Abstract
Hypoxia-inducible factor (HIF) plays a crucial role in the response to hypoxia at the cellular, tissue, and organism level. New agents under development to pharmacologically manipulate HIF may provide new and exciting possibilities in the treatment of anemia of chronic kidney disease (CKD) as well as in multiple other disease states involving ischemia–reperfusion injury. This article provides an overview of recent studies describing current standards of care for patients with anemia in CKD and associated clinical issues, and those supporting the clinical potential for targeting HIF stabilization with HIF prolyl-hydroxylase inhibitors (HIF-PHI) in these patients. Additionally, articles reporting the clinical potential for HIF-PHIs in ‘other’ putative therapeutic areas, the tissue and intracellular distribution of HIF- and prolyl-hydroxylase domain (PHD) isoforms, and HIF isoforms targeted by the different PHDs, were identified. There is increasing uncertainty regarding the optimal treatment for anemia of CKD with poorer outcomes associated with treatment to higher hemoglobin targets, and the increasing use of iron and consequent risk of iron imbalance. Attainment and maintenance of more physiologic erythropoietin levels associated with HIF stabilization may improve the management of patients resistant to treatment with erythropoiesis-stimulating agents and improve outcomes at higher hemoglobin targets.
Highlights
Anemia is a common feature in patients with chronic kidney disease (CKD)
hypoxia-inducible factor (HIF)-α subunits are constantly targeted for hydroxylation at two proline residues by a family of prolyl-hydroxylase enzymes, designated as prolyl-hydroxylase domain PHD1, PHD2, and PHD3 [14,15]
Studies of the extent to which HIF target gene expression is induced by PHD or factor inhibiting HIF (FIH) inhibition showed substantial differences in the role of prolyl and asparaginyl hydroxylation in regulating hypoxia-responsive genes, indicating that FIH-regulated coactivators were not required for the therapeutic regulation of some HIF target genes; simultaneous inhibition of PHDs and FIH are likely to be required for other therapeutic applications [22,23]
Summary
Anemia is a common feature in patients with chronic kidney disease (CKD). optimal treatment of this condition remains controversial, for many years, erythropoiesis-stimulating agents (ESAs) have been utilized and perhaps considered the standard of care. One class of agents under development for the management of anemia in CKD acts by stabilizing hypoxia-inducible factor (HIF) through inhibition of the prolyl hydroxylase family of enzymes. HIF, a transcription factor that plays an important role in the cellular response to systemic oxygen levels, provides a primary means by which systemic oxygen delivery to mammalian cells can be regulated through hemoglobin content. On a basic level, HIF mediates a response to oxygen deficiency at cell, tissue, and systemic levels. This review discusses these responses to hypoxia, the role of the HIF pathway, and ways in which the HIF pathway can be manipulated in the clinical setting
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