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

Abstract

Background The optimal use of erythropoiesis stimulating agents (ESAs) to treat anemia in end stage renal disease (ESRD) 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 non-concurrent 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 (CV) was used to compare the variability of Hgb with that of weight-adjusted EPO in order to explain this relationship. This analysis was done for each quarter during the first year of dialysis. Results ERI is strongly linearly related with weight-adjusted EPO dose in each of the 4 quarters by the equation ERI = 0.0899*(EPO/wt) (range of R2 = 0.97–0.98) and weakly linearly related to 1/Hgb (range of R2 = 0.06–0.16). These correlations hold independent of age, sex, hgb level, ERI level, and epo-naïve stratifications. Conclusions ERI is strongly linearly related to weight-adjusted (and non-weight-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.

Association between resistance to erythropoiesis‐stimulating agents and carnitine profile in patients on maintenance haemodialysis

“…Nonetheless, meal analysis is necessary to confirm this when conducting a similar study. Fourth, as Chait et al reported, as an index, ERI is similar to weight‐ and non‐weight‐adjusted EPO . In the existing guidelines, ERI is not identified as associated with prognosis.…”

“…Fourth, as Chait et al reported, as an index, ERI is similar to weight-and non-weight-adjusted EPO. 24 In the existing guidelines, ERI is not identified as associated with prognosis. ERI should be defined in terms of the results of prospective trials in which its association with prognosis was evaluated.…”

Residual renal function in chronic dialysis is not associated with reduced erythropoietin-stimulating agent dose requirements: a cross-sectional study

“…It has become routine for studies to report ERI as a measure of ESA dose requirements. A recent study found that a strong linear relationship exists between ERI and weight-adjusted ESA dose using a universal formula [ 13 ]. However, it is important to take cognisance of the timing of the ESA initiation and the value of the accompanying Hb concentration when calculating the ERI.…”

Population Pharmacodynamic Modeling of Epoetin Alfa in End‐Stage Renal Disease Patients Receiving Maintenance Treatment Using Bayesian Approach

“…ERI is a complex metric representing the responsiveness to the treatment of anemia. 29 Patients with higher ERIs are less responsive to the drug effect. In the PD model, SC 50 reflects the sensitivity of HGB response to the drug effect.…”