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

Lay Summary Erythropoiesis-stimulating agents (ESAs) have been used for >30 years to treat anaemia in CKD. They have become the standard of care, as haemoglobin (Hb) levels can be raised and maintained within target ranges, with an acceptable safety profile. The typical Hb target range (9-12 g/dl) is lower than the normal range (13-15 g/dl) because of safety concerns, including increased strokes, and cost when targeting higher Hb levels. A new class of orally active agents that simulate low oxygen tension, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), have been discovered and developed. They have the possible added advantage of promoting iron mobilisation to support Hb synthesis. HIF-PHIs were not superior to ESAs in treating or correcting anaemia and did not demonstrate superiority in safety outcomes in phase 3 clinical trials. In some trials, strokes and other thrombotic events were increased beyond that of originator ESAs. The mechanism is not understood, but one possibility is that iron depletion due to mobilization of iron from stores is the cause. 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.