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Transplant Trial Watch

The Transplant Trial Watch provides a monthly overview of the 10 most important new clinical trials in organ transplantation, selected and reviewed by the Peter Morris Centre for Evidence in Transplantation (Oxford University)

October 2021

Heart


  1. Allograft discard risk index for heart transplantation
    Clinical Transplantation. 2021;[record in progress]

    Study Details

    Aims: The primary aim of this study was to develop a discard risk index (DSRI) for predicting heart allograft discard using donor factors.
    Interventions: The study cohort was randomly divided into a training cohort and a validation cohort.
    Participants: 72,652 heart donors.
    Outcomes: The main outcome of interest was to create a DSRI based on the results of univariate and multivariate analyses.

    CET Conclusion

    Reviewer: Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    The study developed a donor heart discard risk index (DSRI) using deceased donor data from UNOS. The DSRI aimed to predict the heart allograft discard using donor factors. The cohort of 72,652 donors was randomly split into a training and validation cohort. The two cohorts had similar demographics. A multivariable logistic regression analysis identified factors that were significantly associated with allograft discard, which included left ventricular ejection fraction, hepatitis B-virus core antibodies, diabetes and a donor age of >45y. The DSRI showed little correlation to mortality after transplantation. Data suggests that allografts with higher risk of discard could be used to increase donor heart utilisation without a significantly increased risk of mortality.

    Abstract

    BACKGROUND The numberof patients awaiting heart transplantation (HTx) substantially exceeds the number of donor hearts transplanted each year, yet nearly 65% of eligible donor hearts are discarded rather than transplanted. METHODS Deceased organ donors listed within the UNOS Deceased Donor Database between 2010 and 2020 were reviewed. Those greater than 10 years old and consented for heart donation were included and randomly separated into training (n = 48 435) and validation (n = 24 217) cohorts. A discard risk index (DSRI) was created using the results of univariable and multivariable analyses. Discard data were assessed at DSRI value deciles, and stratum-specific likelihood ratio (SSLR) analysis and Kaplan-Meier survival function were used for mortality data. RESULTS Factors associated with higher DSRI values included donor age > 45, LVEF, HBV-core antibodies, hypertension, and diabetes. The DSRI C-statistic was .906 in the training cohort and .904 in the validation cohort. The DSRI did not reliably predict 30-day or 1-year mortality after transplantation (C-statistic .539 and .532, respectively). CONCLUSIONS The factors leading to heart allograft discard are not correlated to the same degree with post-transplant outcomes. This suggests that optimizing utilization of certain allografts with slightly higher risk of discard could increase the heart donor pool with limited impact on posttransplant mortality.

Kidney


  1. Significant hospitalization cost savings to the payer with a pharmacist-led mobile health intervention to improve medication safety in kidney transplant recipients
    American Journal of Transplantation. 2021;[record in progress]

    Study Details

    Aims: This economic analysis of a previously published randomised controlled trial aimed to evaluate the impact of a pharmacist-led, mobile health (mHealth) intervention on healthcare costs.
    Interventions: Participants in the original trial were randomised to either the mHealth-based intervention group or the usual care group.
    Participants: 136 kidney transplant recipients.
    Outcomes: The main outcome of interest was an a priori planned economic assessment of the mHealth intervention.

    CET Conclusion

    Reviewer: Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This is a health-economic analysis from the payer perspective of a previously published pharmacist-led, mobile health (mHealth) intervention to facilitate the management of patients using remote monitoring and telehealth. The a priori planned analysis evaluated all costs associated with hospitalisation during the 12-month follow up. The mHealth intervention had previously shown to reduce the hospitalisation rate, medication errors and drug adverse events. Cost data were estimated using validated methods. The hospitalisation costs were significantly lower in the intervention versus the control arm ($390,489 versus $870,468) with a significant return on investment ($4.30 for every $1 spent). The authors suggest that cost-savings should be passed on to the transplant centres so that they can recover the costs of implementing the intervention.

