a focus on CMV and BKV infection.
Follow Up:
12 months.
CETs Conclusions:
The noninferiority ATHENA trial compared the efficacy of everolimus/tacrolimus versus everolimus/cyclosporine versus mycophenolic acid (MPA)/tacrolimus in de novo kidney transplant recipients. The primary, per-protocol analysis aimed to demonstrate non-inferiority in eGFR at 12 months in at least one of the everolimus groups versus the MPA/tacrolimus. The a priori defined noninferiority margin was defined as -7 ml/min per 1.73m2. The multicentre study was conducted in centres in France and Germany. A total of 655 patients were randomised. The intention to treat (ITT) population included 612 patients who had received at least one dose of the study drug and only 338 patients were included in the per-protocol population (all patients without major deviations from the protocol procedures). The per-protocol analysis did not show noninferiority for eGFR at 12 months for everolimus/tacrolimus (62.2 ml/min per 1.73 m2) or everolimus/cyclosporine (58.4 ml/min per 1.73 m2) versus MPA/tacrolimus (67.8 ml/min per 1.73 m2).
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified Intent to Treat (mITT)
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov - NCT01843348; EudraCT number - 2011-005238-21
Funding Source:
Industry funded

Transplant Trial Watch July 2019 – Liver Transplantation

Berry, P. S., Rosenberger, L. H. et al. (2019). Intraoperative Versus Extended Antibiotic Prophylaxis in Liver Transplant Surgery: A Randomized, Controlled Pilot Trial. Liver Transpl; [record in progress].
Aim:
This study aimed to compare the rates of surgical site infection (SSI) in orthotopic liver transplantation (OLT) patients receiving perioperative antibiotic prophylaxis or intraoperative antibiotic prophylaxis alone.
Interventions:
OLT recipients were randomized to receive either intraoperative antibiotics only (short antibiotics) or 72 hours of perioperative antibiotics (extended antibiotics).
Participants:
102 adult orthotopic liver transplant (OLT) patients.
Outcomes:
The primary outcome was measured as SSI rates. Secondary outcomes assessed included rates of nosocomial infection (NI), graft survival, biopsy-proven rejection, and patient survival.
Follow Up:
4 years.
CETs Conclusions:
This pilot, single centre, open-label randomised controlled trial tested the hypothesis that first-time liver transplantation recipients receiving 72 hours of antibiotic prophylaxis would have a decreased rate of surgical site infections at 30 days posttransplant compared to recipients receiving only 2 doses of intraoperative antibiotic prophylaxis. Allocation of the randomisation code was concealed by using sealed, opaque envelopes to randomise patients. Surgical site infections were determined by routine laboratory tests, daily chest x-rays and clinical symptoms. Wounds were evaluated daily by the attending surgeon. The sample size calculation for this pilot study revealed that 100 patients would provide a power of 60% to detect a reduction of 15% in surgical site infections with a type 1 error rate of 0.10. A total 102 patients were randomised of which 5 patients were excluded because they did not receive the transplant. The modified intention to treat and per protocol analyses showed no differences in surgical site or nosocomial infection rate between groups. The authors conclude that extended perioperative prophylaxis does not seem to decease the rate of surgical site infections.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Modified Intent to Treat (mITT)
Allocation Concealment 
Yes
Trial Registration:
Clinicaltrials.gov - NCT02717273
Funding Source:
Non-Industry funded
Brige, P., Hery, G. et al. (2018). Morbidity and mortality of hepatic right lobe living donors: systematic review and perspectives. Journal of Gastrointestinal & Liver Diseases 27(2): 169-178.
Aim:
The aim of this review was to review published studies exploring morbidity and mortality in Living Donor Liver Transplantation (LDLT) and to identify the proposed management and strategies for preventing donor mortality and morbidity in LDLT.
Interventions:
The MEDLINE database was searched between January 2000 to 2017 using the MeSH terms “liver transplantation” and “morbidity” or “mortality” in combination with keywords “living donor liver transplantation”.
Participants:
382 articles were obtained and a total of 64 articles were included in this review (43 about morbidity, 6 about morbidity and mortality and 15 about mortality).
Outcomes:
Outcomes being measured included morbidity and mortality associated with LDLT.
Follow Up:
N/A
CETs Conclusions:
The aim of this systematic review was to review the reported morbidity and mortality rates of donors following living donor liver transplantation (LDLT) and strategies to increase LDLT rates. Medline was searched for studies published between 2000 and 2017. 382 unique search results were sifted by independent reviewers. Sixty-four studies were included in the review of which 21 studies reported on morbidity, 6 studies reported on morbidity and mortality and 15 studies reported on mortality. The authors provided an overview of all the reported deaths in the literature (n=23) following hepatectomy for donation. The reported morbidity ranged from 10% to 78.3%. A number of studies reported on quality of life of donors which showed that quality of life was similar or better than a reference population before donation. The authors also discuss strategies that reduce the risk to the donor, i.e. those that reduce the amount of parenchyma harvested in the donor and those that increase the donor future remnant liver before the hepatectomy.
Trial Registration:
Not reported
Funding Source:
Not reported
Gallinat, A., Hoyer, D. P. et al. (2019). Oxygen Persufflation in Liver Transplantation Results of a Randomized Controlled Trial. Bioengineering 6(2): 27.
Aim:
This study aimed to evaluate whether 2 hours of gaseous oxygen persufflation of isolated liver grafts immediately prior to transplantation will improve early graft function upon reperfusion and mitigate adverse effects associated with preservation/reperfusion injury as compared to standard cold storage.
Interventions:
Patients were assigned to either oxygen persufflation for >2 hr (OPAL) or to standard, cold storage (control).
Participants:
116 liver transplant patients.
Outcomes:
The primary endpoint was aminotransferase peak of AST within the first three days after liver transplantation. Secondary outcomes included retransplantation, early allograft dysfunction, recipient ICU stay, post transplant dialysis, recipient hospital stay, 30-day mortality, in-hospital mortality, post-operation complications and graft rejection within 3 months.
Follow Up:
5 years.
CETs Conclusions:
This is a well-conducted RCT that has been written up in a clear report. The study was adequately randomised. Marginal livers were specifically targeted to enhance any potential impact of the persufflation technology. There was excellent one-year and five-year follow up. The primary endpoint was peak AST in the first three days after transplantation, for which this study was powered. There was no significant difference in peak AST levels within the first three days after transplantation. The study was not powered to detect differences in the secondary endpoints, which were rare in both arms (re-transplant, early allograft dysfunction, 30-day mortality, 3-month rejection). The persufflation did not result in any significant graft loss or damage in this study. Logistic regression was also conducted specifically to identify any parameters that were independent predictors of early allograft function in each arm. Whilst in the treatment group no such parameter was identified, in the control group donors with CPR and elevated AST were associated with greater risk of early allograft dysfunction. In cox proportional hazards there was an association between two factors (macrosteatosis and donor >70 years) and worse patient survival in the control group, but not in the treatment arm. In order to be clinically practice-changing this study would have to be repeated in these specific subgroups, but also compared to normothermic machine perfusion, which has likely leaped beyond the capabilities of cold preservation, oxygenated or not. There is surprisingly no reference in this paper to the recently published RCT of liver NMP from Nature that showed such significant results (Nasralla et al 2018).
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified Intent to Treat (mITT)
Allocation Concealment 
Yes
Trial Registration:
International Standard Randomised Controlled Trial Number - ISRCTN00167887
Funding Source:
Non-Industry funded
Kang, W. H. et al. (2019). A Multicenter, Randomized, Open-Label Study to Compare Micafungin with Fluconazole in the Prophylaxis of Invasive Fungal Infections in Living-Donor Liver Transplant Recipients. JOGS;[record in progress].
Aim:
This non-inferiority study aimed to evaluate the efficacy and safety of micafungin in the prophylaxis of invasive fungal infections (IFIs) in living-donor liver transplantation recipients (LDLTRs), with fluconazole as the comparator.
Interventions:
Patients were randomized to receive either intravenous micafungin 100 mg/day or fluconazole 100~200 mg/day (intravenous or oral).
Participants:
172 LDLTRs.
Outcomes:
Primary outcome was ‘clinical success’: a lack of a proven or probably invasive fungal infection (IFI) defined according to EORTC/MSG crtieria. Secondary efficacy endpoints included absence of IFI at end of prophylaxis, time to IFI and changes in incidence of superficial IFI or colonisation. Safety endpoints included adverse events, vitals signs and biochemistry/haematology.
Follow Up:
6 months.
CETs Conclusions:
This multicenter trial investigates the role of micafungin in antifungal prophylaxis following live donor liver transplantation. The authors conclude that micafungin is non-inferior to fluconazole in the prevention of invasive fungal infections. There are a few issues to note. Firstly, the main analysis presented here is per protocol. When results are analysed including premature withdrawals as treatment failures (important as many withdrawals were due to “efficacy failure or “adverse events”), non-inferiority was not satisfied. Also, recipients here are limited to live donor recipients, and results in a deceased donor population may differ. Finally, no data regarding immunosuppression or renal function are presented, which may be important as one of the arguments against -azole use is the interaction with CNIs.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Strict Intention To Treat (sITT)
Allocation Concealment 
Yes
Trial Registration:
Clinicaltrials.gov - NCT01974375
Funding Source:
Industry funded

