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Haemoadsorption reduces the inflammatory response and improves blood flow during ex vivo renal perfusion in an experimental model.

ABSTRACT: BACKGROUND:Ex-vivo normothermic perfusion strategies are a promising new instrument in organ transplantation. The perfusion conditions are designed to be protective however the artificial environment can induce a local inflammatory response. The aim of this study was to determine the effect of incorporating a Cytosorb adsorber into an isolated kidney perfusion system. METHODS:Porcine kidneys were subjected to 22 h of cold ischaemia then reperfused for 6 h on an ex vivo reperfusion circuit. Pairs of kidneys were randomised to either control (n = 5) or reperfusion with a Cytosorb adsorber (n = 5) integrated into the circuit. Tissue, blood and urine samples were taken for the measurement of inflammation and renal function. RESULTS:Baseline levels of cytokines (IL-6, TNF?, IL-8, IL-10, IL-1?, IL-1?) were similar between groups. Levels of IL-6 and IL-8 in the perfusate significantly increased during reperfusion in the control group but not in the Cytosorb group (P = 0.023, 0.049). Levels of the other cytokines were numerically lower in the Cytosorb group; however, this did not reach statistical significance. The mean renal blood flow (RBF) was significantly higher in the Cytosorb group (162 ± 53 vs. 120 ± 35 mL/min/100 g; P = 0.022). Perfusate levels of prostaglandin E2 were significantly lower in the Cytosorb group (642 ± 762 vs. 3258 ± 980 pg/mL; P = 0.0001). Levels of prostacyclin were significantly lower in the Cytosorb group at 1, 3 and 6 h of reperfusion (P = 0.008, 0.003, 0.0002). Levels of thromboxane were also significantly lower in the Cytosorb group throughout reperfusion (P = 0.005). Haemoadsorption had no effect on creatinine clearance (P = 0.109). CONCLUSION:Haemoadsorption can reduce the inflammatory response and improve renal blood flow during perfusion. Nonetheless, in this model haemoadsorption had no influence on renal function and this may relate to the broad-spectrum action of the Cytosorb adsorber that also removes potentially important anti-inflammatory mediators.

SUBMITTER: Hosgood SA

PROVIDER: S-EPMC5657103 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Haemoadsorption reduces the inflammatory response and improves blood flow during ex vivo renal perfusion in an experimental model.

Hosgood Sarah A SA Moore Tom T Kleverlaan Theresa T Adams Tom T Nicholson Michael L ML

Journal of translational medicine 20171025 1

<h4>Background</h4>Ex-vivo normothermic perfusion strategies are a promising new instrument in organ transplantation. The perfusion conditions are designed to be protective however the artificial environment can induce a local inflammatory response. The aim of this study was to determine the effect of incorporating a Cytosorb adsorber into an isolated kidney perfusion system.<h4>Methods</h4>Porcine kidneys were subjected to 22 h of cold ischaemia then reperfused for 6 h on an ex vivo reperfusion ...[more]

PMID: 29070045

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Project description:Background: A major limitation in expanding the use of donation after circulatory death (DCD) livers in transplantation is the increased risk of graft failure secondary to ischemic cholangiopathy. Warm ischemia causes thrombosis and injury to the peribiliary vascular plexus (PVP), which is supplied by branches of the hepatic artery, causing higher rates of biliary complications in DCD allografts. Aims/Objectives: We aimed to recondition discarded DCD livers with tissue plasminogen activator (tPA) while on normothermic machine perfusion (NMP) to improve PVP blood flow and reduce biliary injury. Methods: Five discarded DCD human livers underwent 12 h of NMP. Plasminogen was circulated in the base perfusate prior to initiation of perfusion and 1 mg/kg of tPA was administered through the hepatic artery at T = 0.5 h. Two livers were split prior to perfusion (S1, S2), with tPA administered in one lobe, while the other served as a control. The remaining three whole livers (W1-W3) were compared to seven DCD control liver perfusions (C1-C7) with similar hepatocellular and biliary viability criteria. D-dimer levels were measured at T = 1 h to verify efficacy of tPA. Lactate, total bile production, bile pH, and difference in biliary injury scores before and after perfusion were compared between tPA and non-tPA groups using unpaired, Mann-Whitney tests. Results: Average weight-adjusted D-dimer levels were higher in tPA livers in the split and whole-liver model, verifying drug function. There were no differences in perfusion hepatic artery resistance, portal vein resistance, and arterial lactate between tPA livers and non-tPA livers in both the split and whole-liver model. However, when comparing biliary injury between hepatocellular and biliary non-viable whole livers, tPA livers had significantly lower PVP injury scores (0.67 vs. 2.0) and mural stroma (MS) injury scores (1.3 vs. 2.7). Conclusion: This study demonstrates that administration of tPA into DCD livers during NMP can reduce PVP and MS injury. Further studies are necessary to assess the effect of tPA administration on long term biliary complications.

Project description:Ischemia reperfusion (IR) injury is a key complication following lung transplantation, and it remains to be fully resolved. Ex vivo lung perfusion (EVLP) has shown its significance as a platform to assess and repair marginal donor lungs prior to transplants with good clinical outcomes. Recently, it has been shown that Glutamax supplementation to Steen solution can improve basic cellular function as well as porcine EVLP duration with stable lung quality. To better understand the molecular mechanisms of IR injury, acellular EVLP, and Glutamax supplementation during EVLP, transcriptomic changes in cell culture models simulating IR and EVLP have been investigated. Briefly, human pulmonary microvascular endothelial cells (HPMEC) and human lung epithelial cells (BEAS-2B) were cultured in DMEM+10%FBS, then were perfused with Perfadex at 4°C for 18H to simulate cold ischemic time (CIT). Subsequently, the cells were perfused in either DMEM+10%FBS (IR model) or in Steen solution or Steen with 4mM Glutamax (EVLP models) for 4H. RNA samples were collected for CIT, IR, and two EVLP conditions, and sequencing data were analyzed for differentially expressed genes and pathways. HPMEC and BEAS-2B cells showed significant changes in gene expressions for IR and EVLP models. In pathway analyses, IR models of both cell types had up-regulated pro-inflammatory responses and down-regulated cell metabolism, and there was up-regulation of epithelial process and/or vascular activation. Steen alone EVLP models exhibited down-regulation of cell metabolism, with an absence of inflammatory and vascular or epithelial signals, while Steen with Glutamax exhibited similar down-regulation of cell metabolism as well as down-regulated inflammatory and vascular process. The commonly used EVLP perfusate, acellular Steen solution, can silence the activation of pro-inflammatory signaling in HPMEC and BEAS-2B cell culture models. This finding may yield insights into how acellular EVLP has been successful in safe preservation of the donor lungs during organ evaluation and repair prior to lung transplantation.

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Haemoadsorption reduces the inflammatory response and improves blood flow during ex vivo renal perfusion in an experimental model.

Publications

Haemoadsorption reduces the inflammatory response and improves blood flow during ex vivo renal perfusion in an experimental model.

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