    Abstract

    This was an economic analysis of a 12-month, parallel arm, randomized controlled trial in adult kidney recipients 6 to 36 months posttransplant (NCT03247322). All participants received usual posttransplant care, while the intervention arm received supplemental clinical pharmacist-led medication therapy monitoring and management, via a smartphone-enabled mHealth app, integrated with risk-based televisits. Hospitalization charges were captured from the study institution accounts payable and non-study institution hospitalization charges were estimated using multiple imputation. Multivariable modeling was used to assess the impact of the intervention on charges. The intervention significantly reduced rates of hospitalization (1.08 per patient-year in the control arm vs 0.65 per patient-year in the intervention arm, p = .007). The control arm had estimated hospitalization costs of $870,468 vs $390,489 in the intervention arm. Modeling demonstrated a 49% lower hospitalization charge risk in the intervention arm (RR 0.51, 95% CI 0.28-0.91; p = .022). From a payer or societal perspective, the net estimated cost savings, after accounting for intervention delivery costs, was $368,839, with a return on investment (ROI) of $4.30 for every $1 spent. These results demonstrate that a mHealth-enabled, pharmacist-led intervention significantly reduced hospitalization costs for payers over a 12-month period and has a positive ROI.
  2. A systematic review and meta-analysis of COVID-19 in kidney transplant recipients: Lessons to be learned
    American Journal of Transplantation. 2021;[record in progress]

    Study Details

    Aims: The main aim of this study was to evaluate all current evidence in order to provide a comprehensive and up-to-date insight into COVID-19 in kidney transplant patients.
    Interventions: A literature search was performed using the World Health Organization (WHO) COVID-19 database. Abstracts and titles of studies were screened by three reviewers, followed by selection of eligible studies by two reviewers and independent extraction of data. The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS).
    Participants: 74 studies were included in the review.
    Outcomes: Hospitalization, length of hospitalization, incidence of acute kidney injury (AKI), kidney function after discharge, requirement for dialysis treatment, kidney graft failure or rejection and mortality.

    CET Conclusion

    Reviewer: Dr Liset Pengel, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    The systematic review aimed to summarise the evidence regarding the clinical course and outcome of COVID-19 in kidney transplant recipients, and treatment modalities and modifications in immunosuppression. The review was registered with PROSPERO. The comprehensive bibliographic search was done up to January 2021 and identified 74 single-arm studies (n=5559) for inclusion that reported on at least five patients. Screening, study selection and data extraction were conducted by independent reviewers. The methodological quality was assessed using the Newcastle-Ottawa scale but it was not described whether this was done by independent reviewers. The overall reported mortality of hospitalised patients with COVID-19 was 23% (95%CI 21% -27%) and reported acute kidney injury (AKI) was 50% (95% CI 44%-56%). No evidence was found for any of the potential risk factors for mortality or AKI, including age, sex, anthropometrics or comorbidities. Dose reductions of immunosuppression were common, particularly of proliferation inhibitors and calcineurin inhibitors although the studies did not provide sufficient details to meta-analyse the data for different subgroups. Sensitivity analyses included only studies reporting on at least 100 patients and reported similar outcomes for the risk of mortality and AKI.

    Abstract

    Kidney transplant recipients (KTR) may be at increased risk of adverse COVID-19 outcomes, due to prevalent comorbidities and immunosuppressed status. Given the global differences in COVID-19 policies and treatments, a robust assessment of all evidence is necessary to evaluate the clinical course of COVID-19 in KTR. Studies on mortality and acute kidney injury (AKI) in KTR in the World Health Organization COVID-19 database were systematically reviewed. We selected studies published between March 2020 and January 18th 2021, including at least five KTR with COVID-19. Random-effects meta-analyses were performed to calculate overall proportions, including 95% confidence intervals (95% CI). Subgroup analyses were performed on time of submission, geographical region, sex, age, time after transplantation, comorbidities, and treatments. We included 74 studies with 5559 KTR with COVID-19 (64.0% males, mean age 58.2 years, mean 73 months after transplantation) in total. The risk of mortality, 23% (95% CI: 21%-27%), and AKI, 50% (95% CI: 44%-56%), is high among KTR with COVID-19, regardless of sex, age and comorbidities, underlining the call to accelerate vaccination programs for KTR. Given the suboptimal reporting across the identified studies, we urge researchers to consistently report anthropometrics, kidney function at baseline and discharge, (changes in) immunosuppressive therapy, AKI, and renal outcome among KTR.
  3. Elevated plasma free thiols are associated with early and one-year graft function in renal transplant recipients
    PLoS ONE [Electronic Resource]. 2021;16(8):e0255930

