New anemia therapies: translating novel strategies from bench to bedside

Recombinant human erythropoietin (epoetin) has been available for the treatment of renal anemia for more than 20 years, and within the last decade two molecularly engineered analogues darbepoetin alfa and pegylated epoetin beta were introduced as longer-acting erythropoiesis-stimulating agents. Recently, newer strategies for correcting anemia have been explored, some of which remain in the laboratory while others are translating across into clinical trials. Peginesatide has completed phase 3 clinical trials for the treatment of anemia associated with chronic kidney disease; this molecule is immunologically distinct from the erythropoietic proteins, with no cross-reactivity with anti-erythropoietin antibodies. HIF (hypoxia inducible factor) stabilization involves the pharmacologic inhibition of prolyl hydroxylation of HIF-α (the major transcription factor controlling erythropoietin gene expression), thereby preventing its degradation in the proteasome. Hepcidin is the master regulator of iron metabolism, and this peptide is upregulated in inflammatory conditions, including uremia; its antagonism has been shown to cause amelioration of inflammatory anemia in animal models. For the time being, erythropoiesis-stimulating agent therapy remains the mainstay of anemia management in chronic kidney disease, but it is possible that one or more of the strategies discussed in this review may have a future role in the treatment of this condition.