Hypoxia-Inducible Factor-Prolyl Hydroxylase Domain Inhibitors to Treat Anemia in Chronic Kidney Disease.

Abstract

Hypoxia-inducible factor (HIF) stabilizers, also known as inhibitors of HIF prolyl hydroxylase domain (PHD) inhibitors enzymes, are novel small-molecule agents to treat renal anemia. They increase endogenous erythropoietin (EPO) production by stabilizing HIF. This review focuses on the mechanisms by which PHD inhibitors ameliorate anemia in chronic kidney disease (CKD) and summarizes the current clinical experience with and prospects for these drugs. Anemia is a serious complication of CKD and is an independent risk factor for congestive heart failure. Appropriate treatment of anemia is important in the management of advanced stage CKD, as it might help to extend life expectancy and improve the physical function of patients with CKD. However, at present, adverse effects of treatment, such as thromboembolic events, as well as high therapeutic cost have a negative impact on society. PHD inhibitors stabilize the transcription factor HIF, increasing the expression of downstream target genes, including EPO and enzymes involved in iron metabolism, resulting in increased EPO production and improved iron utilization. Key Messages: The potential advantages of PHD inhibitors over conventional EPO-based therapies include a more physiologic response to renal anemia, noninvasive oral administration, and lower cost. Phase III trials of more than 5 PHD inhibitors are ongoing, with overall demonstration of success in increasing hemoglobin levels. In this review, we focus on the mechanisms of PHD inhibitors in improving renal anemia in CKD and summarize the current clinical findings regarding these drugs.