Transplant Trial Watch July 2019 – Various Transplantation

Gallant, J. et al. (2019). Predictability of Capillary Blood Spot Toward Venous Whole Blood Sampling for Therapeutic Drug Monitoring of Tacrolimus in Solid Organ Transplant Recipients. EUR J DRUG METAB PH; [record in progress].
Aim:
The aim of this review was to critically evaluate if dried blood spotting (DBS) can replace venepuncture for the purpose of tacrolimus therapeutic drug monitoring (TDM).
Interventions:
Several databases were searched, including: PubMed, Scopus, EMBASE, and Google Scholar. Combinations of the following terms and phrases was conducted—tacrolimus, FK 506, drug monitoring, alternative methods, capillary blood, dried blood spotting.
Participants:
11 articles, comprising 525 transplant patients.
Outcomes:
Outcomes being assessed included bias and precision data reported in the identified papers. Narrative syntyesis is presented.
CETs Conclusions:
This systematic review aimed to assess the evidence for accuracy and precision of use of dried blood spot sampling as an alternative to venous whole blood sampling for tacrolimus trough monitoring. The authors identified 11 studies which they subjected to a narrative analysis. The underlying literature was found to be of limited quality with small sample sizes, poor description and inadequate reporting of precision. The authors conclude that further, adequately powered studies are required. The methodology used in the review is not well reported. Whilst multiple databases were searched using a variety of terms, non-English data were excluded and there is no mention of trial registry searches to identify unpublished studies. Details of screening and data extraction protocols are not provided, and there is no mention of a published protocol or detailed inclusion/exclusion criteria.
Trial Registration:
Not reported
Funding Source:
No funding