    Study Details

    Aims: This post-hoc analysis of the randomised controlled CONTEXT trial examines whether higher levels of plasma free thiols as a marker of reduced oxidative stress is linked to better posttransplant outcomes.
    Interventions: Participants in the CONTEXT trial were randomised to either the remote ischaemic conditioning (RIC) group or the sham-RIC group.
    Participants: 217 kidney transplant patients who participated in the CONTEXT trial.
    Outcomes: Estimated time to a 50% reduction in plasma creatinine (tCr50), delayed graft function and measured glomerular filtration rate (mGFR).

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This post-hoc analysis of samples from the CONTEXT RCT investigates the correlation between plasma free thiols (a marker of oxidative stress) and post-transplant outcomes. The authors find that free thiol levels at day 1 and 5 correlate significantly with 12-month measured GFR. Whilst the correlations are significant, the R-squared values are fairly low (around 0.2) suggesting limited predictive performance. It is therefore unclear how useful this would be as a tool in clinical practice, or indeed how measurement would help guide clinical care of patients to improve outcomes.

    Abstract

    BACKGROUND Reduced free thiols in plasma are indicative of oxidative stress, which is an important contributor to ischaemia-reperfusion injury (IRI) in kidney transplantation leading to kidney damage and possibly delayed graft function (DGF). In a post-hoc, exploratory analysis of the randomised controlled CONTEXT trial, we investigated whether higher (i.e. less oxidised) plasma levels of free thiols as a biomarker of reduced oxidative stress are associated with a better initial graft function or a higher GFR. METHODS Free thiol levels were measured in plasma at baseline, 30 and 90 minutes after reperfusion of the kidney as well as at Day 1, Day 5 and twelve months after kidney transplantation in 217 patients from the CONTEXT study. Free thiol levels were compared to the kidney graft function measured as the estimated time to a 50% reduction in plasma creatinine (tCr50), the risk of DGF and measured GFR (mGFR) at Day 5 and twelve months after transplantation. RESULTS Higher levels of free thiols at Day 1 and Day 5 are associated with higher mGFR at Day 5 (p<0.001, r2adj. = 0.16; p<0.001, r2adj. = 0.25), as well as with mGFR at twelve months (p<0.001, r2adj. = 0.20; p<0.001, r2adj. = 0.16). However, plasma levels of free thiols at 30 minutes and 90 minutes, but not Day 1, were significantly higher among patients experiencing DGF. CONCLUSION Higher levels of plasma free thiols at Day 1 and Day 5, which are reflective of lower levels of oxidative stress, are associated with better early and late graft function in recipients of a kidney graft from deceased donors. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01395719.
  4. Randomized controlled trial of a quadratus lumborum block with liposomal bupivacaine for post-operative analgesia in laparoscopic donor nephrectomy
    Clinical Transplantation. 2021;[record in progress]

    Study Details

    Aims: This study aimed to investigate the effectiveness of a liposomal bupivacaine transmuscular quadratus lumborum (QL) block for post-operative analgesia in patients undergoing laparoscopic donor nephrectomy.
    Interventions: Participants were randomised to receive either standard care including transversus abdominus plane (TAP) block, or standard care plus quadratus lumborum (QL) block intraoperatively.
    Participants: 103 patients undergoing laparoscopic donor nephrectomy.
    Outcomes: The primary endpoints were postoperative pain scores. The secondary endpoints included requirement of pain medication, postoperative nausea and vomiting, satisfaction with pain management and complications related to QL block.

