ENOS & ET-1 in AKI Cardiac Surgery
Current Evidence Status
The available guidelines and research do not provide specific recommendations regarding the use of endothelial nitric oxide synthase (ENOS) or endothelin-1 (ET-1) modulation for preventing acute kidney injury in cardiac surgery patients. While the pathophysiology of cardiac surgery-associated AKI (CSA-AKI) involves renal hypoperfusion and endothelial dysfunction—mechanisms in which ENOS and ET-1 theoretically play roles—no clinical trials or guidelines have established these as therapeutic targets.
Pathophysiological Context
The pathogenesis of CSA-AKI is multifactorial and includes:
- Renal hypoperfusion from low cardiac output and high venous pressure, which would theoretically involve nitric oxide-mediated vasodilation pathways 1
- Direct tubular toxicity via reactive oxygen species and cellular injury mechanisms 1
- Decreased glomerular filtration and renal medullary ischemia 1
High-dose statins administered before cardiac procedures have demonstrated reduction in contrast-induced AKI, possibly through pleiotropic effects that decrease the synthesis of endothelin-1 and inhibit tissue-factor expression by macrophages 1. This represents the only guideline-supported intervention that specifically mentions ET-1 modulation, though it is in the context of contrast-induced rather than surgery-associated AKI.
Evidence-Based Prevention Strategies
Since ENOS and ET-1 are not established therapeutic targets, focus should be on proven preventive measures:
Hemodynamic Optimization
- Maintain adequate intravascular volume for renal perfusion using isotonic crystalloids rather than colloids 1, 2
- Use vasopressors in conjunction with fluids in patients with vasomotor shock 2
- Target mean arterial pressure >65 mmHg to ensure adequate renal perfusion 3
- Implement goal-directed fluid therapy with quantified goals for blood pressure, cardiac index, and urine output 2
Medication Management
- Discontinue ACE inhibitors and ARBs for 48 hours post-surgery 2
- Avoid nephrotoxic agents including NSAIDs and aminoglycosides when alternatives exist 2, 3
- Consider high-dose statins before procedures for their anti-inflammatory effects that may include ET-1 synthesis reduction 1
Surgical Technique
- Use radial artery access when feasible to reduce atheroembolism risk near renal arteries 1
- Minimize contrast media volume and avoid exceeding maximum contrast dose (contrast volume/eGFR) 1
- Consider increasing cardiopulmonary bypass flow to improve renal oxygenation 2
Risk Stratification
Identify high-risk patients with:
- Age >56 years, chronic kidney disease (eGFR <60 mL/min/1.73 m²) 1
- Emergency surgery, active heart failure, diabetes mellitus 1
- Pre-operative creatinine elevation 1
Patients with ≥6 risk factors have a 10% incidence of AKI with a hazard ratio of 46 compared to those with <3 risk factors 1.
Clinical Implications
The absence of ENOS or ET-1-targeted therapies in current guidelines reflects the lack of high-quality evidence supporting their clinical use. While statins may indirectly affect ET-1 synthesis 1, this mechanism is not the primary rationale for their use. The systematic review of 70 randomized controlled trials in cardiac surgery found that most preventive strategies showed wide variation in definitions and limited quality, with only 26% meeting high-quality criteria 4.
Prevention remains the cornerstone of CSA-AKI management since therapeutic interventions and renal replacement therapy have limited influence on outcomes once AKI develops 5, 6. The focus should be on the evidence-based strategies outlined above rather than experimental approaches targeting specific endothelial mediators.