Transplant Trial Watch August 2019 – Kidney Transplantation

Alnasrallah, B., Goh, T. L. et al. (2019). Transplantation and diabetes (Transdiab): a pilot randomised controlled trial of metformin in impaired glucose tolerance after kidney transplantation. BMC Nephrology; 20(1): 147.
Aim:
To investigate the effect of metformin, post kidney transplantation in patients with impaired glucose tolerance (IGT).
Interventions:
Standard care or 500mg metformin, twice, daily in addition to the standard post-transplant care.
Participants:
19 renal transplant patients with IGT were randomized to receive either the metformin or standard care intervention (n=10 metformin; n=9 standard care).
Outcomes:
Primary outcomes were assessed as feasibility of recruitment, tolerability of metformin and efficacy of metformin. Secondary outcomes included the following: lipid profile at 3, 6, 9 and 12months; major cardiac events; change in body weight; all adverse events; and proportion of patients who revert to normal glucose metabolism on OGTT at 12months.
Follow Up:
12 months
CETs Conclusions:
This small feasibility study investigates the use of metformin in renal transplant recipients with impaired glucose tolerance. It demonstrates that recruitment is feasible, with no safety concerns. The small sample size (19 patients randomized) precluded any conclusions on efficacy. The study is well described. All patients had an OGTT between 4 and 12 weeks post-transplant, so the study will only pick up those patients with IGT early post-transplant (some of whom may have had IGT pre-transplant). Ultimately, a larger randomized study would be required to assess efficacy including the longer-term risk of post-transplant diabetes in these patients.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict Intetion to Treat (sITT)
Allocation Concealment 
No
Trial Registration:
Australian Trial Reg - CTRN12614001171606
Funding Source:
Non-Industry funded
Berger, S. P., Sommerer, C. et al. (2019). Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from TRANSFORM study. American Journal of Transplantation;[record in progress].
Aim:
This study aimed to assess the two-year outcomes of patients from the TRANSFORM study receiving everolimus (EVR) with reduced‐exposure calcineurin inhibitors (CNI) (EVR+rCNI) vs mycophenolic acid (MPA) with standard‐exposure CNI (MPA+sCNI).
Interventions:
This is a post-hoc analysis of the TRANSFORM (TRANSplant eFficacy and safety Outcomes with an eveRolimus‐based regiMen) trial, which compared the effect of renal transplant recipients receiving everolimus (EVR) with reduced‐exposure calcineurin inhibitor (EVR + rCNI) or mycophenolate with standard‐exposure CNI.
Participants:
2037 de novo kidney transplant patients from the TRANSFORM study (n=1022 EVR+rCNI; n=1015 MPA+sCNI).
Outcomes:
The primary outcome measured was a binary composite of treated biopsy-proven acute rejection (tBPAR) or suboptimal kidney function (eGFR 50 ml/min per 1.73m2) at 24 months post-transplant. The secondary outcome measured was a composite of efficacy failure and included tBPAR, graft loss, or death.
Follow Up:
24 months
CETs Conclusions:
This manuscript reports 24-month follow-up from the TRANSFORM study. 2037 de novo renal transplant recipients were randomized to everolimus and reduced dose CNI, or to MMF and standard-dose CNI. No difference in efficacy was seen, with similar eGFR and BPAR rates in both arms. As might be expected from previous mTORi studies, medication discontinuation due to adverse events was higher in the everolimus arm. However, infection rates, particularly for viral infections, were lower with everolimus. This is a large multicenter study that is well conducted and reported. Whilst it doesn’t offer a compelling reason to use everolimus over a standard Tac/MMF regimen, it certainly supports it as an alternative strategy with equivalent efficacy. Choice of regimen is likely to be dictated by side-effect profile.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict Intetion to Treat (sITT)
Allocation Concealment 
No
Trial Registration:
Clinicaltrials.gov - NCT01950819
Funding Source:
Industry funded
Chatani, B., Glaberson, W. et al. (2019). GCV/VCVG prophylaxis against CMV DNAemia in pediatric renal transplant patients: A systematic review and meta-analysis. Pediatric Transplantation; [record in progress].
Aim:
The study had three specific aims: evaluating the length of ganciclovir/valganciclovir (GCV/VGCV) prophylaxis as correlated to the prevention of cytomegalovirus (CMV) DNAemia; comparing the incidence of leukopenia among differing lengths of GCV/VGCV prophylaxis; and assessing the optimal length of prophylaxis for preventing CMV DNAemia in high-risk patients.
Interventions:
The PubMed, EMBASE, ISI Web of Science database engines, and Cochrane Central Register were serarched in this systematic review (Inclusion criteria required that studies used GCV/VGCV for prophylaxis of CMV, involved renal transplantation, commented on pediatric data, and commented on incidence of CMV DNAemia. Exclusion criteria removed studies which were duplicates, single case reports, or review articles without original data.)
Participants:
6 studies were included, which focussed on pediatric renal transplantation and the analysis of VCGV/GCV for the prevention of CMV DNAemia.
Outcomes:
Outcomes that were assessed included CMV DNAemia incidence associated with length of GCV/VGCV prophylaxis and incidence of leukopenia by length of prophylaxis.
Follow Up:
N/A
CETs Conclusions:
This is a well-written report of a good quality systematic review. A variety of databases were searched for evidence, and with a comprehensive search strategy. Studies were screened by two reviewers, and studies were evaluated in duplicate using the STROBE checklist. Six studies were included in the subsequent meta-analysis, two were multicentre and four were single centre. All were cohort studies. There is a good amount of information regarding differences and similarities between the included studies. Statistical tests for heterogeneity were conducted (Cochrane Q and I-squared). In the high risk group this study found no significant difference in viraemia risk between the different durations of prophylaxis (<6m, 6-12 and >12m). This may be due to the watering down of numbers to get the risk stratification and affecting the power of the meta-analysis. There was also no significant difference seen in the risk of leukopenia between the different durations of prophylaxis. This meta-analysis is limited by the amount and quality of available study data on CMV prophylaxis in paediatric transplant recipients. The meta-analysis is strongly influenced by the single largest included study, Hocker et al, in which a smaller proportion of patients received induction immune suppression compared to the other included studies.
Reporting Quality:
Quality Notes 
SR - QA not necessary
Trial Registration:
Not reported
Funding Source:
Not reported
Ho, J., Sharma, A. et al. (2019). Multicentre randomised controlled trial protocol of urine CXCL10 monitoring strategy in kidney transplant recipients. BMJ Open; 9(4): e024908
Aim:
To determine if early treatment of rejection, as detected by urine CXCL10 and confirmed by CXCL10-guided biopsy, will improve kidney allograft outcomes.
Interventions:
Patients will be randomized to either the control arm, which comprises usual care, or the intervention arm, which includes urine CXCL10 screening and a study biopsy to check for subclinical rejection.
Participants:
Adult kidney transplant patients will be enrolled, but only those who also present with a high risk of rejection, defined as confirmed elevated urine CXCL10 level will be randomized (n=250) into this study. Patients will be randomized to either the control arm (n=125) or the intervention arm (n=125).
Outcomes:
The primary outcomes will be assessed as death-censored graft loss; clinical biopsy-proven acute rejection; dnDSA development; subclinical chronic active TCMR or inflammation in areas of interstitial fibrosis and tubular atrophy (i-IFTA); or subclinical tubulitis. Subclinical chronic active TCMR and tubulitis will be evaluated on the 12-month study exit biopsy in all randomised patients. Secondary outcomes will be measured as graft function evaluated by Modified Diet in Renal Disease estimated glomerular filtration rate (MDRD eGFR), defined by change in graft function (6–12 months, slope and delta) and absolute graft function (6 and 12 months). Additional secondary outcomes include subclinical microvascular inflammation at 12 months (Banff ptc, g, c4d and cg); development of IFTA from implantation to 12 months (delta Banff ci, ct, cv); days from transplantation to clinical biopsy-proven acute rejection (TCMR, AMR); albuminuria >300 mg/day (6 and 12 months); patient quality of life (EuroQol five-dimension five-level instrument, EQ-5D-5L); cost-effectiveness analysis and the kinetics of urine CXCL10 in response to immunotherapy.
Follow Up:
12 months
CETs Conclusions:
