Spectrum and Burden of Erythropoiesis-Stimulating Agent Hyporesponsiveness Among Contemporary Hemodialysis Patients

Am J Kidney Dis. 2016 Nov;68(5):763-771. doi: 10.1053/j.ajkd.2016.05.031. Epub 2016 Aug 12.


Background: Hemodialysis patients with erythropoiesis-stimulating agent (ESA) hyporesponsiveness have been a topic of active research. However, there have been no studies of ESA hyporesponsiveness among US patients following the dramatic change in anemia management that resulted from the 2011 changes in ESA product labeling and bundling of dialysis remuneration.

Study design: Retrospective observational study.

Setting & participants: We studied prevalent hemodialysis patients treated at a large dialysis organization in calendar years 2012 to 2013 (N=98,972).

Predictor: ESA hyporesponsiveness, defined as 2 consecutive hemoglobin measurements < 10g/dL (every other week) with contemporaneous ESA dose > 7,700U/treatment. Patients with ESA hyporesponsiveness were identified during the first quarter of 2012 and followed up through 2013 using intention-to-treat principles.

Outcomes: Associations between the study exposure (ESA hyporesponsiveness) and mortality, missed hemodialysis treatments, ESA and iron use, and hemoglobin levels were determined using generalized estimating equations adjusting for imbalanced baseline covariates.

Results: At baseline, 12,361 (12.5%) patients were identified as having ESA hyporesponsiveness. The mean hemoglobin level among patients with ESA hyporesponsiveness was ∼1g/dL lower than in patients without ESA hyporesponsiveness at baseline, narrowing over follow-up to 0.4g/dL. Initially, mean ESA use was approximately 3-fold greater for patients with ESA hyporesponsiveness than for those without ESA hyporesponsiveness, decreasing to 2-fold greater at study end; iron use and missed hemodialysis treatment rates were also greater among patients with ESA hyporesponsiveness throughout. ESA hyporesponsiveness was associated with enhanced mortality risk versus non-ESA hyporesponsiveness: adjusted incidence rate ratios were estimated at 2.24 (95% CI, 1.93-2.60) in the second quarter, gradually decreasing to 1.48 (95% CI, 1.18-1.84) by study end.

Limitations: It is possible that an alternative ESA hyporesponsiveness definition may be optimal. As such, the associations we observed may be conservative estimates of true relationships.

Conclusions: When using a contemporary definition at one point in time, ESA hyporesponsiveness was potently and persistently associated with greater mortality, greater iron and ESA use, and lower hemoglobin levels compared to non-ESA hyporesponsiveness.

Keywords: Anemia; ESA dosing; end-stage renal disease (ESRD); erythropoiesis stimulating agent (ESA); hemodialysis; hemoglobin; hyporesponsiveness; iron utilization.

Publication types

  • Observational Study

MeSH terms

  • Aged
  • Anemia / blood*
  • Anemia / drug therapy*
  • Female
  • Hematinics / therapeutic use*
  • Hemoglobins / analysis*
  • Humans
  • Male
  • Middle Aged
  • Renal Dialysis*
  • Retrospective Studies
  • Treatment Failure


  • Hematinics
  • Hemoglobins