Kidney Week Educational Symposia-New Era of Anemia of CKD After the Nobel Prize

Video Transcription

Video Summary

This session introduces a “new era” in treating anemia of chronic kidney disease (CKD) following the 2019 Nobel Prize recognizing discovery of the hypoxia-inducible factor (HIF) oxygen-sensing pathway. Under normal oxygen, prolyl hydroxylase (PHD) enzymes hydroxylate HIF-α (an iron- and oxygen-dependent reaction), enabling VHL-mediated ubiquitination and proteasomal degradation. Under hypoxia or iron deficiency, HIF-α stabilizes, dimerizes with HIF-β, and activates genes such as erythropoietin (EPO) and multiple pathways including iron metabolism, angiogenesis, and energy metabolism.<br /><br />HIF prolyl hydroxylase inhibitors (HIF-PHIs) pharmacologically inhibit PHDs to raise endogenous EPO, offering oral dosing, lower EPO peaks than injectable ESAs, and potential improvements in iron utilization via reduced hepcidin—important given ESA trial safety concerns at high doses.<br /><br />Dr. Haas reviews HIF biology, genetics (e.g., VHL disease, Chuvash polycythemia), and key safety considerations: cancer biology, pulmonary hypertension, thrombosis, and possible cyst progression. Dr. Nangaku presents CKD anemia epidemiology (many untreated), trial data showing agents like vadadustat and roxadustat effectively increase hemoglobin and lower hepcidin, including in inflammatory states and ESA hyporesponders. Reported concerns include GI side effects, possible hyperkalemia signals, and increased thrombosis/embolism in pooled analyses; regulators advise monitoring malignancy and retinopathy. Expert recommendations stress assessing iron status, retinopathy, malignancy risk, and thrombotic history before use.

Asset Subtitle

Jodie Babitt, Volker Haase, Masaomi Nangaku
Support is provided by an educational grant from AstraZeneca Pharmaceuticals LP in collaboration with FibroGen.

Keywords

anemia of chronic kidney disease

hypoxia-inducible factor (HIF) pathway

prolyl hydroxylase domain (PHD) enzymes

HIF prolyl hydroxylase inhibitors (HIF-PHIs)

endogenous erythropoietin (EPO) induction

hepcidin reduction and iron utilization

roxadustat and vadadustat trials

ESA hyporesponsiveness and inflammation

thrombosis and malignancy safety monitoring