HIF-prolylhydroxylase inhibitors: the future for anemia treatment in patients with chronic kidney disease

Anemia is a frequent complication of chronic kidney disease (CKD) and is caused by deficiency of endogenous erythropoietin (EPO) and iron. Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (HIF-PHI) represent a new class of drugs for the treatment of anemia in CKD. Along with iron preparations and erythropoiesis-stimulating agents (ESA), HIF-PHI are attempting to take their place in the correction of anemia to reduce hemotransfusion need in patients and have demonstrated as much efficacy as ESA. In contrast to the latter, HIF-PHI are oral drugs that increase endogenous EPO levels, reduce hepcidin level, and improve iron homeostasis. However, the ability of these drugs to increase the expression of a number of HIF-associated genes, not only EPO and proteins involved in iron metabolism, by stabilizing the transcription factor HIF, leads to nonselective action. The activation of angiogenesis associated with increased formation of vascular endothelial growth factor (VEGF), which may stimulate tumor growth, increase the risk of metastasis, be associated with poor prognosis, drug resistance in various types of malignancies, as well as affect the progression of polycystic kidney disease and diabetic retinopathy is of particular concern. In addition, an increased risk of thrombosis, hyperkalemia, thyroid disorders, etc. is noted. All this dictates the necessity to analyze the benefit-risk ratio when choosing HIF-PHI as antianemic agents and long-term clinical trials of this group of drugs to assess their real safety.