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See all 64 Highlighted Expert Reviews articles matching your criteria
  • Torri F
  • Balzano E
  • Melandro F
  • Maremmani P
  • Bertini P
  • et al.

In Italy, 20 min of continuous, flat-line electrocardiogram are required for death declaration. Despite prolonged warm ischemia time, Italian centers reported good outcomes in controlled donation after circulatory death (cDCD) liver transplantation by combining normothermic regional and end-ischemic machine perfusion (MP). The aim of this study was to evaluate the safety and feasibility of the use of septuagenarian and octogenarian cDCD donors with this approach.


All cDCD older than 70 y were evaluated during normothermic regional perfusion and then randomly assigned to dual hypothermic or normothermic MP.


In the period from April 2021 to December 2022, 17 cDCD older than 70 y were considered. In 6 cases (35%), the graft was not considered suitable for liver transplantation, whereas 11 (65%) were evaluated and eventually transplanted. The median donor age was 82 y, being 8 (73%) older than 80. Median functional warm ischemia and no-flow time were 36 and 28 min, respectively. Grafts were randomly assigned to ex situ dual hypothermic oxygenated MP in 6 cases (55%) and normothermic MP in 5 (45%). None was discarded during MP. There were no cases of primary nonfunction, 1 case of postreperfusion syndrome (9%) and 2 cases (18%) of early allograft dysfunction. At a median follow-up of 8 mo, no vascular complications or ischemic cholangiopathy were reported. No major differences were found in terms of postoperative hospitalization or complications based on the type of MP.


The implementation of sequential normothermic regional and end-ischemic MP allows the safe use of very old donation after circulatory death donors.

  • Czigany Z
  • Putri AJ
  • Michalski CW
  • Mehrabi A
Hepatology. 2024 Mar 5; doi: 10.1097/HEP.0000000000000811.
  • Quick BL
  • Chung M
  • Morrow E
  • Reynolds-Tylus T
J Health Commun. 2024 Mar 3;29(3):200-210 doi: 10.1080/10810730.2024.2313988.

Concerns related to bodily integrity, medical mistrust, superstition, and disgust with respect to organ transplantation remain commonly cited barriers among African American, Caucasian, and Hispanic non-donors. The current study examined two narrative strategies for mitigating these barriers by eliciting feelings of happiness or sadness. African American, Caucasian, and Hispanic non-donors (N = 576) were randomly assigned to a radio ad that communicated either a recipient narrative or a waiting list narrative. As expected, the recipient narrative elicited greater feelings of happiness whereas the waiting list narrative aroused greater feelings of sadness. Moderated mediation analyses revealed models in which happiness, not sadness, was the mediator, such that the narrative frame was associated with ad persuasiveness. Additionally, only medical mistrust interacted with happiness to predict ad persuasiveness The results are discussed with an emphasis on message design strategies to employ among reluctant adult African American, Caucasian, and Hispanic potential donors.

  • Peng S
  • Liang W
  • Liu Z
  • Ye S
  • Peng Z
  • et al.
Hum Cell. 2024 Mar;37(2):420-434 doi: 10.1007/s13577-023-01012-3.

Hypothermic machine perfusion (HMP) has been demonstrated to be more effective in mitigating ischemia-reperfusion injury (IRI) of donation after circulatory death (DCD) organs than cold storage (CS), yet the underlying mechanism remains obscure. We aimed to propose a novel therapeutic approach to ameliorate IRI in DCD liver transplantation. Twelve clinical liver samples were randomly assigned to HMP or CS treatment and subsequent transcriptomics analysis was performed. By combining in vivo HMP models, we discovered that HMP attenuated inflammation, oxidative stress, and apoptosis in DCD liver through a SEPRINA3-mediated PI3Kδ/AKT signaling cascade. Moreover, in the hypoxia/reoxygenation (H/R) model of BRL-3A, overexpression of SERPINA3 mitigated H/R-induced apoptosis, while SERPINA3 knockdown exacerbated cell injury. Idelalisib (IDE) treatment also reversed the protective effect of SERPINA3 overexpression. Overall, our research provided new insights into therapeutic strategies and identified potential novel molecular targets for therapeutic intervention against DCD liver.

  • Patel MS
  • Salcedo-Betancourt JD
  • Saunders C
  • Broglio K
  • Malinoski D
  • et al.
JAMA Netw Open. 2024 Feb 5;7(2):e2353785 doi: 10.1001/jamanetworkopen.2023.53785.

