title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Nephrology, Alessandro Manzoni Hospital, Lecco, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Steven
authors.initials: S
authors.lastname: Fishbane
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Block
authors.forename: Iain C
authors.initials: IC
authors.lastname: Macdougall
mesh_terms: D000740:Anemia / Q000150:complications* / Q000188:drug therapy*; D000818:Animals; D001463:Barbiturates / Q000627:therapeutic use; D001794:Blood Pressure; D004195:Disease Models, Animal; D015195:Drug Design; D004347:Drug Interactions; D005998:Glycine / Q000031:analogs & derivatives / Q000627:therapeutic use; D064451:Hepcidins / Q000737:chemistry; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007249:Inflammation; D007546:Isoquinolines / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000188:drug therapy*; D010848:Picolinic Acids / Q000627:therapeutic use; D000072417:Protein Domains; D011720:Pyrazoles / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use
chemical_list: D001463:Barbiturates; C000599718:GSK1278863; D064451:Hepcidins; D051793:Hypoxia-Inducible Factor 1; D007546:Isoquinolines; D010848:Picolinic Acids; D011720:Pyrazoles; D014230:Triazoles; C000624313:vadadustat; C000603972:molidustat; D005998:Glycine; C584543:roxadustat