    CET Conclusion

    Reviewer: Centre for Evidence in Transplantation
    This single-centre study randomised patients undergoing laparoscopic living donor nephrectomy to either standard care (transversus abdominus (TA) block) or standard care plus quadratus lumborum (QL) block intraoperatively. Patients and outcome assessors were blinded, although surgeons were not. There was no difference in postoperative pain scores, nausea or length of stay between groups, although opioid use on day one was lower in the QL block group. Overall, these results suggest that QL block is safe in this patient cohort but may not add much benefit over a standard TA block. It is worth noting that 7 patients in the control group versus 1 patient in the study group did not receive ketorolac as per protocol. This was at the discretion of the surgeon, who was not blinded to treatment arm, suggesting possible bias that could have been avoided by using a placebo block in the control arm.

    Abstract

    Peri-operative pain management is an important consideration in early recovery and patient satisfaction following laparoscopic donor nephrectomy. Transmuscular quadratus lumborum block has been described to reduce pain and opioid usage following several abdominal surgeries. In this prospective single-blind randomized controlled trial, we compared 52 patients who adhered to our institutional donor nephrectomy Early Recovery After Surgery pathway, which includes a laparoscopic-guided transversus abdominus plane block, to 40 patients who additionally received a transmuscular quadratus lumborum block with liposomal bupivacaine. Compared to control patients, those who received the block spent longer in the operating room prior to the surgical start (65.4 vs. 51.6 minutes, p<0.001). Both groups had similar total hospital length of stay (33.3 hours vs. 34.4 hours, p = 0.61). Pain scores from post-operative days 0 to 30, number of patients requiring opioids, post-operative nausea, and pain management satisfaction were similar between both groups. Patients who received the block consumed less opioid on post-operative day 1 compared to controls (p = 0.006). No complications were attributable to the block. The quadratus lumborum block provides a safe pain management adjunct for some patients, and may reduce opioid use in the early post-operative period when combined with our standard institutional protocol for kidney donors. This article is protected by copyright. All rights reserved.

Liver


  1. Induction Therapy With Antithymocyte Globulin and Delayed Calcineurin Inhibitor Initiation for Renal Protection in Liver Transplantation: A Multicenter Randomized Controlled Phase II-B Trial
    Transplantation. 2021;[record in progress]

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This well-designed multicentre study investigated the use of ATG as a CNI-sparing agent immediately post liver transplant. Recipients were randomised to ATG induction with delayed tacrolimus initiation (to day 10) versus standard of care. The authors report that whilst there was a significantly lower rise in serum creatinine levels to month 9 post-op, this benefit was lost by month 12, and no significant difference in eGFR was seen at any timepoint. Despite a significant clinical benefit, use of ATG appeared safe, and rejection rates were similar between arms. In terms of study design, blinding would clearly have been desirable although not essential given the objective nature of the primary endpoint. Choice of serum creatinine as a primary endpoint, rather than eGFR, is suboptimal and the authors recognize this in their discussion. If you look closely at the figures, GFR loss over 12 months was 14 ml/min in the ATG group, and 20ml/min in the standard of care group. If replicated in a larger sample, and particularly if maintained over longer follow-up, this could be of clinical significance.

