Background
Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors which, in the presence of tissue hypoxia, increase hepatic and renal erythropoietin (EPO) production to stimulate erythropoiesis. They also have a suppressive effect on hepatic production of hepcidin, increasing gastrointestinal absorption of iron and liberating it from stores. 1 Inhibition of oxygen-regulated degradation of
Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors which, in the presence of tissue hypoxia, increase hepatic and renal erythropoietin (EPO) production to stimulate erythropoiesis. They also have a suppressive effect on hepatic production of hepcidin, increasing gastrointestinal absorption of iron and liberating it from stores.1 Inhibition of oxygen-regulated degradation of HIF by prolyl hydroxylase inhibitors (HIF-PHIs) results in sustained EPO stimulating effect, allowing use of the HIF-PHIs as erythropoiesis-stimulating agents (ESAs).1
Potential benefits of HIF-PHIs over conventional ESAs are shown in Table 1.
Table 1. Potential benefit of HIF-PHIs over conventional ESAs
| Oral formulation | - Reduced discomfort over subcutaneous ESA - Ease of administration for non-dialysis requiring patients living with CKD on an outpatient basis - Ease of administration in peritoneal dialysis patients - Does not require refrigeration |
| Improved iron absorption and distribution | - Better absorption of oral iron, potentially reducing need for use for intravenous formulation - Reduced dose of iron required |
| Suppression of hepcidin production | - Improved erythropoiesis in chronic inflammatory states with resistance to conventional ESA |
ESA; erythropoiesis-stimulating agents
Adoption of the HIF-PHI class in clinical practice requires appreciation of the efficacy and side-effect profile of these novel agents relative to conventional ESAs. Current data on these parameters relies on trials that assessed the superiority of the HIF-PHIs over placebo or their non-inferiority to existing ESAs. HIF-PHIs have therefore not been assessed for superiority over available ESAs.
This document considers available literature on the efficacy of the HIF-PHIs in the treatment of anaemia of chronic kidney disease and the side-effect profile of these drugs. Recommendations are provided for the prescription of HIF-PHIs based on current data.
South African Nephrology Society (SANS). Consensus Statement on the Use of Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors (HIF-PHIs). South African Nephrology Society; 2023.