This paper details the protocol for a multicentre randomised controlled trial. Urinary CXCL10 now has some evidence to support its use in identifying kidney recipients who would benefit from a transplant biopsy, by rising prior to creatinine. By catching subclinical acute rejection early, the authors speculate that transplant outcomes will be improved and have designed a large study to prove this. This study will be international and aims to randomise 250 kidney transplant recipients deemed to be at high risk of rejection due to elevated urine CXCL10 levels. An additional 170 patients at low risk of rejection will also be followed up. The power calculation makes allowance for 20% dropout. The method of randomisation will be by a central computer generation that is stratified for centre in randomly permuted blocks to maintain allocation concealment. The study cannot be blinded though as the study arm will have a transplant biopsy.
Reporting Quality:
Quality Notes 
Protocol - QA not necessary
Trial Registration:
ClinicalTrials.gov - NCT03206801
Funding Source:
Industry funded
Jasiak-Panek, N. M., Wenzler, E. et al. (2019). A Randomized, Open-label Pharmacokinetic Trial of Tacrolimus ER Dosing in Obese De Novo Kidney Transplant Recipients. Clinical Transplantation; [record in progress].
Aim:
This study aimed to assess the pharmacokinetics of tacrolimus extended-release (TAC-ER) in obese renal transplant recipients after dosing based on ideal body weight (IBW) to total body weight (TBW).
Interventions:
Patients were randomized to receive TAC‐ER at a dose of 0.15 mg/kg daily in the morning based on either ideal body weight (n=10) or adjusted body weight (n=10).
Participants:
Adult obese de novo renal transplant recipients (n=20).
Outcomes:
The primary outcome was of this study was measured as the difference in TAC‐ER exposure (AUC0‐24) in obese patients who received an initial TAC‐ER dose of 0.15 mg/kg using aBW versus IBW. The secondary endpoint was the difference in the time to reach a therapeutic trough level in aBW group compared with IBW.
Follow Up:
14 days
CETs Conclusions:
The pilot, open-label, randomised controlled trial compared plasma pharmacokinetics of tacrolimus extended release (TAC-ER) in obese (body mass index of ≥30 kg/m2) de novo adult kidney transplant recipients after dosing based on either adjusted body weight versus ideal body weight. The method of generating the randomisation sequence and whether allocation was concealed was not described. The pharmacokinetic assessments were conducted on three separate days (days 1, 7 and 14). As this was a pilot study no sample size calculation was conducted. A total sample size of 20 participants was considered sufficient to generate descriptive data. The two groups were balanced for the baseline characteristics except for age with the ideal body weight group being on average 12 years older. There was no statistically significant difference in the primary outcome TAC‐ER exposure (AUC0‐24) between groups on any of the three days. The safety did also not reveal any differences between groups. These pilot data need to be confirmed in a adequately powered study.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Strict Intetion to Treat (sITT)
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov - NCT02444143
Funding Source:
Industry funded
Vink, P., et al. Ramon Torrell, J. M. (2019). Immunogenicity and Safety of the Adjuvanted Recombinant Zoster Vaccine in Chronically Immunosuppressed Adults Following Renal Transplant: a Phase III, Randomized Clinical Trial. Clinical Infectious Diseases
Aim:
To investigate the immunogenicity and safety of the adjuvanted recombinant zoster vaccine (RZV) in renal transplant (RT) recipients ≥18 years of age receiving daily immunosuppressive therapy.
Interventions:
Patients were randomized to receive either 2 doses of RZV or Placebo 1–2 months apart, 4–18 months post-transplantation.
Participants:
264 renal transplant patients (n=132 RZV; n=132 placebo) were enrolled betewen enrolled between March 2014 and April 2017.
Outcomes:
Outcomes included anti-glycoprotein E (gE) antibody concentrations, gE-specific CD4 T-cell frequencies, and vaccine response rates were assessed at 1M post-dose 1, and 1M and 12M post-dose 2. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days post-each dose, respectively. Solicited general symptoms and unsolicited AEs were also collected 7 days before first vaccination. Serious AEs (including biopsy-proven allograft rejections) and potential immune-mediated diseases (pIMDs) were recorded up to 12M post-dose 2.
Follow Up:
18 months
CETs Conclusions:
This is an interesting study of a subunit varicella zoster vaccine in renal transplant recipients. The study was a multicentre, randomised, placebo-controlled trial. It has some indicators of good quality but the report lacks certain details to confirm this. The paper mentions a randomisation algorithm including some “minimisation factors” but there is not enough detail to understand if this was truly random. The study is described as “observer-blind”, but how this was protected is not described. The sample size calculation can be found in the supplemental material, but data are presented throughout the paper without related p-values. The vaccine showed a good humoral response above the thresholds set for immunogenicity, as it also did for cell-mediated responses. The vaccine was associated with more myalgia, shivering and fever than the placebo, but these results are not presented with any statistical test or associated p-value. There does not appear to be any gross difference in renal function, rejection or graft loss after vaccination in this study. Eight of the authors were employees of the GSK group of companies at the time this study was designed, initiated and/or conducted. The study was funded by GSK, who were involved in all stages of the conduct and analysis.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Modified Intention to Treat (mITT)
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov - NCT02058589
Funding Source:
Industry funded
Waterman, A. D., Anderson, C. et al. (2019). A randomized controlled trial of Explore Transplant at Home to improve transplant knowledge and decision-making for CKD 3-5 patients at Kaiser Permanente Southern California. BMC Nephrology; 20(1): 78.
Aim:
This study aims to assess effectiveness of Explore transplant at home (ET@Home) in English and Spanish for CKD stage 3-5 patients in increasing LDKT knowledge and decision-making by race/ethnicity and primary language spoken as compared to the standard Kaiser Permanente Southern California (KPSC) education.
Interventions:
Patients will be randomly assigned to one of two education conditions: ET@Home or KPSC standard of care education.
Participants:
1200 English and Spanish-speaking CKD Stage 3-5 patients (n=600 ET@Home intervention; n=600 KPSC education intervention).
Outcomes:
The primary outcome measures include patients’ knowledge of CKD and the risks and benefits of transplant and the capacity to make an informed decision about transplant. Secondary outcomes will include self-efficacy to pursue deceased donor kidney transplant (DDKT), living donor kidney transplant (LDKT) and steps taken towards transplant.
Follow Up:
6 months.
CETs Conclusions:
This is the published protocol of an interesting RCT reviewing the effectiveness of the existing Explore Transplant@home programme in CKD 3-5 patients to increase knowledge about the risks and benefits of living donor kidney transplantation in a racially, ethnically and geographically diverse population. The study also aimed to assess existing knowledge and decision-making regarding the risks and benefits of living donor kidney transplantation (before the intervention). The Explore Transplant@home is focused on teaching patients about their treatment options and supporting their decision-making. With an expected response rate of 20%, 6000 patients will be invited by email and recruitment will be stratified by race/ethnicity, language spoken, and CKD stage. After completion of a first survey, patients will be randomised according to a sequence generated by the data capture system. Black, Hispanic, Asian and White patients will be randomised to a video-guided Explore Transplant@home programme delivered by mail including bimonthly postcards and texting over six months or to standard education (1-2 hour course). The primary outcome will be knowledge at 6 months and the sample calculation showed that 1200 patients would provide a power of 90% to detect 0.25 effect size with an expected retention rate of 50% at 6 months. The investigators aim to understand key knowledge gaps in this patient population and between patients speaking different languages. Additionally, the investigators hope that the programme will help to reduce disparities in access to transplant and serve as a model for other healthcare systems.
Reporting Quality:
Quality Notes 
Protocol - QA not necessary
Trial Registration:
ClinicalTrials.gov - NCT02058590
Funding Source:
Industry funded

