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Mass Spectrometry Based Metabolomics Comparison of Liver Grafts from Donors after Circulatory Death (DCD) and Donors after Brain Death (DBD) Used in Human Orthotopic Liver Transplantation.

ABSTRACT: Use of marginal liver grafts, especially those from donors after circulatory death (DCD), has been considered as a solution to organ shortage. Inferior outcomes have been attributed to donor warm ischaemic damage in these DCD organs. Here we sought to profile the metabolic mechanisms underpinning donor warm ischaemia. Non-targeted Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry metabolomics was applied to biopsies of liver grafts from donors after brain death (DBD; n = 27) and DCD (n = 10), both during static cold storage (T1) as well as post-reperfusion (T2). Furthermore 6 biopsies from DBD donors prior to the organ donation (T0) were also profiled. Considering DBD and DCD together, significant metabolic differences were discovered between T1 and T2 (688 peaks) that were primarily related to amino acid metabolism, meanwhile T0 biopsies grouped together with T2, denoting the distinctively different metabolic activity of the perfused state. Major metabolic differences were discovered between DCD and DBD during cold-phase (T1) primarily related to glucose, tryptophan and kynurenine metabolism, and in the post-reperfusion phase (T2) related to amino acid and glutathione metabolism. We propose tryptophan/kynurenine and S-adenosylmethionine as possible biomarkers for the previously established higher graft failure of DCD livers, and conclude that the associated pathways should be targeted in more exhaustive and quantitative investigations.

SUBMITTER: Hrydziuszko O

PROVIDER: S-EPMC5105997 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Controlled donation after circulatory death (cDCD) is a major source of organs for transplantation. A potential cDCD donor poses considerable challenges in terms of identification of those dying within the predefined time frame of warm ischemia after withdrawal of life-sustaining treatment (WLST) to circulatory arrest. Several attempts have been made to develop models predicting the time between treatment withdrawal and circulatory arrest. This time window determines whether organ donation can occur and influences the quality of the donated organs. However, the selected patients used for these models were not always restricted to potential cDCD donors (eg, patients with cancer or severe infections were also included). This severely limits the generalizability of those data. OBJECTIVE:The objectives of this study are the following: (1) to develop a model predicting time to death within 60 minutes in potential cDCD patients; (2) to validate and update previous prediction models on time to death after WLST; (3) to determine timing and patient characteristics that are associated with prognostication and the decision-making process that leads to initiating end-of-life care; (4) to evaluate the impact of timing of family approach on organ donation approval; and (5) to assess the influence of variation in WLST processes on postmortem organ donor potential and actual postmortem organ donors. METHODS:In this multicenter observational prospective cohort study, all patients admitted to the intensive care unit of 3 university hospitals and 3 teaching hospitals who met the criteria of the cDCD protocol as defined by the Dutch Transplant Foundation were included. The target of enrolment was set to 400 patients. Previously developed models will be refitted in our data set. To further update previous prediction models, we will apply least absolute shrinkage and selection operator (LASSO) as a tool for efficient variable selection to develop the multivariable logistic regression model. RESULTS:This protocol was funded in August 2014 by the Dutch Transplant Foundation. We expect to have the results of this study in July 2020. Patient enrolment was completed in July 2018 and data collection was completed in April 2020. CONCLUSIONS:This study will provide a robust multimodal prediction model, based on clinical and physiological parameters, that can predict time to circulatory arrest in cDCD donors. In addition, it will add valuable insight in the process of WLST in cDCD donors and will fill an important knowledge gap in this essential field of health care. TRIAL REGISTRATION:ClinicalTrials.gov NCT04123275; https://clinicaltrials.gov/ct2/show/NCT04123275. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):DERR1-10.2196/16733.

