Associations among Darbepoetin-α, CD34+ Cells and Cardiovascular Disease Events in Patients on Hemodialysis

Abstract

Background and Objectives: Erythropoiesis-stimulating agents (ESAs) might moderate circulating CD34-positive hematopoietic stem (CD34⁺) cells. We assessed associations between ESA therapy and CD34⁺ cells and their impact on cardiovascular disease (CVD) events in patients on prevalent hemodialysis (HD). Design, Setting, Participants and Measurements: We analyzed 95 patients on prevalent HD who received the ESAs epoetin-β (n = 22), darbepoetin-α (n = 60), or neither (control; no ESA, n = 13). Baseline values for CD34⁺ cells, high-sensitivity C-reactive protein, interleukin-6, vascular endothelial growth factor, inter-cellular adhesion molecule-1, and carotid intima-media thickness were determined. The numbers of CD34⁺/erythropoietin receptor (EPOR)⁺ cells were determined in 35 and 8 patients in the darbepoetin-α and control groups, respectively. CD34⁺ cells were counted after 6 and 12 months of darbepoetin-α treatment (n = 35). All patients were followed up for a mean of 28 months. Results: Hemoglobin levels were lower, carotid intima-media thickness was more pronounced, and the ESA dose was higher in patients with a low, than with a high, CD34⁺ cell count. The ratio of CD34⁺/EPOR⁺ to CD34⁺ cells positively correlated with the darbepoetin-α dose. A low, but not a high, dose of darbepoetin-α for 6 and 12 months was associated with more CD34⁺ cells. Although high-dose darbepoetin-α therapy was an independent predictor of composite CVD events, this association disappeared when adjusted for the CD34⁺ cell count with other confounders. Conclusions: High-dose ESA therapy is associated with a low CD34⁺ cell count and comprises a risk factor for CVD events in patients on prevalent HD.