Investigators have identified a new definition of erythropoiesis-stimulating agent (ESA) hyporesponsiveness in hemodialysis (HD) patients, and, using that definition, found that this condition is “potently and persistently” associated with increased mortality, according to a new report.

“This study represents the first analysis of ESA hyporesponsiveness since the 2011 changes in the US ESA labels and reimbursement policy and the concomitant changes in ESA dosing practices,” a team led by Jiacong Luo, MD, MS, MPH, of DaVita Clinical Research in Minneapolis, Minnesota, reported online in the American Journal of Kidney Diseases. “In the context of these changes, we identified a new operational definition of ESA hyporesponsiveness that is conceptually aligned with the underlying construct, meets with expectations regarding its historical prevalence, and is relevant in contemporary practice.”

During 2011, the Centers for Medicare & Medicaid Services changed the reimbursement policy for injected drugs for dialysis patients, and the FDA required changes to ESA product labeling, resulting in marked ESA dose reductions for treating the anemia of kidney disease.

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The investigators defined ESA hyporesponsiveness as 2 consecutive hemoglobin measurements less than 10 g/dL (every other week) with contemporaneous ESA dose greater than 7700 U per treatment. Among candidate definitions, this combination of factors “met with prior expectations with regard to the prevalence of ESA hyporesponsiveness: approximately 9% to 12% of hemodialysis patients receiving ESA therapy at any time.”

Dr Luo and colleagues studied 98,972 HD patients, of whom 12,361 (12.5%) had ESA hyporesponsiveness according to the new definition. Patients with ESA hyporesponsiveness were identified during the first quarter of 2012 and followed up through 2013. At baseline, the mean hemoglobin level among those with ESA hyporesponsiveness was about 1 g/dL lower than in patients without ESA hyporesponsiveness. This difference narrowed during follow-up to 0.4 g/dL, the investigators reported.

Initially, mean ESA use was about 3-fold greater for patients with than without ESA hyporesponsiveness, according to investigators. Mean ESA use decreased to 2-fold greater at the end of the study. Iron use and missed HD treatment rates were greater among patients with than without ESA hyporesponsiveness.

In the second quarter, patients with ESA hyporesponsiveness were 2.2 times as likely to die as those without ESA hyporesponsiveness; by study end, their death risk was 1.5 times greater.

“At a minimum, ESA hyporesponsiveness, as defined here, can be considered to be a prognostic marker with importance clinical and economic implications.”

Dr Luo’s group said it is unclear whether ESA hyporesponsiveness is a causal determinant of mortality, perhaps due to toxic effects of resultantly high ESA doses, or whether the excess mortality is related to the conditions that render patients hyporesponsive to ESAs, or other differences between patients with and without ESA hyporesponsiveness.

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