Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery

Acute kidney injury (AKI) is a common and serious complication of cardiac surgical procedures that require prolonged (>90 min) cardiopulmonary bypass (CPB) (1, 2). Although the presence of AKI after CPB is associated with increased mortality, no medical interventions have yet been shown to be associated with improved long-term kidney function (1–7).

The mechanisms leading to AKI are multifactorial and not fully elucidated. However, hemolysis has been shown to be closely associated with postsurgery AKI (8–13). During hemolysis, Hb is released into the circulation in the form of oxyhemoglobin (Oxy-Hb). Plasma Oxy-Hb is filtered by the kidneys and facilitates development of AKI by intrarenal oxidative reactions (14). Furthermore, plasma oxyhemoglobin depletes vascular nitric oxide (NO) via the dioxygenation reaction to form methemoglobin (Met-Hb) (15, 16). Endogenous NO is a potent vasodilator that relaxes vascular smooth muscle, and NO depletion by plasma Oxy-Hb produces vasoconstriction, impairs tissue perfusion, and causes inflammation (17–22). The administration of therapeutic levels of 80 parts per million (ppm) exogenous NO gas oxidizes plasma Oxy-Hb to Met-Hb. The oxidized iron (Met-Hb) species is unable to deplete plasma NO (10, 14, 16, 23). In a human model of blood transfusion, we found that breathing NO at 80 ppm was safe and prevented depletion of plasma NO by circulating plasma Hb (17). In an experimental canine model of free water-induced hemolysis, Minneci and colleagues showed that plasma hemoglobin oxidized by NO inhalation reduced serum creatinine and renal dysfunction (19).

We hypothesized that administration of 80 ppm NO during and for 24 hours after prolonged CPB would convert plasma Oxy-Hb to Met-Hb and prevent intrarenal oxidative reactions and NO scavenging by plasma Oxy-Hb, thereby preserving kidney function. We performed a randomized trial in cardiac surgery patients undergoing multiple valve replacements requiring prolonged CPB to test whether NO could prevent AKI due to high levels of plasma Oxy-Hb caused by acute hemolysis. We monitored patients for up to 1 year after surgery to assess survival and evaluate whether patients who received NO benefited from improved renal function. Some of the results of these studies have been previously reported in the form of an abstract (24).