Is Nitric Oxide Nephro- or Cardioprotective?

To the Editor:

We read with interest the article recently published in the Journal by Lei and colleagues entitled “Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery” (1). In a single-center, prospective, randomized, controlled trial, the authors compared inhaled nitric oxide (NO) versus inhaled nitrogen (N2), administered via the gas exchanger during cardiopulmonary bypass and then by inhalation for 24 hours postoperatively, in adult patients undergoing multiple-valve cardiac surgery. A total of 244 patients were included. Inhaled NO was associated with a lower incidence of acute kidney injury (50% in the NO group vs. 64% in the control group; relative risk, 0.78; 95% confidence interval, 0.62–0.97; P = 0.014). These findings might appear to contrast with previously published literature suggesting that NO is nephrotoxic (2).

Inhaled NO-associated renal injury has been suggested to result from tissue hypoxia and oxidative stress through NO by-products, including methemoglobin, NO2−, and NO3− (3). In the present study, the authors suggest that the nephroprotective effect of inhaled NO would arise from the prevention of plasma depletion of NO secondary to circulating plasma hemoglobin, thereby preserving microvascular perfusion. Plasma hemoglobin oxidation by NO inhalation could also reduce free hemoglobin–related toxicity to the kidney. This is, however, highly speculative. We propose a unifying mechanism that may account for some degree of nephroprotection in this setting, i.e., a cardioprotective effect. Right ventricular dysfunction is common after cardiopulmonary bypass and has been found to be associated with renal dysfunction (4). Many experimental and clinical studies have highlighted the role of venous congestion in the development of acute kidney injury. An association between high venous pressure (i.e., right atrial pressure or central venous pressure) and worsening renal function has been described in many different clinical settings, including patients who have undergone cardiac surgery and patients with heart failure (5). We suggest that the observed protective effect on kidney function in this study might be due to a decreased right ventricular afterload, which would decrease the right filling pressure and prevent renal venous congestion after NO inhalation (6). The population investigated in this study furthermore suggests this. Cardiopulmonary bypass was prolonged and most of the surgical procedures were for rheumatic valvular disease, including tricuspid valve surgery. These patients, approximately half of whom had pulmonary artery hypertension, had a high risk of postoperative right cardiac failure. However, data regarding the postoperative hemodynamic parameters are not presented. Unfortunately, the authors point out that transesophageal echocardiography or pulmonary artery catheterization is not the standard of care during surgery in their center—but postoperative monitoring of cardiac function, including the cardiac index and filling pressures (such as the central venous pressure), certainly is. Insights into the impact of inhaled NO on hemodynamics and right filling pressure would help us to better understand the potential mechanisms of nephroprotection and identify the patients who would most benefit from this therapy.