The anaemia treatment journey of CKD patients: from epoetins to hypoxia-inducible factor-prolyl hydroxylase inhibitors

Abstract

The discovery and development of erythropoiesis-stimulating agents was a journey lasting more than a century, leading to the cloning and approval of recombinant human erythropoietin (rHuEpo). This was an impressive clinical advance, providing the possibility of correcting the symptoms associated with anaemia in chronic kidney disease. Associated iron use was needed to produce new haemoglobin-containing blood red cells. Partial anaemia correction became the standard of care since trials aiming for near-normal haemoglobin levels showed a higher risk of adverse cardiovascular events. Hoping to reduce the cardiovascular risks, a new category of drugs was developed and tested. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are small molecules than can be formulated into orally active pills. They simulate reduced tissue oxygen pressure, thus stimulating the production of endogenous erythropoietin (Epo) by the kidneys and liver. Clinical trials with these compounds demonstrated that HIF-PHIs are at least as effective as rHuEpo in treating or correcting anaemia in non-dialysis and dialysis patients. Trials with HIF-PHIs did not demonstrate superiority in safety outcomes and in some trials, outcomes were worse. There was also a focus on oral delivery, a possible beneficial iron-sparing effect and the ability to overcome Epo resistance in inflamed patients. A negative effect is possible iron depletion, which may explain adverse outcomes.

Keywords: adherence; anaemia; chronic kidney disease; dialysis; erythropoiesis-stimulating agents.

Figure 1:

RBC homeostasis and Epo-stimulated erythropoiesis. Following stimulation of the HIF system, eEpo production from the kidney (and to a lesser extent from the liver) is increased. HIF-2α is the main subunit regulating eEpo synthesis. Under physiological conditions, 2 IU/kg of eEpo are produced daily with a half-life of 5–8 hours, resulting in a circulating concentration of 4–30 UI/L. ESA administration alters this balance by markedly increasing ESA levels. ESA half-life depends on molecular characteristics, ranging from 8 (epoetins) to 120 hours (methoxy polyethylene glycol-epoetin β) and administration route (for epoetins). eEpo stimulates erythroid progenitor development, leading to their maturation into reticulocytes and RBCs. Nearly 2 × 10¹¹ RBCs are produced daily. Their life span is ≈120 days (shorter in patients with CKD). Senescent RBCs are cleared from circulation via macrophage phagocytosis (0.8–1% per day). The consequent haemoglobin decrease is a stimulus for HIF-2α increase and stimulation of new erythropoiesis.

Figure 2:

Physiology of the HIF system. HIF-PH activity is affected by oxygen, inflammation and iron. In conditions of normal oxygen tension, HIF-α is hydroxylated by the enzyme HIF-PH and undergoes von Hippel–Lindau protein-dependent ubiquitination and rapid proteasomal degradation, with a half-life of only 3 minutes. HIF-PH activity is regulated by oxygen levels and iron; both factors are necessary for its function. With hypoxia or low iron, HIF-PH is inactive and cannot hydroxylate HIF-α, which then accumulates and forms heterodimers with the HIF-β subunit in the nucleus, resulting in an active HIF complex (HIF). HIF promotes transcription of multiple genes, whose function is aimed at restoring oxygen balance and reducing the consequences of tissue hypoxia. Among these functions is the stimulation of eEpo and regulators of iron metabolism.

Figure 3:

Iron metabolism changes following increased erythropoiesis. There are three HIF-α subunits: HIF-1α, HIF-2α and HIF-3α. The HIF-2α subunit is the one mostly involved in the promotion of increased eEpo synthesis and erythropoiesis. In the bone marrow, this process leads to the production of erythroferrone in erythroblasts. In turn, this substance decreases hepcidin expression and increases iron mobilization. HIF activation also regulates iron metabolism by increasing iron absorption from the gut and exporting it to the circulation via increased expression of the iron exporter ferroportin 1. The direct effect of HIF on hepcidin is still a matter of debate.