Erythropoietin Dose and Mortality in Hemodialysis Patients: Marginal Structural Model to Examine Causality.
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.
Harold Simmons Center for Kidney Disease Research and Epidemiology, School of Medicine, University of California, Irvine, Orange, CA, USA.
Elani
E
Streja
Harold Simmons Center for Kidney Disease Research and Epidemiology, School of Medicine, University of California, Irvine, Orange, CA, USA; Division of Nephrology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
Jongha
J
Park
Harold Simmons Center for Kidney Disease Research and Epidemiology, School of Medicine, University of California, Irvine, Orange, CA, USA.
Ting-Yan
TY
Chan
Harold Simmons Center for Kidney Disease Research and Epidemiology, School of Medicine, University of California, Irvine, Orange, CA, USA.
Janet
J
Lee
Harold Simmons Center for Kidney Disease Research and Epidemiology, School of Medicine, University of California, Irvine, Orange, CA, USA.
Melissa
M
Soohoo
Harold Simmons Center for Kidney Disease Research and Epidemiology, School of Medicine, University of California, Irvine, Orange, CA, USA.
Connie M
CM
Rhee
Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA.
Onyebuchi A
OA
Arah
Harold Simmons Center for Kidney Disease Research and Epidemiology, School of Medicine, University of California, Irvine, Orange, CA, USA; Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA; Division of Nephrology and Hypertension, School of Medicine, University of California, Irvine, Orange, CA, USA.
Kamyar
K
Kalantar-Zadeh