Ann Surg. 2023 Nov 1;278(5):e912-e921 doi: 10.1097/SLA.0000000000005934.
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J Hepatol. 2023 Aug;79(2):394-402 doi: 10.1016/j.jhep.2023.04.010.
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Am J Transplant. 2022 Oct;22(10):2401-2408 doi: 10.1111/ajt.17115.
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Transplantation. 2024 Mar 12; doi: 10.1097/TP.0000000000004963.
BACKGROUND:
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. METHODS:All cDCD older than 70 y were evaluated during normothermic regional perfusion and then randomly assigned to dual hypothermic or normothermic MP. RESULTS: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. CONCLUSIONS:The implementation of sequential normothermic regional and end-ischemic MP allows the safe use of very old donation after circulatory death donors. |
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Hepatology. 2024 Mar 5; doi: 10.1097/HEP.0000000000000811.
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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. |
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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. |
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JAMA Netw Open. 2024 Feb 5;7(2):e2353785 doi: 10.1001/jamanetworkopen.2023.53785.
IMPORTANCE:
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. OBJECTIVE:To determine whether hypothermia is superior to normothermia in preventing delayed graft function in low-risk nonpumped kidney donors after brain death. DESIGN, SETTING, AND PARTICIPANTS: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. INTERVENTION:Donor hypothermia (34.0-35.0 °C) or normothermia (36.5-37.5 °C). MAIN OUTCOMES AND MEASURES: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. RESULTS: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). CONCLUSIONS AND RELEVANCE: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. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02525510. |
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Hepatol Commun. 2024 Feb 3;8(2) doi: 10.1097/HC9.0000000000000376.
CET Conclusion
BACKGROUND:
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). METHODS: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. RESULTS: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). CONCLUSIONS: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. |
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Am J Transplant. 2024 Feb;24(2):250-259 doi: 10.1016/j.ajt.2023.09.019.
CET Conclusion
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. |
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BMJ Open. 2023 Dec 28;13(12):e073729 doi: 10.1136/bmjopen-2023-073729.
INTRODUCTION:
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. METHODS AND ANALYSIS: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. ETHICS AND DISSEMINATION: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. TRIAL REGISTRATION NUMBER:NCT03991923. |
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JMIR Res Protoc. 2023 Dec 15;12:e50091 doi: 10.2196/50091.
BACKGROUND:
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. OBJECTIVE: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. METHODS: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. RESULTS: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. CONCLUSIONS: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. TRIAL REGISTRATION:European Union Drug Regulating Authorities Clinical Trials Database 2020-000123-39; https://tinyurl.com/2cfzddw8; ClinicalTrials.gov NCT05754242; https://tinyurl.com/346vw7sm. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):DERR1-10.2196/50091. |
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Hepatology. 2023 Dec 13; doi: 10.1097/HEP.0000000000000715.
CET Conclusion
BACKGROUND AND AIMS:
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. APPROACH AND RESULTS: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). CONCLUSIONS: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. |