Nrf2 Expression on Day Seven Predicts Adverse Kidney Events in Patients with Septic AKI

Background: Sepsis-associated acute kidney injury (AKI) in critically ill patients has high mortality and lacks reliable early prognostic biomarkers. Nuclear factor erythroid 2–related factor 2 (Nrf2) is a transcription factor regulating antioxidant defenses that may protect against kidney injury. We investigated whether peripheral blood Nrf2 expression predicts 28-day renal outcomes in this patient population. Methods: We prospectively enrolled 124 adults with sepsis in the ICU. Nrf2 mRNA expression was measured from buffy coat leukocytes by quantitative PCR on day 0 (enrollment) and day 7, normalized to GAPDH and expressed as ΔCt%. AKI was defined by KDIGO criteria and occurred in 88 patients (71%). The primary outcome was MAKE28, defined as major adverse kidney events by day 28 (dialysis requirement, doubling of serum creatinine, or death). Associations between Nrf2 levels and MAKE28 were analyzed, including multivariable logistic regression adjusting for baseline covariates. Results: Baseline (day 0) Nrf2 expression did not differ between patients who did and did not experience MAKE28. By day 7, Nrf2 levels were significantly lower in AKI patients with MAKE28 compared to those without (median 6.0% vs. 9.8%, p=0.009). Higher day-7 Nrf2 was independently associated with lower MAKE-28 risk in AKI subset (adjusted OR 0.899 per 1% increase, 95% CI 0.809–0.998, p=0.046). Conclusion: Critically ill septic patients with an inadequate Nrf2 response by day 7 had worse 28-day renal outcomes. These findings suggest Nrf2 is a novel prognostic biomarker in sepsis-associated AKI. Failure to mount a robust Nrf2 response during sepsis may identify high-risk patients, and therapeutic strategies targeting Nrf2 pathways could be explored to improve outcomes. Funding: Clinical Revenue Support