Albumin variability and biological instability associated with ESA hyporesponsiveness in maintenance hemodialysis patients

Abstract Introduction Erythropoiesis-stimulating agent (ESA) hyporesponsiveness is common in hemodialysis (HD) patients and is associated with adverse outcomes. Although studies have focused on absolute laboratory values, the clinical significance of biological variability remains unclear. We investigated whether biological instability is associated with ESA hyporesponsiveness and subsequent deterioration in ESA responsiveness. Methods This retrospective longitudinal study included 52 HD patients followed for 24 months (2024–2025). Monthly measurements of hemoglobin (Hb), transferrin saturation (TSAT), ferritin, albumin, and C-reactive protein (CRP) were collected. Biological variability was quantified using coefficients of variation (CVs). ESA responsiveness was assessed by the erythropoiesis resistance index (ERI). An exploratory hematologic instability score was generated by assigning one point for each variability measure within the highest tertile. Results A total of 1248 patient-month observations were analyzed. Albumin-CV showed the strongest association with mean ERI (ρ = 0.521, p < 0.001), followed by Hb-CV (ρ = 0.378, p = 0.0057). The Hematologic Instability Score correlated with mean ERI (ρ = 0.339, p = 0.014), and patients with scores ≥ 3 had significantly higher ERI than those with lower scores (21.32 versus 13.20, p = 0.0032). Early instability scores were also associated with subsequent ERI (ρ = 0.414, p = 0.0023). Albumin-CV remained independently associated with ERI after adjustment for mean albumin, age, dialysis vintage, and CRP (β = 0.737, p = 0.036). Conclusions Albumin variability was the strongest and only independent variability marker associated with ESA hyporesponsiveness. These findings suggest that longitudinal albumin variability may serve as a clinically useful marker of biological instability associated with ESA hyporesponsiveness in HD patients.