Perioperative Acute Kidney Injury: Reply

In Reply:

We thank Spina et al.¹ for their interest in our Clinical Focus Review on perioperative acute kidney injury (AKI).² As noted, the nuanced physiology of cardiac surgery, including cardiopulmonary bypass, hemodilution, blood transfusion, cannulation, and surgical technique (including aortic manipulation), makes this population uniquely susceptible to AKI.² We agree that intravascular hemolysis induced from such stressors merits particular attention and may be amenable to interventions recently reviewed in the Journal.³ We also commend Spina et al. for their own pioneering of investigations into the renoprotective effect of exogenous nitric oxide in cardiac surgery.⁴

Clinicians typically administer inhaled nitric oxide for the properties directly resulting from selective pulmonary vasodilation (i.e., treatment of pulmonary hypertension and right ventricular dysfunction). Spina et al. should be commended for calling attention to less well-understood, indirect effect: counteracting endogenous nitric oxide consumption secondary to intravascular hemolysis.¹ As pointed out in their letter, a single-center randomized controlled trial of 244 patients undergoing elective, multiple valve replacement procedures demonstrated that nitric oxide decreased the incidence of AKI.⁵ In this promising study, the primary indication for mitral valve replacement was rheumatic disease (93%), with a relatively high incidence of pulmonary arterial hypertension (51%), for which the direct indication for nitric oxide is better understood.⁵ We look forward to learning whether these results from a largely Han Chinese surgical subpopulation⁵ extend to more general cardiac surgical practice, across a broader range of cardiac surgical patients and procedures.⁶

Other studies on nitric oxide have been less optimistic. For example, inhaled nitric oxide was surprisingly found to increase AKI incidence in patients with acute respiratory distress syndrome,⁷ limiting widespread adoption for patients with severe hypoxemia. Additionally, the high drug cost and inconsistent clinical benefit^8,9 have led to restrictive recommendations regarding use of inhaled nitric oxide during cardiac surgery.¹⁰ Whereas inhaled nitric oxide is typically employed for procedures at high risk for pulmonary hypertension or right ventricular dysfunction, including heart transplantation, lung transplantation, or left ventricular assist device implantation,¹⁰ cost, availability, and efficacy concerns have translated into limited routine use of exogenous nitric oxide for cardiac surgery.

Still, previous work from Spina, Kamenshchikov, Berra, and colleagues has clarified the ideal timing (before initiation of cardiopulmonary bypass) and dosage (80 ppm NO, which is notably higher than 20 ppm typically employed for pulmonary hypertension or right ventricular dysfunction). Additionally, their work confirmed the safety profile for this therapeutic approach. We eagerly anticipate results from new trials,⁶ which may clarify populations where nitric oxide can have the highest impact.

In conclusion, we broadly agree with Spina et al. that intravascular hemolysis can play an important role in the development of cardiac surgery associated AKI. We caution that more studies are necessary to clarify conflicting results and confirm generalizability to a broad range of cardiac surgical procedures if widespread, cost-effective adoption is to be justified. We thank this team for their contributions to the ongoing discussion surrounding postoperative AKI.