Association between high-dose erythropoiesis-stimulating agents, inflammatory biomarkers, and soluble erythropoietin receptors

Background: High-dose erythropoiesis-stimulating agents (ESA) for anemia of chronic kidney disease (CKD) have been associated with adverse clinical outcomes and do not always improve erythropoiesis. We hypothesized that high-dose ESA requirement would be associated with elevated inflammatory biomarkers, decreased adipokines, and increased circulating, endogenous soluble erythropoietin receptors (sEpoR). Methods: A cross-sectional cohort of anemic 32 CKD participants receiving ESA were enrolled at a single center and cytokine profiles, adipokines, and sEpoR were compared between participants stratified by ESA dose requirement (usual-dose darbepoetin-alpha (< 1 mu g/kg/week) and high-dose (>= 1 mu g/kg/week)). Results: Baseline characteristics were similar between groups; however, hemoglobin was lower among participants on high-dose (1.4 mu g/kg/week) vs usual-dose (0.5 mu g/kg/week) ESA. In adjusted analyses, high-dose ESA was associated with an increased odds for elevations in c-reactive protein and interleukin-6 (p < 0.05 for both). There was no correlation between high-dose ESA and adipokines. Higher ESA dose correlated with higher levels of sEpoR (r(s) = 0.39, p = 0.03). In adjusted analyses, higher ESA dose (per mu cg/kg/week) was associated with a 53% greater odds of sEpoR being above the median (p < 0.05). Conclusion: High-dose ESA requirement among anemic CKD participants was associated with elevated inflammatory biomarkers and higher levels of circulating sEpoR, an inhibitor of erythropoiesis. Further research confirming these findings is warranted.