Regulation of kynurenine metabolism by blood donor genetics and biology impacts red cell hemolysis in vitro and in vivo.
Level 3 - non-randomized controlled study
Multi-stage observational cohort, mQTL genetic association, and donor-recipient linkage study.
PubMed 37976448 · doi:10.1182/blood.2023022052
What was done
Researchers investigated metabolic and genetic predictors of red blood cell (RBC) hemolytic propensity during storage. They performed longitudinal metabolomic profiling of RBC units from 643 blood donors at storage days 10, 23, and 42 (1,929 samples total) and tested end-of-storage osmotic and oxidative hemolytic fragility. They subsequently measured day-42 kynurenine levels in 13,091 genotyped donors (879,000 single nucleotide polymorphisms) to perform metabolite quantitative trait loci (mQTL) mapping. Finally, they evaluated donor-recipient linkage data from 4,470 critically ill patients who received single-unit RBC transfusions to assess post-transfusion markers of in vivo hemolysis.
What was found
Standard metabolic markers of the RBC storage lesion correlated poorly with hemolytic propensity. In contrast, kynurenine levels remained stable across storage duration and served as the top predictor of osmotic fragility. Donor kynurenine levels were influenced by donor age and body mass index and showed intra-donor reproducibility across repeat donations 2 to 12 months apart. The mQTL analysis of 13,091 donors linked kynurenine levels to polymorphisms in SLC7A5, ATXN2, and kynurenine pathway enzymes (kynurenine monooxygenase, indoleamine 2,3-dioxygenase, and tryptophan dioxygenase). In the clinical cohort of 4,470 transfusion recipients, donor SLC7A5 polymorphisms were significantly associated with altered recipient hemoglobin and bilirubin levels, indicating in vivo hemolysis. Specific numerical effect sizes and p-values were not reported in the abstract.
Why it matters
These findings indicate that donor intrinsic biology and genetics, rather than storage duration alone, are key determinants of stored RBC quality and post-transfusion recipient outcomes. Identifying kynurenine and SLC7A5 variants could help refine donor screening and precision transfusion strategies.
Limits
The abstract does not provide exact numerical effect sizes, correlation coefficients, or p-values. In vivo findings are restricted to critically ill single-unit transfusion recipients, which may not generalize to non-critically ill populations or multi-unit transfusions. Clinical outcome endpoints beyond surrogate biomarkers of hemolysis (hemoglobin and bilirubin) were not detailed.
Cited by
- supports Specific genetic polymorphisms can increase activity along the kynurenine metabolic pathway.