The greatly misunderstood erythropoietin resistance index and the case for a new responsiveness measure

Introduction The optimal use of erythropoiesis stimulating agents (ESAs) to treat anemia in end stage renal disease remains controversial due to reported associations with adverse events. In analyzing these associations, studies often utilize ESA resistance indices (ERIs), to characterize a patient's response to ESA. In this study, we examine whether ERI is an adequate measure of ESA resistance. Methods We used retrospective data from a nonconcurrent cohort study of incident hemodialysis patients in the United States (n = 9386). ERI is defined as average weekly erythropoietin (EPO) dose per kg body weight (wt) per average hemoglobin (Hgb), over a 3-month period (ERI = (EPO/wt)/Hgb). Linear regression was used to demonstrate the relationship between ERI and weight-adjusted EPO. The coefficient of variation was used to compare the variability of Hgb with that of weight-adjusted EPO to explain this relationship. This analysis was done for each quarter during the first year of dialysis. Findings ERI is strongly linearly related with weight-adjusted EPO dose in each of the four quarters by the equation ERI = 0.0899*(EPO/wt) (range of R(2)  = 0.97-0.98) and weakly linearly related to 1/Hgb (range of R(2)  = 0.06-0.16). These correlations hold independent of age, sex, hgb level, ERI level, and epo-naïve stratifications. Discussion ERI is strongly linearly related to weight-adjusted (and nonweight-adjusted) EPO dose by a "universal," not patient-specific formula, and thus is a surrogate of EPO dose. Therefore, associations between ERI and clinical outcomes are associations between a confounded EPO dose and those outcomes.