Project description:BackgroundNormothermic machine perfusion (NMP) of liver grafts donated after circulatory death (DCD) has shown promise in large animal and clinical trials. Following procurement, initial flush with a cold preservation solution is the standard of care. There is concern that initial cooling followed by warming may exacerbate liver injury, and the optimal initial flush temperature has yet to be identified. We hypothesize that avoidance of the initial cold flush will yield better quality liver grafts.MethodsTwenty-four anaesthetized pigs were withdrawn from mechanical ventilation and allowed to arrest. After 60-minutes of warm ischemia to simulate a DCD procurement, livers were flushed with histidine-tryptophan-ketoglutarate (HTK) at 4°C, 25°C or 35°C (n = 4 per group). For comparison, an adenosine-lidocaine crystalloid solution (AD), shown to have benefit at warm temperatures in heart perfusions, was also used (n = 4 per group). During 12-hours of NMP, adenosine triphosphate (ATP), lactate, transaminase levels, and histological injury were determined. Bile production and hemodynamics were monitored continuously.ResultsATP levels recovered substantially following 1-hour of NMP reaching pre-ischemic levels by the end of NMP with no difference between groups. There was no difference in peak aspartate aminotransferase (AST) or in lactate dehydrogenase (LDH). Portal vein resistance was lowest in the 4°C group reaching significance after 2 hours (0.13 CI -0.01,0.277, p = 0.025). Lactate levels recovered promptly with no difference between groups. Comparison to AD groups showed no statistical difference in the abovementioned parameters. On electron microscopy the HTK4°C group had the least edema with mean cell thickness of 2.92μm (p = 0.41) while also having the least sinusoidal dilatation with a mean diameter of 5.36μm (p = 0.04). For AD, the 25°C group had the lowest mean cell thickness at 3.14μm (p = 0.09).ConclusionsAvoidance of the initial cold flush failed to demonstrate added benefit over standard 4°C HTK in this DCD model of liver perfusion.

Project description:There are limited data on liver transplant (LT) outcomes with grafts from super obese donors. The present study aims to evaluate a unique cohort of recipients following LT using grafts from donors with body mass index (BMI) ≥50.MethodsPatients receiving grafts from donors with BMI ≥50 and BMI <50 from 2010 to 2019 were identified. A 1:2 case-control match was conducted to compare outcomes between the groups. Survival was analyzed using the Kaplan-Meier curves.ResultsSix hundred sixty-five adult LTs were performed in the study period. Eighteen patients receiving a graft from a donor with BMI ≥50 were identified and matched to 36 patients receiving a graft from a donor with BMI <50. Grafts from male donors were significantly lower in the donor BMI ≥50 group when compared with the donor BMI <50 group (16.7% versus 66.7%, P = 0.001). Liver biopsy was performed in 77.8% of grafts in the donor BMI ≥50 group, whereas only in 38.8% of the grafts in the donor BMI <50 group (P = 0.007). Recipients in the donor BMI ≥50 group had a significantly higher diagnosis rate of hepatocellular carcinoma pretransplant versus the donor BMI <50 group (38.9% versus 8.3%, respectively; P = 0.006). Major complications within 30 d did not differ statistically between groups. Biliary complications within the first 30 d were equal among groups (16.7%). Subanalysis comparing the super obese donor group versus the nonobese donor group showed no differences in terms of postoperative complications, readmission rate, graft rejection, or major complications including the need for reoperation, retransplantation, or mortality. Graft and patient survival at 1-, 3-, and 5-y graft were similar between the donor BMI ≥50 group versus donor BMI <50 group (94%/89%/89% versus 88%/88%/88%, P = 0.89, and 94%/94%/94% versus 88%/88%/88%, P = 0.48, respectively).ConclusionsLT with carefully selected grafts from super obese donors can be safely performed with outcomes comparable with non-super obese donor livers. Therefore, these types of grafts could represent a safe means to expand the donor pool.

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Mass Spectrometry Based Metabolomics Comparison of Liver Grafts from Donors after Circulatory Death (DCD) and Donors after Brain Death (DBD) Used in Human Orthotopic Liver Transplantation.

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