<p><b><i>Background:</i></b> 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. <b><i>Summary:</i></b> 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. <b><i>Key Messages:</i></b> 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.</p