Delayed graft function in kidney-transplant recipients is associated with increased financial cost and patient burden. In donors with high Kidney Donor Profile Index whose kidneys are not pumped, therapeutic hypothermia has been shown to confer a protective benefit against delayed graft function.


To determine whether hypothermia is superior to normothermia in preventing delayed graft function in low-risk nonpumped kidney donors after brain death.


In a multicenter randomized clinical trial, brain-dead kidney donors deemed to be low risk and not requiring machine perfusion per Organ Procurement Organization protocol were prospectively randomized to hypothermia (34.0-35 °C) or normothermia (36.5-37.5 °C) between August 10, 2017, and May 21, 2020, across 4 Organ Procurement Organizations in the US (Arizona, Upper Midwest, Pacific Northwest, and Texas). The final analysis report is dated June 15, 2022, based on the data set received from the United Network for Organ Sharing on June 2, 2021. A total of 509 donors (normothermia: n = 245 and hypothermia: n = 236; 1017 kidneys) met inclusion criteria over the study period.


Donor hypothermia (34.0-35.0 °C) or normothermia (36.5-37.5 °C).


The primary outcome was delayed graft function in the kidney recipients, defined as the need for dialysis within the first week following kidney transplant. The primary analysis follows the intent-to-treat principle.


A total of 934 kidneys were transplanted from 481 donors, of which 474 were randomized to the normothermia group and 460 to the hypothermia group. Donor characteristics were similar between the groups, with overall mean (SD) donor age 34.2 (11.1) years, and the mean donor creatinine level at enrollment of 1.03 (0.53) mg/dL. There was a predominance of Standard Criteria Donors (98% in each treatment arm) with similar low mean (SD) Kidney Donor Profile Index (normothermia: 28.99 [20.46] vs hypothermia: 28.32 [21.9]). Cold ischemia time was similar in the normothermia and hypothermia groups (15.99 [7.9] vs 15.45 [7.63] hours). Delayed graft function developed in 87 of the recipients (18%) in the normothermia group vs 79 (17%) in the hypothermia group (adjusted odds ratio, 0.92; 95% CI, 0.64-1.33; P = .66).


The findings of this study suggest that, in low-risk non-pumped kidneys from brain-dead kidney donors, therapeutic hypothermia compared with normothermia does not appear to prevent delayed graft function in kidney transplant recipients.


ClinicalTrials.gov Identifier: NCT02525510.

  • Czigany Z
  • Uluk D
  • Pavicevic S
  • Lurje I
  • Froněk J
  • et al.
Hepatol Commun. 2024 Feb 3;8(2) doi: 10.1097/HC9.0000000000000376.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This manuscript reports long-term (48 month) outcomes from the HOPE-ECD-DBD trial, which compared end-ischaemic HOPE with static cold storage in extended criteria DBD livers. The authors report a reduction in late onset complications in the HOPE group with superior graft survival mainly due to a reduction in deaths with a functioning graft. Whilst numbers in the original study were small (23 in each arm) follow-up was complete for all participants still alive. Whilst the overall complication rate was higher in the SCS arm, it is not entirely clear what the main cause of complications was – no individual complication had significantly higher rates, and notably there was no difference in the rate of biliary complications. Ultimately the small sample size and secondary nature of the analysis mean that conclusions are limited due to lack of power, but the paper certainly shows the importance of long-term follow-up when assessing preservation strategies.
Aims: This study aimed to report the long-term outcomes of the HOPE-ECD-DBD randomised controlled trial, which investigated the effect of hypothermic oxygenated machine perfusion (HOPE) versus static cold storage (SCS) in patients who underwent liver transplantation using extended criteria donor-donation after brain death (ECD-DBD) allografts.
Interventions: Participants in the original trial were randomised to either the HOPE group or the SCS group.
Participants: 46 liver transplant recipients that received extended criteria donor donation after brain death allografts.
Outcomes: The main outcomes of interest were incidence of late-onset morbidity, readmissions, long-term graft survival, and patient survival.
Follow Up: 48 months (median)

While 4 randomized controlled clinical trials confirmed the early benefits of hypothermic oxygenated machine perfusion (HOPE), high-level evidence regarding long-term clinical outcomes is lacking. The aim of this follow-up study from the HOPE-ECD-DBD trial was to compare long-term outcomes in patients who underwent liver transplantation using extended criteria donor allografts from donation after brain death (ECD-DBD), randomized to either HOPE or static cold storage (SCS).


