No evidence of progressive pro-inflammatory cytokine storm in brain dead organ donors - A time course analysis using clinical samples

Organ donation after brain death (DBD) is an important source of transplanted organs as chronic undersupply means many patients die whilst awaiting a transplant. Improving organ quality and graft survival is key to reducing waiting lists. The interval between brain death confirmation and organ procurement offers an opportunity to reduce organ injury or encourage repair, yet data is lacking on the effects of brain injury on future grafts and which pathways to target. In fact, the consensus view has been that brain death exposes organs to a progressively pro-inflammatory environment, suggesting organ procurement must occur within a limited time window. Here, we developed a novel method of studying time-course changes in serum proteins in a DBD cohort from a UK biobank. Individual donor trajectories were combined to determine the time course of pro-inflammatory (Tumour Necrosis Factor alpha, Interleukin 6, Complement) mediators and markers of central nervous injury (Neuron Specific Enolase, Glial Fibrillary Acidic Protein) after confirmation of brain death. We found no evidence of a rise of TNF-alpha, NSE, IL-6 or C5a with prolonged duration of brain death, questioning the consensus view of progressively pro-inflammatory environment. We also identified complement as a potential target for therapeutic intervention to improve organ quality. ### Competing Interest Statement KDB was supported by the National Institute for Health Research (NIHR) with an NIHR Academic Clinical Fellowship. KDB received a pump priming research grant from the Oxford Transplant Foundation to support this project (R56956/AA001) RJP is the PI for the Quality in Organ Donation (QUOD) programme The remaining authors declare they have no competing interests. ### Funding Statement KDB received a pump priming research grant from the Oxford Transplant Foundation to support this project (R56956/AA001) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The QUOD programme research approval as a Research Tissue Bank (REC ref 13/NW/0017, from North West - Greater Manchester Central Research Ethics Committee,) covers the provision of data and research samples for research into improving the quality of organ quality for transplantation. The approval applies to all research projects conducted in the UK using tissue or data supplied by the tissue bank. The favourable REC decision confirmed that further project-based ethical approval applications (by individual researchers) are not deemed necessary. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript, clarification or further information is available upon reasonable request to the authors * BMI : Body Mass Index C5a : Complement component 5a DBD : Donation after brain death DCD : Donation after circulatory death DGF : Delayed graft function DM : Diabetes Mellitus eGFR : Estimated Glomerular Filtration Rate GFAP : Glial Fibrillary Acidic Protein Hsp70 : Heat Shock Protein 70 HO-1 : Heme Oxygenase 1 ICH : Intracranial haemorrhage IL-6 : Interleukin 6 NSE : Neuron Specific Enolase QUOD : Quality in Organ Donation TNF-alpha : Tumour Necrosis Factor alpha