Hypoxia Inducible Factors Proly-Hydroxylase Inhibitors: A Novel Treatment of CKD Patient Anemia

Dear Colleagues,

The pathogenesis of anemia in chronic kidney disease (CKD) patients includes decreased production of erythropoietin (EPO), often associated with iron deficiency; its current management includes iron supplementation, erythropoiesis-stimulating agents (ESAs), and eventually red blood cell transfusion. The introduction of ESAs in the late 1980s revolutionized the treatment of anemia in CKD and resulted in a significant decline in the need for blood transfusions. However, these agents are associated with increased rates of hypertension, seizures, thrombosis, cardiovascular (CV) events, and functional iron deficiency when aimed at normalizing the hemoglobin (Hb) plasma level. Moreover, resistance to ESAs has been observed in a certain proportion of patients, mainly due to chronic inflammation producing cytokines.

A novel class of therapeutic agents for the treatment of anemia in patients with CKD was developed by inhibiting the enzymes that control hypoxia-inducible factors (HIFs), a family of oxygen-sensitive proteins that regulate the cellular transcriptional response to hypoxia. HIFs are controlled by a family of prolyl hydroxylase enzymes, important for maintaining the relationship between oxygen availability and HIF-α expression. These HIF proteins, known as ‘oxygen sensors’ due to their dependency upon oxygen as a direct substrate, are called PHD1, PHD2, and PHD3 based on their distinctive prolyl-4-hydroxylase domains (PHD). They belong to a larger family of proteins (60+ members in humans) whose role, in addition to ‘sensing’ changes in cellular oxygen, includes collagen synthesis and fatty acid metabolism.

Phase 3 trials recently became available for drugs of this class.

The aim of this Special Issue is to report and discuss the efficacy and safety and clinical impact of these drugs, according to the present available data with the help of major experts in the field of treatment of anemia in CKD patients.

Prof. Dr. Francesco Locatelli
Dr. Lucia Del Vecchio
Dr. Ciro Esposito
Guest Editors

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