Transplant Trial Watch August 2019 – Liver Transplantation

Undre, N., Baccarani, U. et al. (2019). Pharmacokinetic Profile of Prolonged-Release Tacrolimus When Administered via Nasogastric Tube in De Novo Liver Transplantation: A Sub-Study of the DIAMOND Trial. Annals of Transplantation; 14(24): 268-272
Aim:
This sub-study of the DIAMOND trial aimed to assess the absorption and pharmacokinetic profile of prolonged-release tacrolimus when administered by nasogastric tube immediately post-transplant.
Interventions:
Patients were randomized to 1 of 3 study arms (1: 1: 1) to receive prolonged-release tacrolimus. In Arms 1 and 2, patients received prolonged- release tacrolimus at an initial dose of 0.2 mg/kg/day and 0.15–0.175 mg/kg/day on Day 1 post-transplant, respectively, while in Arm 3 tacrolimus initiation at a dose of 0.2 mg/kg/day was delayed until Day 5 post-transplant. All patients received MMF and 1 bolus of corticosteroid, and patients in Arms 2 and 3 also received basiliximab.
Participants:
10 de novo liver transplant recipients from the DIAMOND study.
Outcomes:
Pharmacokinetic profile was measured using area under the concentration–time curve from 0 to 24 hours post-tacrolimus dose (AUC0–24), maximum observed concentration of tacrolimus (Cmax), time to Cmax (Tmax), minimum observed concentration of tacrolimus at 24-h post-dose (Cmin), and dose and body weight normalized AUC0–24, Cmax, and Cmin.
Follow Up:
3 days
CETs Conclusions:
The DIAMOND study was a randomized controlled trial investigating the use of prolonged-release tacrolimus in liver transplant recipients. This small sub-study looks at the pharmacokinetics of prolonged-release tacrolimus delivered as a suspension via a nasogastric tube. The authors demonstrate that by day 3 post-transplant, AUC increases and variability reduces, presumably as gut motility returns. The authors conclude that delivery via nasogastric tube is safe and equivalent to oral administration in these patients. However, there is no comparison group (using intact capsules taken orally), so equivalence is only inferred from the results reported in previous manuscripts. Sample size is small (just 10 patients), so a formal prospective comparison would be required to confirm these conclusions.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified Intention to Treat (mITT)
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT01011205
Funding Source:
Industry funded
Guo, T., Lei, J. et al. (2019). The hepatic protective effects of tacrolimus as a rinse solution in liver transplantation: A meta-analysis. Medicine (Baltimore); 98(21): e15809.
Aim:
To investigate the protective effects of tacrolimus as a rinse solution against ischaemia-reperfusion injury (IRI) in liver transplantation.
Interventions:
The MEDLINE, EMBASE and Cochrane Central databases were searched to identify randomized controlled trials (RCTs) investigating the effects of tacrolimus as a rinse solution in liver transplantation. No restriction of publication time or status was applied.
Participants:
3 RCTs, incuding 70 liver transplants investigating the effects of tacrolimus (20ng/mL) as a rinse solution were evaluated in this study.
Outcomes:
Outcomes were assessed as postoperative liver function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) at postoperative day (POD) 1, 2 and 7.
Follow Up:
7 days
CETs Conclusions:
This meta-analysis looked at the evidence for tacrolimus-rinse to prevent ischaemia-reperfusion injury of liver allografts. It is a well-conducted meta-analysis, but was based upon just three RCTs, therefore limiting the power of the statistical analysis. The review was prospectively registered with the PROSPERO system. MEDLINE, EMBASE and the Cochrane database were searched for relevant studies with a sensitive search strategy, and only three RCTs were included. The potential risk of bias in the studies was assessed and presented clearly in the supplemental material. The pooled estimates showed no significant impact of tacrolimus rinse on post-operative serum ALT, AST or bilirubin. Tacrolimus rinse concentration was the same in all three RCTs. This systematic review was conducted to good standards, as described above, and even going as far as funnel plots to assess for publication bias, calculating egger’s tests, and doing a sensitivity analysis to exclude the one study with extended criteria donors. However, this does not change the fact that the three included RCTs were small and each individually did not show any benefit of the tacrolimus rinse. In conclusion, this review did not find clinical evidence to support the use of tacrolimus rinse solutions in liver transplantation.
Reporting Quality:
Quality Notes 
SR - QA not necessary
Trial Registration:
PROSPERO - 108191
Funding Source:
No funding

Transplant Trial Watch August 2019 – Lung Transplantation

Okamoto, T., Wheeler, D. et al. (2019). Transplant suitability of rejected human donor lungs with prolonged cold ischemia time in low flow acellular and high flow cellular ex vivo lung perfusion systems. Transplantation; 12: 12.
Aim:
This study aimed to investigate the transplant suitability of lungs with a prolonged cold ischaemia time (CIT) in two ex vivo lung perfusion (EVLP) systems and to investigate the difference between the two EVLP systems.
Interventions:
Rejected lung donors with a prolonged CIT of 13.8 hours were randomized to either low flow acellular or high flow cellular EVLP systems (n=8 per system).
Participants:
Rejected lung donors were obtained from the period of January 2012 and February 2014 (n=16).
Outcomes:
The primary outcome being measured was transplant suitability, which was assessed using a number of parameters which were in accordance of the standard criteria of each EVLP systems. Transplant suitability was measured using the left atrium PaO2/FiO2 (P/F) ratio (< 400mmHg in the low flow acellular system and < 300 mmHg in the high flow cellular system were considered unsuitable for transplantation); airway parameters; final flow; airway fluid or abnormal visual findings, such as lung oedema or haematoma following perfusion. Lung tissues analysis was also measured using wet/dry ratios and pathological findings, including the presence of interstitial oedema, intra-alveolar oedema, arteriolar thickening, vascular thrombosis, haemorrhage/congestion, acute inflammation and intra-alveolar fibrin deposition used to detect typical morphological changes during lung ischaemic reperfusion injury. Finally, the inflammatory cytokine profile of the perfusate was also evaluated in duplicate.
Follow Up:
N/A
CETs Conclusions:
The study aimed to compare the transplant suitability of lungs with prolonged cold ischaemia time (>8 hours) that were rejected for transplantation for two ex vivo lung perfusion (EVLP) systems. Sixteen donor lungs that were rejected by clinical staff, and/or had a PaO2/FiO2 (P/F) ratio <300 mmHG, and/or an abnormal chest X-ray showing infiltrates in lower lung fields were included. Lungs were randomised to perfusion with a low flow acellular or high flow cellular EVLP system but no details of the randomisation process were described. The mean CIT of lungs was 13.8 (9-19.5) hours. The high flow cellular system showed a significantly lower P/F ratio and higher vascular pulmonary resistance than the low flow acellular system. Transplant suitability was determined by two assessors although it was not clear whether each lung was assessed by two independent reviewers. In the low flow acellular group 3/8 lungs were considered transplantable versus none in the high flow cellular group.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol (PP)
Allocation Concealment 
No
Trial Registration:
Not reported
Funding Source:
Non-Industry funded

