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

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.

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