Lipidomics comparing DCD and DBD liver allografts uncovers lysophospholipids elevated in recipients undergoing early allograft dysfunction

Xu, Jin; Casas-Ferreira, Ana María; Ma, Yuanfang; Sen, Arundhuti; Kim, Min; Proitsi, Petroula; Shkodra, M.; Tena, M.; Srinivasan, Parthi; Heaton, Nigel; Jassem, Wayel; Legido‐Quigley, Cristina

doi:10.1038/srep17737

Cited by 23 publications

(25 citation statements)

References 48 publications

(57 reference statements)

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“…Subsequently, ROS production after reperfusion is greater and more pronounced leading to increased cellular injury. 33 These mechanisms help explain the clinical observation as to why steatotic allografts and those from NHBD are at higher risk for early allograft dysfunction ( Figure 5).…”

Section: Reactive Oxygen Species and Inflammatory Cytokinesmentioning

confidence: 97%

“…NHBD donor livers demonstrate increased levels of ceramide18, a pro‐apoptotic activator correlating with increased cell death from IRI. VWF is also elevated in NHBD donor livers indicating higher risk of microthrombi formation and loss of sinusoidal blood flow contributing to ongoing IRI during organ recovery …”

Section: Clinical Context Of Iri In Liver Transplantationmentioning

confidence: 99%

“…VWF is also elevated in NHBD donor livers indicating higher risk of microthrombi formation and loss of sinusoidal blood flow contributing to ongoing IRI during organ recovery. 33,34 Increasing donor age is a risk factor for IRI in liver transplantation. Livers from donors over the age of 70 experience more injury at prolonged cold ischaemic times as compared to livers from younger donors.…”

Section: Donor Challengesmentioning

confidence: 99%

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Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms

Dar

Sullivan

Bynon

et al. 2019

Liver International

262

245

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Liver disease causing end organ failure is a growing cause of mortality. In most cases, the only therapy is liver transplantation. However, liver transplantation is a complex undertaking and its success is dependent on a number of factors. In particular, liver transplantation is subject to the risks of ischaemia‐reperfusion injury (IRI). Liver IRI has significant effects on the function of a liver after transplantation. The cellular and molecular mechanisms governing IRI in liver transplantation are numerous. They involve multiple cells types such as liver sinusoidal endothelial cells, hepatocytes, Kupffer cells, neutrophils and platelets acting via an interconnected network of molecular pathways such as activation of toll‐like receptor signalling, alterations in micro‐RNA expression, production of ROS, regulation of autophagy and activation of hypoxia‐inducible factors. Interestingly, the cellular and molecular events in liver IRI can be correlated with clinical risk factors for IRI in liver transplantation such as donor organ steatosis, ischaemic times, donor age, and donor and recipient coagulopathy. Thus, understanding the relationship of the clinical risk factors for liver IRI to the cellular and molecular mechanisms that govern it is critical to higher levels of success after liver transplantation. This in turn will help in the discovery of therapeutics for IRI in liver transplantation – a process that will lead to improved outcomes for patients suffering from end‐stage liver disease.

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Section: Reactive Oxygen Species and Inflammatory Cytokinesmentioning

confidence: 97%

Section: Clinical Context Of Iri In Liver Transplantationmentioning

confidence: 99%

Section: Donor Challengesmentioning

confidence: 99%

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Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms

Dar

Sullivan

Bynon

et al. 2019

Liver International

262

245

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“…A systematic review on the use of metabolomics to discover liver biomarkers for transplantation outcomes in liver tissue biopsies highlighted promising results [17]. These first studies identified lipid molecules [18][19][20], tryptophan, kynurenine and S-adenosylmethionine as liver biomarkers [21,22].…”

Section: Of 13mentioning

confidence: 99%

Deregulation of the Purine Pathway in Pre-Transplant Liver Biopsies Is Associated with Graft Function and Survival after Transplantation

Hassan-Ally

Casas-Ferreira

et al. 2020

JCM

Self Cite

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The current shortage of livers for transplantation has increased the use of marginal organs sourced from donation after circulatory death (DCD). However, these organs have a higher incidence of graft failure, and pre-transplant biomarkers which predict graft function and survival remain limited. Here, we aimed to find biomarkers of liver function before transplantation to allow better clinical evaluation. Matched pre- and post-transplant liver biopsies from DCD (n = 24) and donation after brain death (DBD, n = 70) were collected. Liver biopsies were analysed using mass spectroscopy molecular phenotyping. Discrimination analysis was used to parse metabolites differentiated between the two groups. Five metabolites in the purine pathway were investigated. Of these, the ratios of the levels of four metabolites to those of urate differed between DBD and DCD biopsies at the pre-transplantation stage (q < 0.05). The ratios of Adenosine monophosphate (AMP) and adenine levels to those of urate also differed in biopsies from recipients experiencing early graft function (EGF) (q < 0.05) compared to those of recipients experiencing early allograft dysfunction (EAD). Using random forest, a panel consisting of alanine aminotransferase (ALT) and the ratios of AMP, adenine, and hypoxanthine levels to urate levels predicted EGF with area under the curve (AUC) of 0.84 (95% CI (0.71, 0.97)). Survival analysis revealed that the metabolite classifier could stratify six-year survival outcomes (p = 0.0073). At the pre-transplantation stage, a panel composed of purine metabolites and ALT could improve the prediction of EGF and survival.

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“…Furthermore, analyses of human bile during liver transplantation by capillary electrophoresis showed distinct metabolic fingerprints in donors and recipients [8]. Whereas more recent publication has been focussed on much larger group of liver grafts belonging to two distinct organ donor sources, namely the cadaveric donation after circulatory death (DCD), and donation after brain death (DBD) and applied lipidomics studies identify markers of early allograft dysfunction [9]. …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Lipidomics comparing DCD and DBD liver allografts uncovers lysophospholipids elevated in recipients undergoing early allograft dysfunction

Cited by 23 publications

References 48 publications

Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms

Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms

Deregulation of the Purine Pathway in Pre-Transplant Liver Biopsies Is Associated with Graft Function and Survival after Transplantation

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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