Non-Classical Monocyte Expansion Is Independently Associated with Anemia Severity in Patients with ESKD

BACKGROUND: Anemia remains a major contributor to morbidity and mortality in patients treated by hemodialysis despite current anemia management strategies. Non-classical monocytes (CD14+CD16++), which expand in end-stage kidney disease and participate in iron recycling through heme scavenging, represent an unexplored link to anemia in this population. METHODS: In this two-center cross-sectional analysis of 408 patients treated by prevalent hemodialysis from the prospective Immunity in End-Stage Renal Disease (iESRD) cohort, monocyte subsets were quantified by multicolor flow cytometry. Associations between non-classical monocyte percentage (%M3) and hemoglobin were evaluated using Spearman rank correlations and multivariable linear regression adjusted for demographics, dialysis vintage, erythropoietin dose, iron parameters, inflammatory markers, and comorbidities. RESULTS: Mean age was 62±12 years, 57% were male, and 45% had diabetes. Patients in the highest %M3 tertile had lower hemoglobin than those in the lowest tertile (10.6±1.2 versus 11.1±1.6 g/dL; P=0.01). In multivariable regression, each one-tertile higher %M3 was independently associated with 0.29 g/dL lower hemoglobin (β=-0.29; 95% CI, -0.43 to -0.15; P<0.001), and this association persisted after further adjustment for blood urea nitrogen and serum creatinine (β=-0.31; P<0.001). The association was not attenuated by adjustment for high-sensitivity C-reactive protein, and %M3 showed no correlation with interleukin-6 or tumor necrosis factor-α. The association was strongest among diabetic patients (ρ = -0.27; P < 0.001). CONCLUSIONS: Non-classical monocyte expansion is independently associated with anemia severity in patients treated by hemodialysis through an inflammation-independent pathway involving altered iron homeostasis. Monocyte subset profiling may identify patients at risk for refractory anemia.