Hypoxia in chronic kidney disease: towards a paradigm shift?

Area of Science:

• Nephrology
• Pathophysiology
• Pharmacology

Background:

• Chronic kidney disease (CKD) affects 10% of adults, incurring significant healthcare costs.
• The role of hypoxia in CKD progression is debated, with limited evidence on its timing, stage correlation, and causative link to fibrosis.
• The classical view posits hypoxia worsens CKD via inflammation and oxidative stress, but recent studies question this paradigm.

Purpose of the Study:

• To review the literature on hypoxia, the hypoxia-inducible factor (HIF) pathway, and HIF hydroxylase inhibitors (HIs) in CKD progression.
• To summarize evidence supporting or refuting the hypoxia hypothesis in CKD.
• To evaluate the therapeutic potential of HIs in experimental CKD models.

Main Methods:

• Literature review of studies investigating hypoxia, HIF, and HIs in CKD.
• Analysis of experimental data from murine models with genetic and pharmacological HIF modulation.
• Synthesis of evidence regarding the causative role of hypoxia in CKD progression.

Main Results:

• Genetic HIF modulation yields variable effects on CKD progression in different murine models.
• Pharmacological modulation using HIF hydroxylase inhibitors (HIs) generally demonstrates protective effects against fibrosis progression experimentally.
• Evidence for hypoxia's causative role in CKD progression remains inconclusive, lacking time-course and spatial correlation data.

Conclusions:

• The role of hypoxia in CKD progression requires further investigation.
• HIF hydroxylase inhibitors represent a promising therapeutic strategy for mitigating CKD progression and fibrosis.
• Clarifying the precise mechanisms and timing of hypoxia's involvement is crucial for validating the hypoxia hypothesis in CKD.