    Abstract

    BACKGROUND Calcineurin inhibitor (CNI) based immunosuppression in liver transplantation (LTx) is associated with acute and chronic deterioration of kidney function. Delaying CNI initiation by using induction rabbit anti-thymocyte globulin (rATG) may provide kidneys with adequate time to recover from a perioperative insult reducing the risk of early post-LTx renal deterioration. METHODS This was an open-label, multicenter, randomized controlled clinical trial comparing use of induction rATG with delayed CNI initiation (day-10) against upfront CNI commencement (SOC; standard of care) in those patients deemed at standard risk of postoperative renal dysfunction following LTx. The primary end point was change in (delta) creatinine from baseline to month-12. RESULTS Fifty-five patients were enrolled in each study arm. Mean Tacrolimus levels remained comparable in both groups from day-10 throughout the study period. A significant difference in delta creatinine was observed between rATG and SOC groups at 9-months (p=0.03) but not at month-12 (p=0.05). eGFR levels remained comparable between cohorts at all time points. Rates of biopsy-proven acute rejection at 1-year were similar between groups (16.3 vs 12.7%, p= 0.58). rATG showed no significant adverse effects. Survival at 12-months was comparable between groups (p= 0.48). CONCLUSIONS Although the use of induction rATG and concurrent CNI deferral in this study did not demonstrate a significant difference in delta creatinine at 1 year, these results indicate a potential role for rATG in preserving early kidney function, especially when considered with CNI deferral beyond 10 days and/or lower target Tacrolimus levels, with acceptable safety and treatment efficacy.
  2. A novel MSC-based immune induction strategy for ABO-incompatible liver transplantation: a phase I/II randomized, open-label, controlled trial
    Stem Cell Research & Therapy. 2021;12(1):244

    Study Details

    Aims: The aim of this study was to assess the feasibility and safety of using mesenchymal stem cells (MSCs) as a replacement for rituximab in ABO-incompatible liver transplantation (ABO-i LT).
    Interventions: Participants were randomised to either the rituximab group or the MSC group.
    Participants: 22 patients receiving ABO-incompatible liver transplantation.
    Outcomes: Primary outcomes included the assessment of MSC-related adverse events, incidence of antibody-mediated rejection (AMR) and acute cellular rejection (ACR). The secondary outcomes included graft survival and recipient survival, and the incidence of posttransplant complications (including biliary complications and specific infections).

    CET Conclusion

    Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This is a very interesting RCT in ABO incompatible liver transplantation. This high risk subgroup of liver transplantation may be required for patients in desperate need of a liver and comes with high risks of rejection, infection and hepatic artery thrombosis. In this study, the control drug for immune induction was rituximab and this was compared to mesenchymal stem cells (MSC) as the study intervention. The trial is randomised, but the method of randomisation is not fully described so we cannot be sure it was free from bias. Also, the study was open-label and this is another potential avenue for bias. The primary endpoint was the tolerability and safety of multidose MSC administration in this population and the therapy appears to be well tolerated from the results of this study. The trial is too small to be powered to assess the secondary outcomes fully; despite an apparently large reduction in acute rejection, it is not statistically significant. There was, however, a significant reduction in sepsis episodes with MSC compared to Rituximab, and also a significant reduction in biliary complications. These results need to be viewed in the context of an unblinded trial. This study does however provide an informative stepping stone towards a larger RCT to properly assess the comparative effects of MSC in ABO incompatible liver transplantation, and the authors have such a trial registered (ChiCTR2000037732).

    Abstract

    BACKGROUND ABO-incompatible liver transplantation (ABO-i LT) has become a rescue therapeutic option for patients with severe hepatic failure. Although the use of rituximab greatly reduces the morbidity of antibody-mediated rejection (AMR), severe adverse effects, such as infection and biliary complications, still seriously threaten the survival of transplant recipients. The aim of this study was to evaluate the safety and feasibility of using mesenchymal stem cells (MSCs) to replace rituximab in ABO-i LT. METHODS Twenty-two patients with severe hepatic failure undergoing ABO-i LT were enrolled and randomly divided into two groups: the MSC group and the rituximab group. The safety of the application of MSCs and the incidence of allograft rejection, including antibody-mediated rejection (AMR) and acute cellular rejection (ACR), were evaluated in both groups at the 2-year follow-up period as primary endpoints. Recipients and graft survival and other postoperative complications were compared as secondary endpoints. RESULTS No severe MSC-related adverse events were observed during the trial. MSC treatment yielded comparable, if not better, results than rituximab at decreasing the incidence of acute rejection (9.1% vs 27.3%). Inspiringly, compared to those in the rituximab group, the rates of biliary complications (0% vs 45.5%) and infection (9.1% vs 81.8%) were significantly decreased in the MSC group. In addition, there were no significant differences in 2-year graft and recipient survival between the two groups (81.8% vs 72.7%). CONCLUSIONS Our data show that MSC transfusion is comparable to rituximab treatment for AMR prophylaxis following ABO-i LT. Additionally, the results indicate that MSCs are more beneficial to the prevention of infection and biliary complications and may be introduced as a novel immunosuppressive approach for ABO-i LT. TRIAL REGISTRATION Trial registration: chictr.org.cn , ChiCTR2000037732. Registered 31 August 2020- Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=57074 .
  3. Renal Protective Effect of Everolimus in Liver Transplantation: A Prospective Randomized Open-Label Trial
    Transplantation Direct. 2021;7(7):e709