Transplant Trial Watch September 2019 – Kidney Transplantation

Aquil, S. et al. (2019). Use of a Muscle Pump Activator Leads to Improved Lower Limb Edema, Lower Limb Blood Flow, and Urine Output Compared With Standard TED Stockings and Compression Devices Following Kidney Transplant: A Randomized Controlled Trial.
Aim:
This study aimed to evaluate the effects of using thromboembolic deterrent (TED) stockings and intermittent pneumatic compression (IPC) vs a muscle pump activator (MPA) device on limb oedema and patient satisfaction after transplant.
Interventions:
Patients were randomly assigned to wear TED + IPC (n = 64) or the MPA device (n = 54) from postoperative days 1 to 6.
Participants:
118 kidney transplant patients.
Outcomes:
The primary outcome asssesed patient lower limb oedema after surgery and patient satisfaction with the MPA device vs TED + IPC stockings following kidney transplant. Secondary outcomes included: weight gain, DVT risk, total urine output, kidney function, and kidney blood flow.
Follow Up:
6 days
CETs Conclusions:
This small RCT from Ontario investigates the use of a muscle pump activator as an alternative to TEDs and intermittent pneumatic compression as DVT prophylaxis following renal transplantation. The authors report a reduction in gain of leg circumference, increased urine output, and reduction in weight gain in the MPA group. In addition, patients found MPA more comfortable. The study is well designed and clearly reported. Randomization and allocation concealment were adequate, and there was no loss to follow-up. It is not blinded, and therefore risks reporting bias in the patient reported outcome measures, although blinding would be difficult. Larger studies would be required to confirm that MPA is equivalent to IPC and TEDs in the prevention of DVT.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict Intention To Treat (sITT)
Allocation Concealment 
Yes
Trial Registration:
Not reported
Funding Source:
Not reported
Ferreira, A. N., Felipe, C. R. et al. (2019). Prospective randomized study comparing everolimus and mycophenolate sodium in de novo kidney transplant recipients from expanded criteria deceased donor. Transplant International 06: 06.
Aim:
This study aimed to compare everolimus and mycophenolate sodium in de novo kidney transplant recipients from expanded criteria deceased donors (ECD) to identify an optimal immunosuppressive regimen for ECD kidneys.
Interventions:
Patients were randomized to receive either antithymocyte globulin induction, delayed introduction of reduced dose tacrolimus, prednisone and everolimus (r-ATG/EVR) or mycophenolate (r-ATG/MPS).
Participants:
171 ECD kidney transplant patients.
Outcomes:
The primary end-point was assessed as the incidence of CMV infection at 12 months. Secondary endpoints of this study included treatment failure (first biopsy proven acute rejection (BPAR), graft loss or death) and safety.
Follow Up:
12 months
CETs Conclusions:
This is clearly reported trial that was well conducted with adequate randomization, although blinding was not undertaken. The study was adequately powered taking into account expected event rates and dropouts. The everolimus arm had a drastically reduced risk of CMV infection/disease in the first year (14% versus 72% approximately). However, the balance between preventing infection, and risking allograft rejection, seemed to be tipped too far in this study; The incidence of graft loss, death and rejection were all significantly higher in the everolimus arm, and mean GFR was significantly worse. The study was therefore terminated before reaching the target inclusion numbers. ECD kidneys have a higher risk of graft loss and mortality, in this group it seems that the proposed immune suppression regimen to reduce CMV disease comes at too high a risk to the transplant. There is pressure in the healthcare setting of this trial to avoid CMV prophylaxis, but that looks inadvisable given the results of this study in this particular setting. The authors agree that, under the conditions of this trial, everolimus should be avoided in ECD kidney transplantation.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified Intent to Treat (mITT)
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT01895049
Funding Source:
Industry funded
Russell, C. L. et al. (2019). Improving medication adherence and outcomes in adult kidney transplant patients using a personal systems approach: SystemCHANGETM results of the MAGIC randomized clinical trial.American Journal of Transplantation. 10:10
Aim:
The objective of this study was to determine if a SystemCHANGETM intervention was more efficacious than attention control in increasing immunosuppressive medication adherence and improving outcomes in adult kidney transplant recipients during a 6-month intervention phase and a subsequent 6-month (no intervention) maintenance phase.
Interventions:
Patients were randomly assigned to a 6 month SystemCHANGETM intervention or a no intervention, maintenance phase. The SystemCHANGETM approach taught patients to use person-level quality improvement strategies to link adherence to established daily routines.
Participants:
There were 89 kidney transplant patients which participated in this study.
Outcomes:
Primary outcome was assessed as the average 6-month immunosuppressive medication adherence rate, which was defined as doses taken on time/total doses as measured by the Medication Event Monitoring System SmartCap® (MEMSCap™). The secondary outcome was adherence of immunosuppressive medication at 12 months.
Follow Up:
12 months
CETs Conclusions:
This interesting RCT investigates the use of a behavioural intervention (SystemChange) to improve medication adherence following renal transplantation. Patients were randomized to intervention or control, and the authors demonstrate a significant improvement in adherence following the intervention, which importantly is preserved for 6 months after the intervention is complete. Interventions that demonstrate sustained improvement in adherence in transplant recipients are far and few between, so these findings are important. However, it is not clear from this study how easy it would be to implement the intervention outside of the trial setting as it is quite resource intensive. Whilst the intervention effect was sustained in patients for 6 months after completion, this was with a stipend and continued electronic pill monitoring. It is possible that the effect will reduce over time outside of a trial. A pragmatic real-world trial in more centres would help to answer some of these outstanding questions.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol (PP)
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT02416479
Funding Source:
Not reported
Sabe, N., Oriol, I. et al. (2019). Antibiotic Treatment Versus No Treatment for Asymptomatic Bacteriuria in Kidney Transplant Recipients: A Multicenter Randomized Trial." Open Forum Infectious Diseases 6(6): ofz243.
Aim:
This study aimed to test the evaluate the impact of no treatment for Asymptomatic Bacteriuria (AB) in kidney transplant recipients vs antibiotic treatment in the prevention of acute graft pyelonephritis (AGP).
Interventions:
Patients with AB were assigned no treatment or antibiotic treatment.
Participants:
205 kidney transplant recipients were enrolled in the study and underwent randomization. Of these participants, 102 were assigned to the antibiotic treatment group and 103 were assigned to the no treatment group.
Outcomes:
The primary outcome was the occurrence of AGP. Secondary endpoints included: bacteremic AGP, cystitis, susceptibility of urine isolates, graft rejection, graft function, graft loss, opportunistic infections, need for hospitalization, and mortality.
Follow Up:
12 months
CETs Conclusions:
This multicentre trial investigated whether antibiotic treatment of asymptomatic bacteriuria improved outcomes in renal transplant recipients. The authors found no difference in risk of graft pyelonephritis or transplant outcomes, with a suggestion of increased bacterial resistance in the treated arm. These findings should be interpreted with caution, as the study is underpowered. The sample size calculation provided suggests a power of 65.8% to detect a difference in pyelonephritis, and the confidence interval for the primary endpoint spans from a risk ratio of 0.4 to 4.8 – either of which would be a clinically important difference in risk. Further studies are required to confirm these findings.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified Intent to Treat (mITT)
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT01771432
Funding Source:
Industry funded, Non-Industry funded
Weinrauch, L. A., D'Elia, J. A. et al. (2018). Infection and Malignancy Outweigh Cardiovascular Mortality in Kidney Transplant Recipients: Post Hoc Analysis of the FAVORIT Trial." American Journal of Medicine 131(2): 165-172.
Aim:
This post-hoc analysis aimed to investigate the effect of diabetes on outcomes in renal transplant recipients.
Interventions:
This is a post-hoc analysis of the FAVORIT trial. All patients from the trial were randomized into three groups: nondiabetic (n=2447), type 1 diabetic (n=166), or type 2 diabetic (n=1497).
Participants:
4110 renal transplant recipients from the FAVORIT trial.
Outcomes:
Outcomes were assessed as all-cause mortality, cardiovascular mortality, non-cardiovascular mortality, infection and malignancy.
Follow Up:
6 Years
CETs Conclusions:
CET Conclusion: This is an interesting post hoc analysis of an RCT, the FAVORIT study. Approximately 4000 stable renal transplant recipients were included, an average of 3.8 years after transplantation and followed up for 6 years. Non-cardiovascular mortality was more common than cardiovascular mortality in both diabetic and nondiabetic patients, with infection and malignancy being the two most common causes. Diabetes increased the risk of non-cardiovascular mortality. This study highlights the importance of focussing attention on non-cardiovascular mortality in the long-term survival of renal transplant recipients, both for a preventative and treatment efficacy standpoint. The fundamental bias in this study is that it does not take into account mortality in the first 4 years after transplantation. The study population was also purely patients with elevated homocysteine levels, which, whilst very common in renal transplant recipients, probably excludes about 25% minimum. Patients with low homocysteine levels would be expected to have even lower risk of cardiovascular mortality.
Reporting Quality:
Jadad Score 
5
Data Analysis 
Per Protocol (PP)
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT00064753
Funding Source:
Non-Industry funded

