An omics approach to study trace metals in sera of hemodialysis patients treated with erythropoiesis stimulating agents

Hemodialysis (HD) represents a life-sustaining treatment for patients with end-stage renal disease. However, it is associated with several complications, including anemia. Erythropoiesis-stimulating agents (ESAs) are often administered to HD patients with renal anemia, but a relevant proportion of them fail to respond to the therapy. Since trace metals are involved in several biological processes and their blood levels can be altered by HD, we study the possible association between serum trace metal concentrations and ratios with the administration and response to ESA. For this study, data and sample information of 110 HD patients were downloaded from the UC San Diego Metabolomics Workbench public repository (PR000565). The blood serum levels (and ratios) of antimony, cadmium, copper, manganese, molybdenum, nickel, selenium, tin, and zinc were studied applying an omics statistical approach. The Random Forest model was able to discriminate between HD-dependent patients treated and not treated with ESAs, with an accuracy of 71.7% (95% CI 71.5-71.9%). Logistic regression analysis identifies alterations of Mn, Mo, Cd, Sn, and several of their ratios as characteristic of patients treated with ESAs. Moreover, patients with scarce response to ESAs were shown to be characterized by reduced Mn to Ni and Mn to Sb ratios. In conclusion, our results show that trace metals, in particular manganese, play a role in the mechanisms underlying the human response to ESAs, and if further confirmed, the re-equilibration of their physiological levels could contribute to a better management of HD patients, hopefully reducing their morbidity and mortality.