    Study Details

    Aims: This study aimed to compare the renal protective effect of everolimus (EVR) versus standard calcineurin inhibitor (CNI)-based immunosuppression in liver transplant recipients.
    Interventions: Participants were randomly assigned to either the EVR arm or the standard of care (SOC) arm.
    Participants: 24 liver transplant recipients.
    Outcomes: Primary outcome: renal function (assessed by 24-hour urine Cockcroft-Gault creatinine clearance (CrCl)). Secondary outcomes: CrCl, modification of diet in renal disease (MDRD), estimated glomerular filtration rate (eGFR), iothalamate clearance, 24-h urine protein, white blood cell count, absolute neutrophil count, and testosterone.

    CET Conclusion

    Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This is an RCT in liver transplantation examining the effect of using everolimus instead of CNI in terms of renal function. The study was small, with only 12 patients per arm, and a significant proportion (4/12) did not complete the follow up in the everolimus arm, one of whom had hepatic artery thrombosis (HAT). 105 patients were screened for the study and 93 were not suitable. Confusingly, the study was powered for a reduction in estimated GFR, but the primary outcome is described as difference in measured creatinine clearance with 24 hour urine sample. The results show a significantly improved serum creatinine and measured clearance at 24 months in the everolimus arm. However, this is based upon available data. The authors did make imputations for missing data and this is included in the supplemental digital content, showing similar outcomes. It is a highly selected population, and even then there were a concerning proportion of dropouts and with HAT in one case.

    Abstract

    Renal dysfunction is associated with poor long-term outcomes after liver transplantation. We examined the renal sparing effect of everolimus (EVR) compared to standard calcineurin inhibitor (CNI) immunosuppression with direct measurements of renal function over 24 months. Methods: This was a prospective, randomized, open-label trial comparing EVR and mycophenolic acid (MPA) with CNI and MPA immunosuppression. An Investigational New Drug Application (IND # 113882) was obtained with the Food and Drug Administration as EVR is only approved for use with low-dose tacrolimus. Serum creatinine, 24-hour urine creatinine clearance, iothalamate clearance, Cockcroft-Gault creatinine clearance (CrCl), and Modification of Diet in Renal Disease estimated glomerular filtration rate were prospectively measured at 4 study visits. Nonparametric statistical tests were used for analyses, including the Mann-Whitney U test for continuous outcomes and Pearson's chi-square test for binary outcomes. Effect size was measured using Cohen's d. Patients also completed quality of life surveys using the FACT-Hep instrument at each study visit. Comparison between the 2 groups was performed using the Student t test. Results: Each arm had 12 subjects; 4 patients dropped out in the EVR arm and 1 in the CNI arm by 24 months. Serum creatinine (P = 0.015), Modification of Diet in Renal Disease estimated glomerular filtration rate (P = 0.013), and 24-hour urine CrCL (P = 0.032) were significantly better at 24 months with EVR. Iothalamate clearance showed significant improvement at 12 months (P = 0.049) and a trend toward better renal function (P = 0.099) at 24 months. There was no statistical significance with Cockcroft-Gault CrCl. Adverse events were not significantly different between the 2 arms. The EVR group also showed significantly better physical, functional, and overall self-reported quality of life (P = 0.01) at 24 months. Conclusions: EVR with MPA resulted in significant long-term improvement in renal function and quality of life at 24 months after liver transplantation compared with standard CNI with MPA immunosuppression.
  4. Hypothermic Oxygenated Machine Perfusion (HOPE) Reduces Early Allograft Injury and Improves Post-Transplant Outcomes in Extended Criteria Donation (ECD) Liver Transplantation from Donation After Brain Death (DBD): Results from a Multicenter Randomized Controlled Trial (HOPE ECD-DBD)
    Annals of Surgery. 2021;[record in progress]

