IL-33 as a component of neutrophil extracellular traps mediates contrast-induced acute kidney injury by promoting ferroptosis in tubular epithelial cells.

Summary

This translational study identified IL-33-enriched neutrophil extracellular traps as a mechanistic driver of contrast-induced acute kidney injury. In 330 patients undergoing coronary angiography, circulating neutrophil extracellular trap markers and IL-33 rose after contrast exposure and were associated with injury. Genetic deletion of PAD4 or IL-33 reduced renal injury in mice, while cellular experiments linked the pathway to IKKα–β-catenin disruption and amplified ferroptosis.

Key Findings

• Contrast-induced acute kidney injury occurred in 12.1% of the 330-patient coronary angiography cohort.
• Circulating neutrophil extracellular trap markers and IL-33 increased after contrast exposure, while neutrophils were identified as the predominant renal source of IL-33 in mice.
• PAD4 or IL-33 deficiency attenuated renal ferroptosis, and mechanistic experiments implicated suppression of IKKα and impaired β-catenin nuclear translocation.

Clinical Implications

The NETs–IL-33–IKKα–β-catenin–ferroptosis axis could support biomarker-guided risk prediction and development of preventive therapies for patients undergoing coronary angiography. These targets are investigational and should not yet replace established hydration, contrast minimization, and renal-risk management strategies.

Limitations

• The human component is observational and cannot by itself establish that NETs or IL-33 cause kidney injury.
• The clinical cohort was drawn from patients undergoing coronary angiography, which may limit generalizability to other contrast-enhanced procedures.
• Therapeutic inhibition of the pathway was demonstrated experimentally but not tested in human clinical trials.

Future Directions

Future work should validate NETs and IL-33 as early clinical biomarkers, determine whether baseline levels identify high-risk patients, and test selective pathway inhibitors or ferroptosis-modulating strategies in randomized preventive trials without impairing host defense or vascular healing.