Future perspectives of anemia management in chronic kidney disease using hypoxia-inducible factor-prolyl hydroxylase inhibitors

For the past 3 decades, erythropoiesis-stimulating agents (ESA) in conjunction with iron supplementation has been the mainstay of treatment for anemia in chronic kidney disease (CKD). Although ESAs are well-established and highly efficacious treatment, clinical trials demonstrated that the use of ESAs with a high hemoglobin (Hb) target was associated with increased risk of cardiovascular events. This safety concern raised considerable interest in developing an alternative therapeutic strategy. Hypoxia-inducible factor-prolyl hydrox-ylase inhibitors (HIF-PHIs) are such novel agents to treat anemia in CKD. They stimulate endogenous erythropoi-etin production via HIF activation and thereby induce erythropoiesis. At least 6 small-molecule HIF-PHIs have been developed to date. The phase 3 clinical trials demonstrated that their effects were noninferior to ESAs. HIF-PHIs may have several advantages over the conventional treatment, such as oral route of administration and their ability to raise Hb levels in patients with chronic inflammation. Although many of the phase 3 clinical trials demonstrated that HIF-PHIs were noninferior to placebo or ESAs with respect to cardiovascular safety, one of the compounds failed to meet the prespecified noninferiority criterion in non-dialysis-dependent CKD pa-tients, and some studies of another HIF-PHI indicated potential risks for thromboembolic events. While the reg-ulatory agencies of some countries including Japan and the European Union concluded that roxadustat, one of the HIF-PHIs, had a favorable benefit-risk profile, the U.S. Food and Drug Administration decided not to approve the drug because of safety reasons. In order to establish the optimal anemia management in CKD, further studies are needed to evaluate important aspects of HIF-PHIs, such as long-term safety, appropriate Hb target, and the types of patients who would gain benefits from these new drugs.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

For the past 3 decades, erythropoiesis-stimulating agents (ESA) in conjunction with iron supplementation has been the mainstay of treatment for anemia in chronic kidney disease (CKD). However, recent studies have raised concerns about the cardiovascular risks associated with high hemoglobin (Hb) targets. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as novel agents that stimulate endogenous erythropoietin production and induce erythropoiesis in CKD patients. While HIF-PHIs have shown noninferiority to ESA in clinical trials, there are still concerns about their long-term safety and potential risks.