{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:03:16Z","timestamp":1790067796901,"version":"4.0.1"},"reference-count":113,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>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\u2013prolyl 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key messages<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1862346","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T08:25:18Z","timestamp":1790065518000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Erythropoiesis-stimulating agent hyporesponsiveness in chronic kidney disease: mechanistic insights and emerging precision approaches"],"prefix":"10.3389","volume":"13","author":[{"given":"Haifeng","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Nephrology, Affiliated Hospital of Shandong Second Medical University","place":["Weifang, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Affiliated Hospital of Shandong Second Medical University","place":["Weifang, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuexun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Affiliated Hospital of Shandong Second Medical University","place":["Weifang, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Affiliated Hospital of Shandong Second Medical University","place":["Weifang, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jigang","family":"Shan","sequence":"additional","affiliation":[{"name":"Department of Laboratory, The 960th Hospital of the PLA Joint Logistics Support Force","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.1016\/S0140-6736(25)01853-7","article-title":"Global, regional, and national burden of chronic kidney disease in adults, 1990\u20132023, and its attributable risk factors: a systematic analysis for the Global Burden of Disease Study 2023","volume":"406","author":"Mark","year":"2025","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1093\/ckj\/sfac240","article-title":"Prevalence of anaemia in adults with chronic kidney disease in a representative sample of the United States population: analysis of the 1999\u20132018 national health and nutrition examination survey","volume":"16","author":"Kovesdy","year":"2023","journal-title":"Clin Kidney J"},{"key":"B3","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1053\/j.ajkd.2004.03.023","article-title":"Anemia management and outcomes from 12 countries in the Dialysis outcomes and practice patterns study (DOPPS)","volume":"44","author":"Pisoni","year":"2004","journal-title":"Am J Kidney Dis"},{"key":"B4","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1007\/s12325-020-01524-6","article-title":"Burden of anemia in chronic kidney disease: beyond erythropoietin","volume":"38","author":"Hanna","year":"2021","journal-title":"Adv Ther"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e005336","DOI":"10.1161\/JAHA.116.005336","article-title":"Risk factors for heart failure in patients with chronic kidney disease: the CRIC (chronic renal insufficiency cohort) study","volume":"6","author":"He","year":"2017","journal-title":"J Am Heart Assoc"},{"key":"B6","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1186\/s12882-022-02778-8","article-title":"Epidemiology and outcomes in patients with anemia of CKD not on dialysis from a large US healthcare system database: a retrospective observational study","volume":"23","author":"Lamerato","year":"2022","journal-title":"BMC Nephrol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1056\/NEJM198701083160203","article-title":"Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. 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