Between September 2017 and September 2020, recipients of liver transplantation from 4 European centers receiving extended criteria donor-donation after brain death allografts were randomly assigned to HOPE or SCS (1:1). Follow-up data were available for all patients. Analyzed endpoints included the incidence of late-onset complications (occurring later than 6 months and graded according to the Clavien-Dindo Classification and the Comprehensive Complication Index) and long-term graft survival and patient survival.


A total of 46 patients were randomized, 23 in both arms. The median follow-up was 48 months (95% CI: 41-55). After excluding early perioperative morbidity, a significant reduction in late-onset morbidity was observed in the HOPE group (median reduction of 23 Comprehensive Complication Index-points [p=0.003] and lower incidence of major complications [Clavien-Dindo ≥3, 43% vs. 85%, p=0.009]). Primary graft loss occurred in 13 patients (HOPE n=3 vs. SCS n=10), resulting in a significantly lower overall graft survival (p=0.029) and adverse 1-, 3-, and 5-year survival probabilities in the SCS group, which did not reach the level of significance (HOPE 0.913, 0.869, 0.869 vs. SCS 0.783, 0.606, 0.519, respectively).


Our exploratory findings indicate that HOPE reduces late-onset morbidity and improves long-term graft survival providing clinical evidence to further support the broad implementation of HOPE in human liver transplantation.

  • Klein A
  • Toll A
  • Stewart D
  • Fitzsimmons WE
Am J Transplant. 2024 Feb;24(2):250-259 doi: 10.1016/j.ajt.2023.09.019.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This interesting study evaluates the use of real-world registry data as a control cohort, combined with propensity matching, for evaluation of long-term outcomes in a clinical trial. The authors use the BENEFIT study as an example, comparing outcomes from the belatacept and original control arms to two registry-based arms – cyclosporine-treated controls, and a tacrolimus-based control group. They demonstrate that the registry-based controls have very similar 5-year graft survival to the original control cohort, resulting in similar conclusions to the original trial. Registry-based approaches to clinical trials may help to make trials more efficient, particularly when the patient cohort is rare or long-term follow-up is required. There are some obvious limitations – outcomes are limited to those included in the registry data, and in order to apply study inclusion/exclusion criteria to the registry cohort, the criteria must be reliably recorded in the registry. A natural extension to this approach may be use of synthetic data, which would circumvent some of the data privacy concerns of using real patient data.
Aims: The aim of this study was to test the feasibility and value of using real-world registry data as a control cohort to compare drug treatment effects to those observed in the BENEFIT study.
Interventions: Participants in the BENEFIT study were randomised to receive either more intensive or less intensive regimens of BELA-based immunosuppressive therapy, or to cyclosporine.
Participants: 1443 kidney transplant recipients.
Outcomes: The main outcomes of interest were covariate-adjusted overall and death-censored graft survival and patient survival at 3- and 5-years posttransplant.
Follow Up: 5 years posttransplantation

To address the challenges of assessing the impact of a reasonably likely surrogate endpoint on long-term graft survival in prospective kidney transplant clinical trials, the Transplant Therapeutics Consortium established a real-world evidence workgroup evaluating the scientific value of using transplant registry data as an external control to supplement the internal control group. The United Network for Organ Sharing retrospectively simulated the use of several distinct contemporaneous external control groups, applied multiple cause inference methods, and compared treatment effects to those observed in the BENEFIT study. Applying BENEFIT study enrollment criteria produced a smaller historical cyclosporine control arm (n = 153) and a larger, alternative (tacrolimus) historical control arm (n = 1069). Following covariate-balanced propensity scoring, Kaplan-Meier 5-year all-cause graft survivals were 81.3% and 81.7% in the Organ Procurement and Transplantation Network (OPTN) tacrolimus and cyclosporine external control arms, similar to 80.3% observed in the BENEFIT cyclosporine treatment arm. Five-year graft survival in the belatacept-less intensive arm was significantly higher than the OPTN controls using propensity scoring for comparing cyclosporine and tacrolimus. Propensity weighting using OPTN controls closely mirrored the BENEFIT study's long-term control (cyclosporine) arm's survival rate and the less intensive arm's treatment effect (significantly higher survival vs control). This study supports the feasibility and validity of using supplemental external registry controls for long-term survival in kidney transplant clinical trials.

  • Brouckaert J
  • Dellgren G
  • Wallinder A
  • Rega F
BMJ Open. 2023 Dec 28;13(12):e073729 doi: 10.1136/bmjopen-2023-073729.

