Table of Contents Author Guidelines Submit a Manuscript
International Journal of Nephrology
Volume 2016 (2016), Article ID 6087134, 8 pages
Research Article

Erythropoietin Dose and Mortality in Hemodialysis Patients: Marginal Structural Model to Examine Causality

1Harold Simmons Center for Kidney Disease Research and Epidemiology, School of Medicine, University of California, Irvine, Orange, CA, USA
2Division of Nephrology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
3Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA
4Division of Nephrology and Hypertension, School of Medicine, University of California, Irvine, Orange, CA, USA

Received 3 December 2015; Accepted 6 April 2016

Academic Editor: Jochen Reiser

Copyright © 2016 Elani Streja et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


It has been previously reported that a higher erythropoiesis stimulating agent (ESA) dose in hemodialysis patients is associated with adverse outcomes including mortality; however the causal relationship between ESA and mortality is still hotly debated. We hypothesize ESA dose indeed exhibits a direct linear relationship with mortality in models of association implementing the use of a marginal structural model (MSM), which controls for time-varying confounding and examines causality in the ESA dose-mortality relationship. We conducted a retrospective cohort study of 128 598 adult hemodialysis patients over a 5-year follow-up period to evaluate the association between weekly ESA (epoetin-α) dose and mortality risk. A MSM was used to account for baseline and time-varying covariates especially laboratory measures including hemoglobin level and markers of malnutrition-inflammation status. There was a dose-dependent positive association between weekly epoetin-α doses ≥18 000 U/week and mortality risk. Compared to ESA dose of <6 000 U/week, adjusted odds ratios (95% confidence interval) were 1.02 (0.94–1.10), 1.08 (1.00–1.18), 1.17 (1.06–1.28), 1.27 (1.15–1.41), and 1.52 (1.37–1.69) for ESA dose of 6 000 to <12 000, 12 000 to <18 000, 18 000 to <24 000, 24 000 to <30 000, and ≥30 000 U/week, respectively. High ESA dose may be causally associated with excessive mortality, which is supportive of guidelines which advocate for conservative management of ESA dosing regimen in hemodialysis patients.