Navigating Anemia Therapy in CKD With Hypoxia-Inducible Factor Activators: A Review

The clinical challenges and safety concerns associated with the use of erythropoiesis-stimulating agents (ESAs) have provided the rationale for developing novel therapeutic approaches that address the complex pathophysiology of anemia in chronic kidney disease (CKD). Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of oral agents that effectively increase and maintain hemoglobin levels in patients with CKD. These agents stimulate the endogenous production of erythropoietin and enhance iron metabolism by activating hypoxia-inducible factors. Despite their efficacy, the use of some HIF-PHIs has been limited to patients on maintenance dialysis in some countries, including the United States, due to unresolved cardiovascular safety concerns in patients with CKD not on dialysis. In this review, we examine the mechanisms of action and erythropoietic effects of HIF-PHIs, evaluate undesirable on-target and off-target effects, and address cardiovascular and other safety concerns that have been raised in comparison to ESAs. We discuss how this novel class of oral anemia drugs may impact clinical practice, including their potential use in kidney transplant recipients.