    Study Details

    Aims: This study aimed to investigate peak serum alanine aminotransferase (ALT) and postoperative clinical outcomes following hypothermic oxygenated machine perfusion (HOPE) compared to static cold storage (SCS) in extended criteria donation (ECD) after brain death (DBD) liver transplantation (LT).
    Interventions: Participants were randomised to either the HOPE group or the SCS group.
    Participants: 46 adult patients (>18 years) listed for LT and fulfilling the predefined ECD-criteria.
    Outcomes: The primary outcome was the difference in early allograft injury between the two treatment groups. The secondary outcomes were the incidence of post-transplant complications; further serum laboratory parameters; early allograft dysfunction (EAD); duration of intensive care unit (ICU) stay; duration of hospital stay; one-year patient and graft survival; and the analysis of serum, bile, tissue and perfusate biomarkers of ischemia-reperfusion injury (IRI).

    CET Conclusion

    Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This is a well conducted and well reported clinical trial in liver transplantation. Livers were randomised to static cold storage or to hypothermic oxygenation machine perfusion (HOPE). The study found clear evidence of reduced peak in AST in the first 7 days, by almost 50%. Preservation with HOPE was also associated with reduced hospital and ICU stay as well as reduced major complications. There was a trend towards improved early allograft dysfunction as well, but the study was underpowered to demonstrate this outcome, and in a larger study it may have been statistically significant. The study was conducted using extended criteria livers from DBD only, and potentially this allowed an effect to be demonstrated that may not be so apparent with standard criteria livers. Blinding of clinicians involved in the study was not feasible, which is understandable given the nature of the intervention. The study demonstrates significant clinical beneficial effects of HOPE in liver transplantation.

    Abstract

    OBJECTIVE To evaluate peak serum alanine aminotransferase (ALT) and postoperative clinical outcomes after hypothermic oxygenated machine perfusion (HOPE) versus static cold storage (SCS) in extended criteria donation (ECD) liver transplantation (LT) from donation after brain death (DBD). BACKGROUND HOPE might improve outcomes in LT, particularly in high-risk settings such as ECD organs after DBD, but this hypothesis has not yet been tested in a randomized controlled clinical trial (RCT). METHODS Between 09/2017-09/2020 46 patients undergoing ECD-DBD LT from four centers were randomly assigned to HOPE (n=23) or SCS (n=23). Peak-ALT levels within seven days following LT constituted the primary endpoint. Secondary endpoints included incidence of postoperative complications (Clavien-Dindo classification (CD), Comprehensive Complication Index (CCI)), length of intensive care- (ICU) and hospital-stay, and incidence of early allograft dysfunction (EAD). RESULTS Demographics were equally distributed between both groups (donor age: 72 [IQR:59-78] years, recipient age: 62 [IQR:55-65] years, labMELD: 15 [IQR:9-25], 38 male and 8 female recipients). HOPE resulted in a 47% decrease in serum peak ALT (418 [IQR: 221-828] vs. 796 [IQR:477-1195] IU/L, p=0.030), a significant reduction in 90-day complications (44% vs. 74% CD grade >=3, p=0.036; 32 [IQR:12-56] vs. 52 [IQR:35-98] CCI, p=0.021), and shorter ICU- and hospital-stays (5 [IQR:4-8] vs. 8 [IQR:5-18] days, p=0.045; 20 [IQR:16-27] vs. 36 [IQR:23-62] days, p=0.002) compared to SCS. A trend towards reduced EAD was observed for HOPE (17% vs. 35%; p=0.314). CONCLUSION This multicenter RCT demonstrates that HOPE, in comparison to SCS, significantly reduces early allograft injury and improves post-transplant outcomes in ECD-DBD liver transplantation.

