Perioperative Nitric Oxide Conditioning in Cardiac Surgery: A Paradigm Shift for Protecting Renal Function in CKD Patients (DEFENDER Trial Review)

Highlights

• Perioperative inhaled nitric oxide (NO) reduces postoperative acute kidney injury (AKI) incidence in cardiac surgery patients with chronic kidney disease (CKD).
• NO therapy preserves glomerular filtration rate (GFR) six months post surgery, suggesting protective effects against CKD progression.
• Reduced postoperative pneumonia incidence indicates additional benefits of NO beyond renal protection.
• NO administration is safe with no significant adverse hematologic or oxidative stress effects detected.

Background

Postoperative acute kidney injury (AKI) is a frequent and serious complication after cardiac surgery, especially in patients with preexisting chronic kidney disease (CKD). AKI not only increases short-term morbidity and mortality but also accelerates CKD progression, leading to long-term renal dysfunction and elevated healthcare costs. Despite numerous attempts, effective pharmacologic interventions to prevent AKI in this patient population remain limited. Nitric oxide (NO), a critical endogenous vasodilator and signaling molecule, has been extensively studied for its potential cytoprotective and anti-inflammatory properties in various ischemia-reperfusion injury models. The DEFENDER Trial fills the gap by rigorously assessing perioperative inhaled NO therapy in cardiac surgery patients with CKD, a high-risk group for postoperative renal impairment.

Key Content

Chronological Development of Evidence on NO in Renal Protection

Initial animal studies demonstrated that NO donors mitigated ischemia-reperfusion injury in kidneys by improving microvascular perfusion and reducing inflammation. Early-phase clinical trials focused on NO for pulmonary hypertension and hypoxia but hinted at systemic protective effects. The DEFENDER Trial (2025) represents the first large randomized controlled trial specifically targeting perioperative NO to prevent AKI in CKD patients undergoing cardiopulmonary bypass (CPB).

DEFENDER Trial Design and Population

The trial enrolled 136 adult patients with established CKD scheduled for elective cardiac surgery requiring CPB. Patients were randomized 1:1 to receive either inhaled NO at 80 ppm intraoperatively and for 6 hours postoperatively or sham treatment. The primary endpoint was AKI incidence within 7 days after surgery defined by standard KDIGO criteria. Secondary endpoints included renal function at 6 months, incidence of postoperative pneumonia, safety biomarkers (methemoglobin, nitrogen dioxide levels), blood transfusion needs, platelet counts, and postoperative bleeding.

Major Findings

– The NO group showed a significantly lower AKI incidence (23.5%) compared to controls (39.7%), with a relative risk reduction to 0.59 (P=0.043).
– GFR at 6 months post-surgery was significantly higher in the NO group, indicating sustained renal protection.
– Postoperative pneumonia was halved in NO-treated patients, suggesting immunomodulatory or anti-inflammatory benefits.
– Safety monitoring revealed stable methemoglobin and nitrogen dioxide concentrations, absence of increased oxidative-nitrosyl stress, and no difference in surgery-related bleeding or transfusion.

Mechanistic Insights and Translational Implications

NO’s renal protective effects likely stem from its ability to maintain renal microcirculation during CPB-induced ischemia-reperfusion injury, reducing endothelial dysfunction and inflammation. Additionally, NO may modulate systemic inflammatory response and oxidative stress, which contribute to postoperative complications including pneumonia. The synergistic effects impact both renal and pulmonary outcomes, representing a novel multi-organ protective strategy.

Expert Commentary

The DEFENDER Trial provides high-level evidence supporting the integration of inhaled NO therapy in perioperative management protocols for CKD patients undergoing cardiac surgery. This advancement addresses a critical unmet need given the vulnerability of this population to AKI and its long-term sequelae. Importantly, the trial confirmed safety, a crucial factor considering potential concerns about NO-related methemoglobinemia or bleeding risks. While these findings are compelling, future larger multicenter trials are warranted to confirm benefits across diverse populations and surgical settings. The potential interplay between NO and other renoprotective measures, such as hemodynamic optimization and avoidance of nephrotoxic agents, requires further elucidation.

Current guidelines have yet to incorporate perioperative NO for AKI prevention, but mechanistic advantages and emerging clinical efficacy position it as a promising adjunctive therapy. The translational relevance extends to other ischemia-reperfusion injuries beyond cardiac surgery, perhaps including transplantation and vascular surgery.

Conclusion

Perioperative inhaled nitric oxide represents a safe and effective pharmacologic intervention that reduces acute kidney injury incidence and helps preserve long-term renal function in CKD patients undergoing cardiac surgery with cardiopulmonary bypass. It also lowers postoperative pneumonia rates, suggesting broader systemic benefits. This therapeutic approach addresses a critical clinical gap, offering hope for improved perioperative outcomes in a vulnerable patient subset. Further research should validate these findings and explore integration into comprehensive perioperative care pathways.

References

• Kamenshchikov NO, Tyo MA, Berra L, et al. Perioperative Nitric Oxide Conditioning Reduces Acute Kidney Injury in Cardiac Surgery Patients with Chronic Kidney Disease (the DEFENDER Trial): A Randomized Controlled Trial. Anesthesiology. 2025;143(2):287-299. doi:10.1097/ALN.0000000000005494. PMID: 40203179.
• KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2(1):1-138.
• Gladwin MT. Nitric oxide: physiology and pathophysiology in the cardiovascular system. J Am Coll Cardiol. 2006;47(4):815-825.
• Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet. 2012;380(9843):756-766.