Post-Iron ESA Hyporesponsiveness and Risk-Associated Functional Copper Deficiency in Maintenance Hemodialysis

Background Erythropoiesis-stimulating agent (ESA) hyporesponsiveness remains a frequent and incompletely explained problem in maintenance hemodialysis. Although iron deficiency is routinely evaluated and corrected, some patients exhibit persistent ESA resistance. Copper deficiency is a recognized cause of anemia, and reliance on serum copper alone may fail to detect impaired copper bioavailability. We hypothesized that cumulative clinical stressors induce stage-dependent disruption of copper utilization, contributing to ESA hyporesponsiveness in iron-replete dialysis patients. Methods We conducted a single-center, retrospective observational study of adult hemodialysis patients screened over a three-month period. Serum copper, ceruloplasmin, zinc, and selenium were measured simultaneously in 52 patients without prior copper or zinc supplementation. Biochemical copper deficiency was defined as serum copper < 66 µg/dL. A cumulative clinical risk score reflecting impaired absorption, malnutrition, and acute physiological stress was calculated. Associations between copper-related markers and the ESA resistance index (ERI) were evaluated using a matched case–control design. Results Biochemical copper deficiency was identified in 13.5% of patients. Zinc (98%) and selenium (85%) deficiencies were highly prevalent in the cohort. Copper-deficient patients had significantly higher ERI values and cumulative risk scores than controls. In the advanced-stage cohort, ERI showed significant inverse correlations with serum copper, serum zinc, and serum ceruloplasmin, with ceruloplasmin demonstrating the strongest association. No significant associations were observed in the screening cohort. Conclusions These findings support a risk-associated, stage-transition model in which cumulative clinical stressors impair copper bioavailability before overt biochemical deficiency becomes apparent. Functional copper deficiency may represent a reversible contributor to post-iron ESA hyporesponsiveness, more sensitively reflected by reduced ceruloplasmin than by serum copper alone. A cumulative, risk-based diagnostic approach may refine anemia management in maintenance hemodialysis.