Various


  1. Simultaneous pancreas and kidney transplantation for end-stage kidney disease patients with type 2 diabetes mellitus: a systematic review and meta-analysis
    Langenbecks Archives of Surgery. 2021;[record in progress]

    Study Details

    Aims: The aim of this study was to investigate the survival outcomes of simultaneous pancreas and kidney transplantation (SPK) among end‑stage kidney disease patients (ESKD) with type 2 diabetes mellitus (T2DM).
    Interventions: A literature search was conducted on MEDLINE, PubMed, EMBASE, Cochrane CENTRAL, Chinese Biomedical Literature Database, China National Knowledge Infrastructure (CNKI), and the Wan-Fang database. Study selection and data extraction were performed by two independent reviewers. The risk of bias was assessed using the Newcastle–Ottawa Scale (NOS).
    Participants: 16 studies were included in the review.
    Outcomes: Primary outcomes were graft survival and patient survival. Secondary outcomes included hazard ratio of patient survival, graft survival and post-transplant complications for type 1 diabetes mellitus (T1DM) versus T2DM, and for SPK versus kidney transplant alone (KTA) among T2DM patients.

    CET Conclusion

    Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
    This is a well written and well conducted systematic review. Multiple databases were searched and references were filtered in duplicate by 2 authors. Data extraction was also completed in duplicate. All included studies were retrospective cohort studies, and were appropriately and formally assessed using the Newcastle Ottawa Scale. Meta-analysis was done to estimate combined outcomes for survival outcomes and complication rates. Sensitivity analysis was done to search for sources of heterogeneity and in one case identified a single study with short follow up that explained this. Despite the Type 2 diabetes patients tending to be older and larger BMI, the patient and graft outcomes following SPK transplant were similar compared to patients with Type1 diabetes. A key limitation of this review is the lack of defined complications in pancreas transplantation that hampers data synthesis across studies. The key analysis of interest in this paper is SPK in Type 2 diabetes compared to kidney transplant alone. Unfortunately, this is a highly selected population and the possibility for bias is very high. In this analysis, SPK in Type 2 diabetes was associated with improved kidney graft and patient survival compared to kidney transplant alone. This should be viewed with caution as it is based upon 4 cohort studies and these need to be analysed independently to find out what population specifics there are for the patients with Type 2 diabetes undergoing SPK.

    Abstract

    PURPOSE The indications for patients with type 2 diabetes mellitus (T2DM) combined with end-stage kidney disease (ESKD) undertaking simultaneous pancreas and kidney transplantation (SPK) remain an unresolved issue. This study aimed to systematically review the survival outcomes of SPK among T2DM-ESKD patients. METHODS Online databases including PubMed, MEDLINE, EMBASE, and the CENTRAL Library, CNKI, Chinese Biomedical Literature Database, and Wan-Fang database were used to locate the studies of ESKD patients with T2DM undertaking SPK up to May 2021. A third reviewer was consulted if there were disagreements. Data were analyzed with STATA (15.0). RESULTS Nine cohort studies were identified. The pooled 1-year, 3-year, and 5-year patient survival rates of patients with T2DM and ESKD after SPK were 98%, 95%, and 91% respectively. Comparing the treatment effect of SPK between type 1 diabetes mellitus (T1DM) and T2DM, the survival estimates were comparable. For T2DM patients, SPK had a survival advantage compared with KTA. CONCLUSIONS The synthesized clinical outcomes of T2DM patients with ESKD after SPK were relatively better than KTA, but a subset of T2DM-ESKD patients who would benefit the most from SPK was to be defined. PROSPERO registration number CRD42019118321. Date of registration: 14 Jan 2019 (retrospectively registered).