Evolving Strategies in the Treatment of Anaemia in Chronic Kidney Disease: The HIF-Prolyl Hydroxylase Inhibitors

Abstract

Chronic kidney disease (CKD) affects approximately 10% of the worldwide population; anaemia is a frequent complication. Inadequate erythropoietin production and absolute or functional iron deficiency are the major causes. Accordingly, the current treatment is based on iron and erythropoiesis stimulating agents (ESAs). Available therapy has dramatically improved the management of anaemia and the quality of life. However, safety concerns were raised over ESA use, especially when aiming to reach near-to-normal haemoglobin levels with high doses. Moreover, many patients show hypo-responsiveness to ESA. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) inhibitors (HIF-PHIs) were developed for the oral treatment of anaemia in CKD to overcome these concerns. They simulate the body’s exposure to moderate hypoxia, stimulating the production of endogenous erythropoietin. Some molecules are already approved for clinical use in some countries. Data from clinical trials showed non-inferiority in anaemia correction compared to ESA or superiority for placebo. Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors may also have additional advantages in inflamed patients, improving iron utilisation and mobilisation and decreasing LDL-cholesterol. Overall, non-inferiority was also shown in major cardiovascular events, except for one molecule in the non-dialysis population. This was an unexpected finding, considering the lower erythropoietin levels reached using these drugs due to their peculiar mechanism of action. More data and longer follow-ups are necessary to better clarifying safety issues and further investigate the variety of pathways activated by HIF, which could have either positive or negative effects and could differentiate HIF-PHIs from ESAs.