title: The greatly misunderstood erythropoietin resistance index and the case for a new responsiveness measure.
abstract: 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.
authors: Department of Mechanical and Industrial Engineering, University of Massachusetts, Amherst, MA, USA.
authors: Yossi
authors: Y
authors: Chait
authors: Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors: Sahir
authors: S
authors: Kalim
authors: Department of Mathematics and Statistics, University of Massachusetts, Amherst, MA, USA.
authors: Joseph
authors: J
authors: Horowitz
authors: Department of Electrical and Computer Engineering, University of Massachusetts, Amherst, MA, USA.
authors: Christopher V
authors: CV
authors: Hollot
authors: Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors: Elizabeth D
authors: ED
authors: Ankers
authors: Baystate Medical Center, Springfield, and Tufts University School of Medicine, MA, USA.
authors: Michael J
authors: MJ
authors: Germain
authors: Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors: Ravi I
authors: RI
authors: Thadhani
mesh_terms: D000740:Anemia / Q000188:drug therapy*; D004921:Erythropoietin / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D012189:Retrospective Studies
chemical_list: D004921:Erythropoietin
keywords: Anemia; biostatistics; mathematical models