Ischaemic cold static storage (ICSS) is the gold standard in donor heart preservation. This ischaemic time frame renders a time constraint and risk for primary graft dysfunction. Cold oxygenated heart perfusion, known as non-ischaemic heart preservation (NIHP), theoretically limits the ischaemic time, while holding on to the known advantage of hypothermia and cardioplegia, a low metabolic rate.


The NIHP 2019 study is an international, randomised, controlled, open, multicentre clinical trial in 15 heart transplantation centres in 8 European countries and includes 202 patients undergoing heart transplantation, allocated 1:1 to NIHP or ICSS. Enrolment is estimated to be 30 months after study initiation. The patients are followed for 12 months after transplantation.The primary objective is to evaluate the effect of NIHP on survival, allograft function and rejection episodes within the first 30 days after transplantation. The secondary objectives are to compare treatment groups with respect to survival, allograft function, cardiac biomarkers, rejection episodes, allograft vasculopathy, adverse events and adverse device effects within 12 months.


This protocol was approved by the Ethics Committee (EC) for Research UZ/KU Leuven, Belgium, the coordinating EC in Germany (Bei Der LMU München), the coordinating EC in the UK (West Midlands-South Birmingham Research), the EC of Hospital Puerta de Hierro, Madrid, Spain, the EC of Göteborg, Sweden, the coordinating EC in France, the EC of Padova, Italy and the EC of the University of Vienna, Austria. This study will be conducted in accordance with current local regulations and international applicable regulatory requirements according to the principles of the Declaration of Helsinki and ISO14155:2020. Main primary and secondary outcomes will be published on modified intention-to-treat population and per-protocol population.



  • Gajate L
  • de la Hoz I
  • Espiño M
  • Martin Gonzalez MDC
  • Fernandez Martin C
  • et al.
JMIR Res Protoc. 2023 Dec 15;12:e50091 doi: 10.2196/50091.

Liver transplantation is the last therapeutic option for patients with end-stage liver disease. Postreperfusion syndrome (PRS), defined as a fall in mean arterial pressure of more than 30% within the first 5 minutes after reperfusion of at least 1 minute, can occur in liver transplantation as a deep hemodynamic instability with associated hyperfibrinolysis immediately after reperfusion of the new graft. Its incidence has remained unchanged since it was first described in 1987. PRS is related to ischemia-reperfusion (I/R) injury, whose pathophysiology involves the release of several mediators from both the donor and the recipient. The antioxidant effect of ascorbic acid has been studied in resuscitating patients with septic shock and burns. Even today, there are publications with conflicting results, and there is a need for further studies to confirm or rule out the usefulness of this drug in this group of patients. The addition of ascorbic acid to preservation solutions used in solid organ transplantation is under investigation to harness its antioxidant effect and mitigate I/R injury. Since PRS could be considered a manifestation of I/R injury, we believe that the possible beneficial effect of ascorbic acid on the occurrence of PRS should be investigated.


The aim of this randomized controlled trial is to assess the benefits of ascorbic acid over saline in the development of PRS in adult liver transplantation.


We plan to conduct a single-center randomized controlled trial at the Hospital Universitario Ramón y Cajal in Spain. A total of 70 participants aged 18 years or older undergoing liver transplantation will be randomized to receive either ascorbic acid or saline. The primary outcome will be the difference between groups in the incidence of PRS. The randomized controlled trial will be conducted under conditions of respect for fundamental human rights and ethical principles governing biomedical research involving human participants and in accordance with the international recommendations contained in the Declaration of Helsinki and its subsequent revisions.


The enrollment process began in 2020. A total of 35 patients have been recruited so far. Data cleaning and analysis are expected to occur in the first months of 2024. Results are expected around the middle of 2024.


We believe that this study could be particularly relevant because it will be the first to analyze the clinical effect of ascorbic acid in liver transplantation. Moreover, we believe that this study fills an important gap in the knowledge of the potential benefits of ascorbic acid in the field of liver transplantation, particularly in relation to PRS.


European Union Drug Regulating Authorities Clinical Trials Database 2020-000123-39; https://tinyurl.com/2cfzddw8; ClinicalTrials.gov NCT05754242; https://tinyurl.com/346vw7sm.



