Regulation of kynurenine metabolism by blood donor genetics and biology impacts red cell hemolysis in vitro and in vivo

Research Article| November 17, 2023 Regulation of kynurenine metabolism by blood donor genetics and biology impacts red cell hemolysis in vitro and in vivo Travis Nemkov, Travis Nemkov University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States https://orcid.org/0000-0001-8566-7119 Search for other works by this author on: This Site PubMed Google Scholar Daniel Stephenson, Daniel Stephenson University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, United States Search for other works by this author on: This Site PubMed Google Scholar Christopher Erickson, Christopher Erickson University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, United States https://orcid.org/0000-0001-8116-7221 Search for other works by this author on: This Site PubMed Google Scholar Monika Dzieciatkowska, Monika Dzieciatkowska University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, United States Search for other works by this author on: This Site PubMed Google Scholar Alicia Key, Alicia Key University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States https://orcid.org/0000-0002-8787-8144 Search for other works by this author on: This Site PubMed Google Scholar Amy Moore, Amy Moore RTI International, Research Triangle Park, North Carolina, United States https://orcid.org/0000-0002-5083-0577 Search for other works by this author on: This Site PubMed Google Scholar Eric J Earley, Eric J Earley RTI International, Durham, North Carolina, United States https://orcid.org/0000-0001-6576-1319 Search for other works by this author on: This Site PubMed Google Scholar Grier P Page, Grier P Page RTI International, Atlanta, Georgia, United States https://orcid.org/0000-0003-2582-3786 Search for other works by this author on: This Site PubMed Google Scholar Ian S Lacroix, Ian S Lacroix University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, United States https://orcid.org/0000-0002-4859-7024 Search for other works by this author on: This Site PubMed Google Scholar Mars Stone, Mars Stone Vitalant Research Institute, San Francisco, California, United States Search for other works by this author on: This Site PubMed Google Scholar Xutao Deng, Xutao Deng Vitalant Research Institute, San Francisco, California, United States Search for other works by this author on: This Site PubMed Google Scholar Thomas J Raife, Thomas J Raife University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States Search for other works by this author on: This Site PubMed Google Scholar Steven H Kleinman, Steven H Kleinman Canada Search for other works by this author on: This Site PubMed Google Scholar James C Zimring, James C Zimring University of Virginia, CHARLOTTESVILLE, Virginia, United States Search for other works by this author on: This Site PubMed Google Scholar Nareg H. Roubinian, Nareg H. Roubinian Kaiser Permanente Division of Research, Oakland, California, United States Search for other works by this author on: This Site PubMed Google Scholar Kirk C Hansen, Kirk C Hansen UC Denver, Aurora, Colorado, United States Search for other works by this author on: This Site PubMed Google Scholar Michael P Busch, Michael P Busch Vitalant Research Institute, United States Search for other works by this author on: This Site PubMed Google Scholar Philip J Norris, Philip J Norris Vitalant Research Institute, United States https://orcid.org/0000-0003-0526-2088 Search for other works by this author on: This Site PubMed Google Scholar Angelo D'Alessandro Angelo D'Alessandro University of Colorado Denver, Aurora, Colorado, United States * Corresponding Author; email: angelo.dalessandro@ucdenver.edu https://orcid.org/0000-0002-2258-6490 Search for other works by this author on: This Site PubMed Google Scholar Blood blood.2023022052. https://doi.org/10.1182/blood.2023022052 Article history Submitted: August 1, 2023 Revision Received: October 26, 2023 Accepted: November 4, 2023 Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Request Permissions Cite Icon Cite Search Site Citation Travis Nemkov, Daniel Stephenson, Christopher Erickson, Monika Dzieciatkowska, Alicia Key, Amy Moore, Eric J Earley, Grier P Page, Ian S Lacroix, Mars Stone, Xutao Deng, Thomas J Raife, Steven H Kleinman, James C Zimring, Nareg H. Roubinian, Kirk C Hansen, Michael P Busch, Philip J Norris, Angelo D'Alessandro; Regulation of kynurenine metabolism by blood donor genetics and biology impacts red cell hemolysis in vitro and in vivo. Blood 2023; blood.2023022052. doi: https://doi.org/10.1182/blood.2023022052 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBlood Search Key Points Kynurenine is a marker of osmotic fragility and its levels are reproducible within donor across donations;Genetic polymorphisms in SLC7A5 and ATXN2 associate with kynurenine in stored RBCs, Hgb increments and in vivo hemolysis upon transfusion. Subjects: Transfusion Medicine In the field of Transfusion Medicine, the clinical relevance of the metabolic markers of the red blood cell (RBC) storage lesion is incompletely understood. Here we performed metabolomics of RBC units from 643 donors enrolled in the Recipient Epidemiology and Donor Evaluation Study - REDS RBC Omics. These units were tested at storage day 10, 23 and 42 for a total of 1,929 samples, and also characterized for end of storage hemolytic propensity following oxidative and osmotic insults. Our results indicate that the metabolic markers of the storage lesion poorly correlated with hemolytic propensity. On the other hand, kynurenine was not affected by storage duration and was identified as the top predictor of osmotic fragility. RBC kynurenine levels were affected by donor age and BMI, and were reproducible within the same donor across multiple donations 2-12 months apart. To delve into the genetics underpinnings of kynurenine levels in stored RBCs, we thus tested kynurenine levels in day 42 stored RBCs from 13,091 donors from the REDS RBC Omics study, a population that was also genotyped for 879,000 single nucleotide polymorphisms. Through a metabolite Quantitative Trait Loci analysis, we identified polymorphisms in SLC7A5, ATXN2 and a series of rate-limiting enzymes (e.g., IDO1, KMO, TDO) in the kynurenine pathway as critical factors impacting RBC kynurenine levels. By interrogating a donor-recipient linkage vein-to-vein database, we then report that SLC7A5 polymorphisms are also associated with changes in hemoglobin and bilirubin levels suggestive of in vivo hemolysis in 4,470 critically-ill recipients receiving single unit transfusions. Subjects: Transfusion Medicine This content is only available as a PDF. Copyright © 2023 American Society of Hematology2023 Article PDF first page preview Close Modal You do not currently have access to this content. Sign in via your Institution