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

Erythropoiesis-stimulating agents (ESA) are a cornerstone treatment for anemia in chronic kidney disease, but some patients show inadequate hemoglobin response despite appropriate or increasing ESA exposure. 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. Inflammation may impair red blood cell production not only through hepcidin-mediated iron sequestration but also through disruption of erythropoietin-responsive signaling pathways. Management should 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 efficacy and safety profiles differ between agents, and evidence in well-defined ESA-hyporesponsive populations remains limited.