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