Stabilizing Hypoxia-Inducible Factor to Manage Anemia in Chronic Kidney Disease: From Basic Theory to Clinical Study

Abstract

<b><i>Background:</i></b> Anemia is one of the common complications of chronic kidney disease (CKD), and its prevalence has been arising globally. The key cause of anemia in CKD patients is the diseased kidney’s reduced ability to synthesize endogenous erythropoietin (EPO), yet this is not the sole reason. Inflammatory elements, functional iron deficiency, and uremic toxins together participate in the development of anemia. According to research data, anemia is an independent risk factor for cardiovascular events, all-cause mortality, and worsening renal function and affects the clinical prognosis and quality of life of CKD patients. Regular treatments for anemia in CKD patients include the use of erythropoiesis-stimulating agents (ESAs), iron supplements, and blood transfusions. <b><i>Summary:</i></b> Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel and small-molecule pharmacological compounds that target the hypoxia-inducible factor (HIF) pathway and are another option for improving anemia in CKD patients. HIF-PHIs simulate hypoxia, stabilize HIF protein, stimulate EPO synthesis, reduce hepcidin level, boost iron utilization, induce the creation of red blood cells, and alleviate anemia. The results of several HIF-PHI phase III trials indicated that HIF-PHIs are similarly effective as ESA at raising hemoglobin concentration. <b><i>Key Messages:</i></b> This article summarizes the structure of HIF and the mechanism of stabilizing HIF to improve anemia, discusses the efficacy of HIF-PHIs in CKD patients with or without dialysis, as well as emphasizes the potential safety concerns with HIF-PHIs.