Supplementary Material for: Regional Variation of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Global Daprodustat Dialysis Study (ASCEND-D)

Introduction: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) affects 10–15% of the chronic dialysis population. We explored baseline characteristics and predictors of ESA hyporesponsiveness in a global randomized cardiovascular outcomes study comparing an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), daprodustat, with conventional ESA treatment. Methods: ASCEND-D (NCT02879305) recruited 2964 chronic dialysis patients receiving ESA treatment (standardized to weekly intravenous [IV] epoetin) who were iron replete at baseline. The primary ESA hyporesponsiveness definition was an ESA Resistance Index (ERI, ESA Units/kg/week/hemoglobin g/l) ≥2 or IV standardized ESA dose ≥450 Units/kg/week. Predictors of ESA hyporesponsiveness were determined using a multivariable regression model. Alternative hyporesponder definitions were explored. Results: Using the primary definition, 354 (12%) patients were ESA hyporesponsive. Geographic region, notably Latin America, lower baseline body mass index and transferrin saturation, younger age, lower albumin concentration, and a higher baseline IV iron dose were identified as strongly associated (P < 0.001) with ESA hyporesponsiveness. Additional predictors of ESA hyporesponsiveness included female sex (P = 0.010), history of heart failure (P = 0.035), longer dialysis vintage (P = 0.077), smoking status (P = 0.247), aspirin use (P = 0.121), and angiotensin-converting enzyme inhibitor/ angiotensin receptor blocker use (P = 0.214). Conclusion: This is the first global HIF-PHI study to report pre-specified definitions and predictors of ESA hyporesponsiveness. While most of the predictors identified in our study have been previously reported, geographic region stands out as an unexpected finding, meriting further investigation.