Transplant Trial Watch September 2019 – Liver Transplantation

Beckmann, S., et al. (2019). Body weight parameters are related to morbidity and mortality after liver transplantation - A systematic review and meta-analysis. Transplantation 24: 24.
Aim:
This systematic review aimed to summarise the evidence available on the impact of pre- and post-liver transplant (LTx) body weight parameters (e.g., BMI, BMI category, post-transplant weight gain) on post-transplant outcomes such as patient and graft survival, metabolic and cardiovascular comorbidities and healthcare use.
Interventions:
Medline via PubMed, Cochrane library, CINAHL, PsycINFO, and EMBASE databases were searched without filters or limits. The inclusion criteria included quantitative or mixed method studies on first time solid organ transplant recipients that examined pre- and post-LTx body weight parameters related to any post-LTx outcome.
Participants:
37 studies comprising body weight parameters pre and post liver-transplant surgeries.
Outcomes:
Outcomes assessed included body weight parameters associated with patient survival, graft survival, new on-set diabetes and length of hospital stay, pre and post-liver transplant.
Follow Up:
3 Years
CETs Conclusions:
The systematic review evaluated the evidence on the impact of pre- and post-liver transplantation body weight parameters on posttransplant outcomes. The comprehensive literature search was conducted in February 2016. Study selection and data extraction were done by independent reviewers. The methodological quality was assessed using a 19-item tool. The search identified 184 studies for inclusion that reported posttransplant outcomes of which 37 were included in meta-analyses. Liver transplant recipients with a pre-transplant BMI≥30 or BMI≥35 had worse overall patient survival when to compared to patients with normal weight. Graft survival was worse in patients with a BMI≥30 when compared to patients with normal weight and there was a significant relationship between pretransplant BMI and development of new-onset diabetes after 6 months posttransplant. Posttransplant BMI was not shown to be associated the development of new-onset diabetes. The authors attempted to explain high heterogeneity by conducting explorative subgroup analyses. The methodological quality inadequate for most trials and the authors suggested that this may have caused the high heterogeneity.
Trial Registration:
PROSPERO - CRD42014009151
Funding Source:
Industry funded

Transplant Trial Watch September 2019 – Lung Transplantation

Yu, H., et al. (2019). Bilateral lung transplantation provides better long-term survival and pulmonary function than single lung transplantation: A systematic review and meta-analysis. Transplantation 24: 24.
Aim:
This systematic review aimed to compare bilateral lung transplantation (BLT) and single lung transplantation (SLT) to identify the better clinical choice for lung transplantation.
Interventions:
The Web of Science, EMBASE, Cochrane Library, Ovid MEDLINE, PubMed, ScienceDirect, and Google Scholar database engines were reviewed for randomised controlled trials on single lung transplantation (SLT) and bilateral lung transplantation (BLT) ( the search was conducted from inception to January 5, 2019.)
Participants:
Thirty studies including 1980 recipients in the SLT group and 2112 recipients in the BLT group of lung transplant patients.
Outcomes:
Outcomes assessed included: perioperative indexes, postoperative complications, pulmonary functions and survival.
Follow Up:
5 Years
CETs Conclusions:
This systematic review identified cohort studies comparing the outcomes of bilateral versus single lung transplantation. From 30 studies, the authors conclude that long-term and BOS-free survival (4-5 years) is improved with bilateral lung transplantation. Surgical time and post-operative ITU stay were lower in the single-lung group. This is an interesting study and the methodology in general is good. The obvious caveat is that these are (necessarily) retrospective cohort studies and there is likely to be an element of selection bias. There is heterogeneity in some analyses which is not explained. It is possible that SLT may be as suitable in some subpopulations that could not be examined in these data.
Trial Registration:
PROSPERO - CRD42019131582
Funding Source:
Industry funded

