Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in chronic kidney disease: a clinical practice document by the European Renal Best Practice board of the European Renal Association

Abstract

Anaemia is a common complication of chronic kidney disease (CKD) and is associated with poor long-term outcomes and quality of life. The use of supplemental iron, erythropoiesis-stimulating agents (ESAs) and blood transfusions has been the mainstay for treatment of anaemia in CKD for more than 3 decades. Despite available treatments, CKD patients with anaemia are undertreated and moderate-severe anaemia remains prevalent in the CKD population. Anaemia has consistently been associated with greater mortality, hospitalization, cardiovascular events and CKD progression in CKD patients, and the risk increases with anaemia severity. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) inhibitors have a novel mechanism of action by mimicking the body's response to hypoxia and have emerged as an alternative to ESAs for treatment of anaemia in CKD. Their efficacy in correcting and maintaining haemoglobin has been demonstrated in >30 phase 3 clinical trials. Additionally, HIF activation results in various pleiotropic effects beyond erythropoiesis, with cholesterol reduction and improved iron homeostasis and potential anti-inflammatory effects. The long-term safety of these agents, particularly with respect to cardiovascular and thromboembolic events, and their possible effect on tumour growth needs to be fully elucidated. This article presents in detail the effects of HIF-PH inhibitors, describes their mechanisms of action and pharmacologic properties and discusses their place in the treatment of anaemia in CKD according to the available evidence.

Keywords: anaemia; chronic kidney disease; erythropoiesis-stimulating agents; erythropoietin; hypoxia-inducible factor prolyl hydroxylase inhibitors.

Figure 1:

HIF pathway in the presence of normal oxygen levels, under hypoxic conditions and after pharmacological inhibition of the prolyl hydroxylases. In conditions of normal oxygen tension, HIF-α is hydroxylated by the oxygen-sensitive HIF-prolyl hydroxylases (HIF-PHs) and undergoes rapid proteasomal degradation. Factor inhibiting HIF (FIH) is an asparaginyl (Asn) hydroxylase enzyme that regulates the transcriptional activity of HIF. Under hypoxic conditions, HIF-PH is inactive and cannot hydroxylate HIF-α, which then accumulates, translocates to the nucleus and forms heterodimers with the HIF-β, resulting in an active HIF complex. The HIF complex activates transcription of multiple genes promoting erythropoiesis via stimulation of endogenous erythropoietin production and regulators of iron metabolism.

Figure 2:

Effects of different HIF-PHis and ESAs in parameters of iron homeostasis and hepcidin.

Figure 3:

Potential advantages of HIF-PHi compared to ESA therapy in different CKD populations.