  • Panayotova GG
  • Lunsford KE
  • Quillin RC
  • Rana A
  • Agopian VG
  • et al.
Hepatology. 2023 Dec 13; doi: 10.1097/HEP.0000000000000715.
CET Conclusion
Reviewer: Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This large open labelled multi-centre randomised control trial is an exciting development in the field of liver HMP. The key strength of this work is that 43% (n=27) of the HMP-O2 livers had continuous perfusion, having been placed on device at the donor. This is the first trial in liver HMP to do this and is an important development. Made possible by Organ Recovery Systems portable Lifeport Liver device, especially considering 81% travelled by air, a current limitation of the portable NMP devices. They demonstrated a nonsignificant reduction in EAD with 11% in HMP-O2 and 16% in SCS, while the finding is not significant it is in keeping with the 5 other published RCTs on HMP liver. The lack of significance may derive from the fact that within the intervention group only 24% were ECDs (including 5 DCD), upon sub-group analysis of these ECDs they find the reduction of EAD to be significant (20% in HMP-O2 and 33.3% in SCS p=0.004). This is in keeping with previous large RCTs that the beneficial effects of HMP-O2 are amplified in the ECD cohort, especially in DCDs seen in Rijn et al’s 2021 trial published in the New England Journal who perfused only DCD livers. None of their secondary outcomes reach significance, but with PNF only occurring in the SCS group with 3 patients and a further 2 (n=5 6.8%) went on to require re-transplant also due to ischaemic cholangiopathy. In HMP-O2 only 1 required retransplant, this was due to HAT. Biliary complications were nearly double in the SCS group (26.4% vs 12.7%) which is impressive, but again this failed to reach significance. The trends are encouraging, but the lack of significance is disappointing, the trial having not been powered for overall EAD rates. An increase cohort size and a focus on EADs could have led to more dramatic results with potentially significance in many of the outcomes. An interesting note is the preservation fluid used in HMP-O2 was Vasosol, a UW-like solution with the addition of nitric oxide donors and vasodilators, this is the first HMP RCT across all organs to utilise this solution and could, in part be responsible for some of the beneficial trends. Unfortunately, the study was not sufficiently powered to compare continuous HMP-O2 with end-ischaemic HMP-O2 and SCS, the overall storage duration being comparable, but the percentage of that time being perfusion obviously being highest in the continuous group. They demonstrate safety and non-inferior efficacy of a novel portable device, which as it becomes more popular and people become more familiar with placing livers on device at retrieval more data should emerge on continuous HMP-O2, this trial was an important step.
Aims: To assess if HMP-O2 improves liver transplant outcomes compare to cold storage.
Interventions: Livers were randomised to intervention, which was HMP-O2 on the Lifeport Liver Transporter device, perfused with Vasosol, or control, which was static cold storage.
Participants: 179 adult whole liver transplant recipients.
Outcomes: The primary outcome was early allograft dysfunction (EAD) as defined by the Olthoff criteria. Secondary outcome measures were PNF, AKI, graft survival, biliary complications. Vascular complications and death. Additional exploratory outcomes were hospital LOS, ICU LOS, lactate clearance, bleeding, incisional hernia and SAEs.
Follow Up: 12 months

In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic oxygenated machine perfusion (HMP-O 2 ) has shown benefits compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O 2 device in the first US randomized control trial.


The PILOT trial (NCT03484455) was a multicenter, randomized, open-label, noninferiority trial, with participants randomized to HMP-O 2 or SCS. HMP-O 2 livers were preserved using the Lifeport Liver Transporter and Vasosol perfusion solution. The primary outcome was early allograft dysfunction. Noninferiority margin was 7.5%. From April 3, 2019, to July 12, 2022, 179 patients were randomized to HMP-O 2 (n=90) or SCS (n=89). The per-protocol cohort included 63 HMP-O 2 and 73 SCS. Early allograft dysfunction occurred in 11.1% HMP-O 2 (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O 2 and SCS was -5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. The risk of graft failure as predicted by Liver Graft Assessment Following Transplant score at seven days (L-GrAFT 7 ) was lower with HMP-O 2 [median (IQR) 3.4% (2.4-6.5) vs. 4.5% (2.9-9.4), p =0.024]. Primary nonfunction occurred in 2.2% of all SCS (n=3, p =0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O 2 ( p =0.18). Nonanastomotic biliary strictures occurred only in SCS (n=4).


HMP-O 2 demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. Early allograft failure by L-GrAFT 7 was lower in HMP-O 2 , suggesting improved early clinical function. Recipients of HMP-O 2 livers also demonstrated a lower incidence of primary nonfunction and biliary strictures, although this difference did not reach significance.