Challenging the Validity of the EPO Index George A. Kaysen, MD, PhD, Hans G. Müller, MD, PhD, Jimin Ding, MS, and Glenn M. Chertow, MD ● Background: With use of recombinant erythropoietin (EPO) and intravenous iron, the majority of hemodialysis patients can achieve target hemoglobin concentrations. EPO resistance arises as a consequence of inflammation and other processes that can adversely affect survival. We hypothesized that the EPO dose– hematocrit (EPO/Hct) ratio, also known as the EPO index, may be a surrogate for inflammation and that greater EPO/Hct ratios would be associated with decreased survival. Methods: We used proportional hazards regression models and time-varying logistic models to analyze the association between EPO index and survival in US hemodialysis patients initiating hemodialysis therapy between January 1, 1999, and December 31, 2000, and followed up for up to 3 years until December 31, 2001. Results: We found an unexpected and consistent association between greater EPO index and survival in all models. The associations of EPO/Hct ratio were most prominent at intermediate Hct values and with longer dialysis vintage. Iron administration was associated with a lower risk for death independent of Hct. Conversely, greater average prior EPO dose was associated with a greater risk for death. Conclusion: EPO resistance may be reflected better by total cumulative EPO dose than the EPO/Hct ratio. The mechanism(s) responsible for the association between a greater EPO/Hct ratio and survival remains to be established, but may be a result of nonerythrogenic effects of EPO. Am J Kidney Dis 47:157-166. © 2005 by the National Kidney Foundation, Inc. INDEX WORDS: Inflammation; iron; end-stage renal disease (ESRD); hemodialysis (HD); mortality; anemia. S INCE THE INTRODUCTION of recombi- nant erythropoietin (EPO) in 1989, the mean hemoglobin concentration in prevalent dialysis patients has increased significantly within the United States. 1 Correction of anemia has been associated with reductions in mortality and hos- pitalization, as well as improvements in quality of life, 2,3 across multiple cohorts. However, a prospective randomized clinical trial attempting to normalize hematocrit (Hct; 42%) values in hemodialysis patients with cardiovascular dis- ease was terminated early because subjects ran- domly assigned to an Hct value greater than 42% tended to have decreased survival than subjects randomly assigned to an Hct value of 30%. 4 Although results of the randomized clinical trial are indisputable, it is curious that within each randomized group, survival increased with increasing Hct. This finding suggests that pa- tient characteristics associated with achieving greater hemoglobin concentrations may con- found the nil or negative effects of the interven- tion. In another randomized clinical trial of normalization of Hct values in subjects with advanced chronic kidney disease (CKD) not requiring dialysis, subjects randomly assigned to a group with a normal hemoglobin level (13.5 to 16 g/dL [135 to 160 g/L]) reported superior quality of life compared with subjects randomly assigned to a hemoglobin concentra- tion of 9 to 12 g/dL (90 to 120 g/L); there was no difference in survival despite greater inter- group differences in achieved hemoglobin con- centrations. 5 Survival increased with greater Hct values within each group; however, be- tween-group survival rates essentially were identical. Thus, the hypothesis that survival can be en- hanced by EPO-induced increases in Hct levels From the Division of Nephrology, Departments of Medi- cine and Biochemistry, University of California Davis, De- partment of Veterans Affairs, Medical Northern California Health Care System; Department of Statistics, University of California Davis; and Division of Nephrology, Departments of Medicine and Epidemiology and Biostatistics, University of California San Francisco, CA. Received May 17, 2005; accepted in revised form Septem- ber 7, 2005. Originally published online as doi:10.1053/j.ajkd.2005.09.013 on December 7, 2005. Support: Supported by contract N01-DK-1-2450 from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Potential conflicts of interest: None. The data reported here have been supplied by the US Renal Data System (USRDS). The interpretation and report- ing of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpreta- tion of the US government. Address reprint requests to George A. Kaysen, MD, PhD, University of California Davis, Genome and Biomedical Sciences Facility, 451 East Health Sciences Dr, Ste 6300, Davis, CA 95616. E-mail: gakaysen@ucdavis.edu © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4701-0019$30.00/0 doi:10.1053/j.ajkd.2005.09.013 American Journal of Kidney Diseases, Vol 47, No 1 (January), 2006: pp 157-166 157