Interest of HIF stabilizers in home dialysis

Abstract

Hypoxia-inducible factor (HIF) stabilizers or dustats are orally administered small molecules with very low renal elimination (without adaptation during chronic kidney disease (CKD) analogues with antagonistic effect of 2-oxoglutarate, a naturally occurring substrate of HIF-Prolyl Hydroxylase at the origin of the inhibition of this enzyme. This results in a simulated state of hypoxia allowing the accumulation of HIF-α in the cells followed by coordinated erythropoiesis with erythropoietin synthesis, decreased hepatic hepcidin production and optimization of iron metabolism. HIF stabilizers have only been studied in non-inferiority clinical trials versus erythropoiesis stimulating agents (ESAs). The primary endpoint for the therapeutic trials of all these different molecules was the change in hemoglobin level. Dustat corrects anemia in advanced non-dialysis and dialysis CKD in a similar way to ESAs.
Six HIF stabilizers molecules are in advanced development: Roxadustat, Daprodustat, Vadadustat, Enarodustat, Desidustat and Molidustat. Only Roxadustat or Evrenzo®, currently has a marketing authorization in Europe obtained in August 2021. Only two studies have been dedicated to peritoneal dialysis, one with Roxadustat, the other with Daprodustat. Home dialysis appears to be an elective indication for HIF stabilizers because of their absence of cold chain necessity and their positive impact on iron metabolism and the difficulties and imperfections of the current treatment of anemia with ESA and intravenous iron in this patient population.