Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients

Abstract

Background: Anemia, a common complication of chronic kidney disease (CKD), has previously been attributed primarily to decreased production of erythropoietin. More recently, it has become apparent that the etiology of anemia involves several other factors, most notably dysfunctional iron metabolism, mediated via increased hepcidin activity and reduced clearance. Current management of anemia in patients with advanced CKD is based on erythropoiesis-stimulating agents and iron supplementation, along with red blood cell transfusions when necessary; however, safety considerations associated with these therapies highlight the need to pursue alternative treatment options targeting other mechanisms such as hypoxia-inducible factors (HIFs) that act as central regulators of erythropoiesis by coordinating a series of graded hypoxic responses. Summary: This review discusses the discovery of the HIF pathway and its regulation via HIF prolyl hydroxylase enzymes in the context of erythropoiesis and iron metabolism. The rationale for targeting this pathway and the clinical development of HIF prolyl hydroxylase inhibitors are reviewed, with a commentary on the potential implications of this class of agents in CKD anemia management. Key Messages: Pharmacologic activation of the HIF pathway results in a transient pseudo-hypoxic state that stimulates erythropoiesis in CKD patients with anemia. Results from clinical studies of a number of HIF prolyl hydroxylase inhibitors are increasingly available and provide support for the continued evaluation of the risk-benefit ratio of this novel therapeutic approach to the treatment of anemia in CKD.

A Placebo-Controlled, Randomized Trial of Enarodustat in Patients with Chronic Kidney Disease Followed by Long-Term Trial

“…In such patients, chronic inflammation may lead to increased hep- cidin production [21][22][23], inhibiting the uptake and mobilization of iron. Patients with CKD receiving ESAs are prone to iron deficiency because of increased demand for iron to support erythropoiesis; iron deficiency is the commonest cause of hypo-responsiveness to ESA therapy [24][25][26]. Given the changes in iron-related parameters observed in this study, enarodustat may support erythropoiesis by using available iron stored in the body.…”

Intermittent Oral Dosing of Roxadustat in Peritoneal Dialysis Chronic Kidney Disease Patients with Anemia: A Randomized, Phase 3, Multicenter, Open‐Label Study

“…Anemia is a common complication in patients with chronic kidney disease (CKD) and has been associated with increased risk of cardiovascular events, hospitalization, and mortality. Anemia in CKD is associated with dysregulation of oxygen sensing by the malfunctioning kidneys, leading to inadequate synthesis of erythropoietin, functional iron deficiency, reduced erythrocyte survival, and inflammation. The prevalence of anemia increases as CKD progresses and, in the United States, varies from 8.4% at stage 1 to 53.4% at stage 5 CKD.…”

Review of WADA Prohibited Substances: Limited Evidence for Performance-Enhancing Effects

“…Small molecule HIFs are in clinical development but have not yet been approved for clinical use. The published clinical studies show that these compounds produce modest increases in erythropoietin in both anaemic patients and healthy volunteers [45, 46], however there are currently no studies evaluating effects on the performance of healthy or trained subjects.…”