Transplant Trial Watch September 2019 – Heart Transplantation

Starling, R. C., Armstrong, B. et al. (2019). Accelerated Allograft Vasculopathy With Rituximab After Cardiac Transplantation. Journal of the American College of Cardiology 74(1): 36-51.
Aim:
This study aimed to identify whether B cell depletion therapy would decrease the development of cardiac allograft vasculopathy.
Interventions:
Patients were randomized to receive either rituximab 1000mg intravenous or placebo on days 3 and 12 post-heart transplantation.
Participants:
163 heart transplant recipients (age: 18-75 years).
Outcomes:
The primary outcome of this study was change in percent of atheroma volume (PAV) from baseline to one year. Secondary outcomes assessed included treated episodes of acute rejection, de novo anti-HLA antibodies and phenotypic differentiation of B cells.
Follow Up:
1 year.
CETs Conclusions:
This is a well written report of a good quality clinical trial in cardiac transplantation. The proposed hypothesis was that Rituximab treatment would prevent cardiac allograft vasculopathy compared to placebo following heart transplantation, by depleting B-cells and preventing antibody-mediated damage. Both the treatment arm and control arm received standard immune suppression post-operatively with tacrolimus, mycophenolate and tapering steroids (or alternatives at local investigators’ discretion). The study was adequately powered based on previous results. Unfortunately there are no details in the report of the method of randomisation or how blinding was maintained. The primary outcome was the mean change in percent atheroma volume at one year, as assessed by intra-vascular ultrasound. This outcome was significantly worse in the Rituximab arm, an unexpected outcome. There were no significant clinical outcomes associated with this (such as retransplantation, rejection or death) but the study was not powered for these. There was a similar proportion of patients who developed anti-HLA antibodies in both arms. It is speculated that certain B-cells have a regulatory function and the depletion with Rituximab can lead to other cell phenotypes filling the void. Whilst the authors would not discourage the use of Rituximab in cardiac transplantation to treat antibody mediated rejection, or PTLD, they agree that Rituximab should be avoided as induction therapy for non-sensitized cardiac transplant recipients.
Reporting Quality:
Jadad Score 
4
Data Analysis 
Per Protocol (PP)
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT01278745
Funding Source:
Not reported

Transplant Trial Watch September 2019 – Various Transplantation

Chung, E. Y. M., et al. (2019). Interventions to Prevent Nonmelanoma Skin Cancers in Recipients of a Solid Organ Transplant: Systematic Review of Randomized Controlled Trials." Transplantation 103(6): 1206-1215.
Aim:
This systematic review aimed to explore the benefits and harms of interventions to prevent non-melanoma skin cancer in solid organ transplant recipients.
Interventions:
The MEDLINE, Embase, and the Cochrane CENTRAL register was searched for randomized controlled trials (RCTs) evaluating interventions to prevent nonmelanoma skin cancers in solid organ transplantation.
Participants:
93 trials were identified and included in this review, including 20012 solid organ patients.
Outcomes:
The primary efficacy outcome was skin cancer and the primary safety outcome was intervention-specific adverse events. Secondary outcomes included keratotic skin lesions, graft function, acute rejection, graft loss, all-cause mortality, cardiovascular events or mortality, infection, nonskin cancer and life participation.
Follow Up:
Median: 24 months
CETs Conclusions:
This thorough systematic review evaluated interventions to prevent non-melanoma skin cancer in solid organ transplant patients. A comprehensive bibliographic search including hand-searching was conducted which identified 91 randomised controlled trials and one quasi-randomised controlled trial for inclusion, reporting on 20,012 patients. Risk of bias was assessed and GRADE was used to evaluate the certainty of the evidence. Study selection, data extraction and risk of bias assessment were done by two independent reviewers. Treatment effects were calculated using random effects meta-analysis and subgroup analyses to explore sources of heterogeneity were defined a priori. Risk of bias across different domains was high or unclear in most trials. Most of the evidence was of low or very low certainty. Two analyses provided moderate certainty evidence: mTOR inhibitors probably reduced the risk of skin cancer compared to calcineurin inhibitors (12 trials 2225 patients, RR 0.62, 95% confidence interval 0.45-0.85) and the effect of imiquimod was uncertain when compared to placebo (2 trials, 63 patients). Overall the evidence is limited, also due to the low incidence of skin cancers in the trials.
Trial Registration:
Not reported
Funding Source:
No funding
Degenholtz, H. B., Creppage, K. et al. (2019). The Patients Save Lives Program to Facilitate Organ Donor Designation in Primary Care Offices. Progress in Transplantation; [record in progress].
Aim:
This study aimed to assess variation in training protocols in a primary care setting regarding organ donation and transplantation. The trial proposed to identify whether this intervention would facilitate donor designation.
Interventions:
Primary care physician offices were randomly assigned to either web-based training, in-person training, or a control condition.
Participants:
121 primary care clinics in the donor designation region of the collaborating Organ Procurement Organizations were included in this trial.
Outcomes:
The primary was the percentage of people who were not already on the registry who chose to designate when provided with the opportunity to do so as part of a primary care office visit. This outcome was captured using the patients save lives (PSL) forms.
Follow Up:
6 months
CETs Conclusions:
This RCT compared the effect of a web-based training, in-person training and a control condition about organ and tissue donation on donor registrations. Primary care clinics were randomised to one of the three conditions. All clinics received a poster promoting organ donation, brochures and donor designation forms. The web-based training and in-person training consisted of a 1-hour continuing education course. The primary outcome was the percentage of people who were not on the donor registry who chose to designate during a primary care office visit. 269 primary care practices were approached of which 108 agreed to participate and 21,189 patients were exposed to the interventions over 6-months. Baseline differences existed between groups in terms of education of clinic staff, number of patients, and age and race of patients. There were more patients already registered as a donor in the two training groups and after 6 months 8.6% and 7.1% of non-registered patients in the in-person and web-based training group, respectively, registered as donor. No patients in the control group registered as a donor. The authors list a number of valid limitations of the study and these should be addressed in future research.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict Intention To Treat (sITT)
Allocation Concealment 
No
Trial Registration:
Not reported
Funding Source:
Industry funded, Non-Industry funded