Long-term treatment of chronic kidney disease patients with anemia using hypoxia-inducible factor prolyl hydroxylase inhibitors: potential concerns

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been approved in several countries as a supplement or even an alternative to the clinical treatment of anemia in patients with chronic kidney disease (CKD). Activation of HIF by HIF-PHIs effectively increases hemoglobin (Hb) level in CKD patients by inducing multiple HIF downstream signaling pathways. This indicates that HIF-PHIs have effects beyond erythropoietin, while their potential benefits and risks should be necessarily assessed. Multiple clinical trials have largely demonstrated the efficacy and safety of HIF-PHIs in the short-term treatment of anemia. However, in terms of long-term administration, especially over 1 year, the benefits and risks of HIF-PHIs still need to be assessed. Particular attention should be paid to the risk of kidney disease progression, cardiovascular events, retinal diseases, and tumor risk. This review aims to summarize the current potential risks and benefits of HIF-PHIs in CKD patients with anemia and further discuss the mechanism of action and pharmacological properties of HIF-PHIs, in order to provide direction and theoretical support for future studies.