Recent advances and clinical application of erythropoietin and erythropoiesis-stimulating agents

Erythropoietin (EPO) is an essential glycoprotein that facilitates red blood cell maturation from erythroid progenitors and mediates erythropoiesis. The use of recombinant human EPO (rhEPO) dramatically changed management of anemic patients with chronic kidney disease and improved their quality of life. EPO is mainly produced in the fetal liver and the postnatal kidney, although the molecular determinants for tissue-specific expression are elusive. Meanwhile, recent advances established a role of hypoxia-inducible factors (HIF) in transcriptionally upregulating EPO in hypoxia. Out of three HIF- isoforms, HIF-2 appears to play a central role. Prolyl hydroxylase domain-containing protein (PHD), a key regulator connecting oxygen availability and HIF-α expression, is also involved in hypoxic induction of EPO mRNA and the precise roles of PHD paralogs in erythropoiesis are now beginning to be uncovered. On the other hand, widespread expression of EPO receptors (EPOR) beyond erythroid progenitors led to the discovery of non-hematopoietic, pleiotropic roles of EPO in the brain, the heart and the kidney. The precise signal transduction pathways of pleiotropic EPO remain unclear, but carbamylated EPO, which fails to bind to the canonical EPOR homodimers or transduce the JAK2-STAT5 signaling, conferred organ protection through multimeric receptors composed of EPO-R and the common β subunit (βCR). The clinical benefit of normalization of anemia in pre-dialysis CKD by EPO therapy is controversial and recent large-scale, randomized-controlled trials do not favor normalization of anemia by EPO in improving cardiovascular as well as renal outcomes. The optimal EPO therapy should be determined based on the clinical context of individual patients.