Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients as a function of therapeutic transfusion and hydroxyurea treatment
Angelo D’Alessandro,
S. Mehdi Nouraie,
Yingze Zhang,
Francesca Cendali,
Fabia Gamboni,
Julie A. Reisz,
Xu Zhang,
Kyle W. Bartsch,
Matthew D. Galbraith,
Joaquin M. Espinosa,
Victor R. Gordeuk,
Mark T. Gladwin
Affiliations
Angelo D’Alessandro
Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO, USA; Department of Medicine – Division of Hematology, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO
S. Mehdi Nouraie
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pennsylvania
Yingze Zhang
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pennsylvania
Francesca Cendali
Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO
Fabia Gamboni
Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO
Julie A. Reisz
Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO
Xu Zhang
Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
Kyle W. Bartsch
Linda Crnic Institute for Down Syndrome, University of Colorado – Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus
Matthew D. Galbraith
Linda Crnic Institute for Down Syndrome, University of Colorado – Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus
Joaquin M. Espinosa
Linda Crnic Institute for Down Syndrome, University of Colorado – Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus; School of Medicine Information Services, University of Colorado Anschutz Medical Campus
Victor R. Gordeuk
Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
Mark T. Gladwin
University of Maryland School of Medicine, University of Maryland, Baltimore, MD
Metabolomics studies in sickle cell disease (SCD) have been so far limited to tens of samples, owing to technical and experimental limitations. To overcome these limitations, we performed plasma metabolomics analyses on 596 samples from patients with SCD enrolled in the WALK-PHaSST study (clinicaltrials gov. Identifier: NCT00492531). Clinical covariates informed the biological interpretation of metabolomics data, including genotypes (hemoglobin [Hb] SS, hemoglobin SC), history of recent transfusion (HbA%), response to hydroxyurea treatment (fetal Hb%). We investigated metabolic correlates to the degree of intravascular hemolysis, cardiorenal function, as determined by tricuspid regurgitation velocity (TRV), estimated glomerular filtration rate (eGFR), and overall hazard ratio (unadjusted or adjusted by age). Recent transfusion events or hydroxyurea treatment were associated with elevation in plasma-free fatty acids and decreases in acyl-carnitines, urate, kynurenine, indoles, carboxylic acids, and glycine- or taurine-conjugated bile acids. High levels of these metabolites, along with low levels of plasma S1P and L-arginine were identified as top markers of hemolysis, cardiorenal function (TRV, eGFR), and overall hazard ratio. We thus uploaded all omics and clinical data on a novel online portal that we used to identify a potential mechanism of dysregulated red cell S1P synthesis and export as a contributor to the more severe clinical manifestations in patients with the SS genotype compared to SC. In conclusion, plasma metabolic signatures - including low S1P, arginine and elevated kynurenine, acyl-carnitines and bile acids - are associated with clinical manifestation and therapeutic efficacy in SCD patients, suggesting new avenues for metabolic interventions in this patient population.
