Erythropoiesis-stimulating agent hyporesponsiveness in chronic kidney disease: mechanistic insights and emerging precision approaches.

Background: Erythropoiesis-stimulating agents (ESAs) remain a cornerstone of anemia management in chronic kidney disease (CKD). However, some patients show an inadequate hemoglobin response despite appropriate or increasing ESA exposure. ESA hyporesponsiveness is clinically important because persistent dose escalation may provide limited benefit while increasing treatment burden and potential cardiovascular and thrombotic risk. Summary: ESA hyporesponsiveness is a heterogeneous phenotype driven by overlapping mechanisms, particularly inflammation, iron-restricted erythropoiesis, uremic and metabolic disturbances, and impaired erythroid responsiveness to erythropoietin. Emerging evidence further suggests that inflammation may impair erythropoiesis not only through hepcidin-mediated iron sequestration but also through disruption of EPO-responsive signaling pathways. Management should therefore prioritize systematic identification and correction of reversible causes before further intensification of erythropoietic therapy. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) may provide an alternative erythropoietic option in selected patients, but agent-specific efficacy and safety profiles differ, and evidence in rigorously defined ESA-hyporesponsive populations remains limited. Biomarker-guided and data-driven approaches may ultimately enable more mechanism-based patient stratification. Key messages: ESA hyporesponsiveness should be viewed as a multifactorial clinical phenotype rather than simply insufficient EPO replacement. Integrating mechanistic phenotyping with structured clinical evaluation may help shift anemia management from empirical ESA dose escalation toward more individualized, mechanism-based treatment.