Unlocking Hope for Anemia in Chronic Kidney Disease: The Potential of Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitors

Abstract Anemia in chronic kidney disease (CKD) is a prevalent and debilitating condition resulting from diminished erythropoietin (EPO) production, iron deficiency, chronic inflammation, and reduced erythrocyte lifespan. Traditional erythropoiesis-stimulating agents (ESAs) have been the cornerstone of treatment but are associated with significant cardiovascular risks and logistical challenges. Hypoxia-inducible factor–prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as a novel therapeutic class that mimics the body’s adaptive response to hypoxia, stabilizing HIF proteins to enhance endogenous EPO synthesis, suppress hepcidin, and optimize iron utilization. This review examines the pathophysiology of HIF-PHIs in CKD anemia, focusing on their mechanism of action, effects on erythropoiesis, and impact on iron metabolism. We provide a comparative analysis of key HIF-PHI agents, including FDA-approved drugs such as daprodustat and vadadustat, as well as emerging agents like roxadustat and molidustat. Particular attention is given to desidustat, an oral HIF-PHI recently approved in India, which demonstrates promising efficacy, improved iron homeostasis, and a favorable cardiovascular safety profile compared to ESAs. Despite their advantages, HIF-PHIs are associated with potential risks, including hypertension, gastrointestinal disturbances, and concerns regarding long-term safety and tumorigenesis. Ongoing clinical investigations aim to further delineate their safety and efficacy, particularly in diverse patient populations. Given their potential to transform CKD anemia management, future research should focus on long-term outcomes, cardiovascular safety, and cost-effectiveness to establish their role as a superior alternative to ESAs.