Commentary: Encouraging Findings for the Renal-Protective Effect of Nitric Oxide Administration During Cardiopulmonary Bypass.

Central MessageIn a novel ovine study, nitric oxide administration during cardiopulmonary bypass resulted in decreased postoperative creatinine levels and histopathologic evidence of ≥moderate acute kidney injury.See Article page XXX. In a novel ovine study, nitric oxide administration during cardiopulmonary bypass resulted in decreased postoperative creatinine levels and histopathologic evidence of ≥moderate acute kidney injury. See Article page XXX. Acute kidney injury (AKI) remains a persistent source of morbidity and mortality following cardiac surgery with cardiopulmonary bypass (CPB). Although the pathophysiology of AKI is multifactorial, hemolysis during CPB represents 1 important mechanism because it leads to depletion of vascular nitric oxide, a potent vasodilator responsible for modulating organ perfusion and vascular homeostasis.1Spina S. Lei C. Pinciroli R. Berra L. Hemolysis and kidney injury in cardiac surgery: the protective role of nitric oxide therapy.Semin Nephrol. 2019; 39: 484-495Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Decreased nitric oxide in the bloodstream can lead to organ malperfusion, inflammation, oxidative stress, and direct tubular injury, all of which can contribute to AKI after cardiac surgery.1Spina S. Lei C. Pinciroli R. Berra L. Hemolysis and kidney injury in cardiac surgery: the protective role of nitric oxide therapy.Semin Nephrol. 2019; 39: 484-495Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Provision of supplemental exogenous nitric oxide via the CPB oxygenator is one promising new therapy to potentially mitigate CPB-associated AKI.1Spina S. Lei C. Pinciroli R. Berra L. Hemolysis and kidney injury in cardiac surgery: the protective role of nitric oxide therapy.Semin Nephrol. 2019; 39: 484-495Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Greenberg and colleagues2Greenberg J.W. Hogue S. Raees M.A. Ahmed H.F. Abplanap W.A. Guzman-Gomez A. et al.Exogenous nitric oxide delivery protects against cardiopulmonary bypass-associated acute kidney injury: histologic and serologic evidence from an ovine model.J Thorac Cardiovasc Surg. 2023; XX (X-XX)Google Scholar present an animal study that evaluated the renal-protective effect of nitric oxide administration during CPB. Utilizing a novel low-flow then normal-flow CPB strategy, AKI was successfully induced in a subset of animals. Although the study size was limited, the results appear persuasive. Compared with controls, nitric oxide supplementation was associated with decreased postoperative creatinine levels, less histopathologic evidence of moderate/severe AKI, and a trend toward decreased stage 3 AKI. Blood urea nitrogen and cystatin C levels also trended lower at multiple postoperative time points, and may have reached significance in a higher-powered study. The authors conclude that this study corroborates other clinical reports that nitric oxide therapy during CPB may be associated with improved kidney function. Thus far, the results in human clinical studies have been mixed, with the more favorable outcomes shown in adults. In 1 randomized controlled trial of 96 adults undergoing elective cardiac surgery, nitric oxide administration during CPB was associated with decreased AKI.3Kamenshchikov N.O. Anfinogenova Y.J. Kozlov B.N. Svirko Y.S. Pekarskiy S.E. Evthushenko V.V. et al.Nitric oxide delivery during cardiopulmonary bypass reduces acute kidney injury: a randomized trial.J Thorac Cardiovasc Surg. 2022; 163: 1393-1403Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar In another randomized controlled trial of 244 adults undergoing valve replacement surgery, nitric oxide supplementation during CPB and by inhalation for an additional 24 hours decreased the incidence of AKI, transition to stage 3 chronic kidney disease, and major adverse kidney events.4Lei C. Berra L. Rezoagli E. Yu B. Dong H. Yu S. et al.Nitric oxide decreases acute kidney injury and stage 3 chronic kidney disease after cardiac surgery.Am J Respir Crit Card Med. 2018; 198: 1279-1287Crossref PubMed Scopus (65) Google Scholar Currently, similar positive studies in children are lacking. In a retrospective cohort study of 591 children younger than age 18 years, nitric oxide during CPB was not associated with differences in postoperative creatinine levels or incidence of AKI.5Vuong T.A. Rana S. Moore B. Cronin J. Ceneri N.M. Sinha P. et al.Association between exogenous nitric oxide given during cardiopulmonary bypass and the incidence of postoperative kidney injury in children.J Cardiothorac Vasc Anesth. 2022; 36: 2352-2357Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Likewise, in the multicenter NITRIC (Nitric Oxide During Cardiopulmonary Bypass to Improve Recovery in Infants With Congenital Heart Defects) randomized control trial involving 1371 children younger than age 2 years, nitric oxide during CPB was also not associated with differences in postoperative creatinine levels or rates of AKI.6Schlapbach L.J. Gibbons K.S. Horton S.B. Johnson K. Long D.A. Buckley D.H.F. et al.Effect of nitric oxide via cardiopulmonary bypass on ventilator-free days in young children undergoing congenital heart disease surgery: the NITRIC randomized clinical trial.JAMA. 2022; 328: 38-47Crossref PubMed Scopus (5) Google Scholar Although speculative, these conflicting findings in adults and children may be potentially attributable to differences in the underlying health of the vascular endothelium. In response to hemolysis and nitric oxide depletion, a healthy endothelium can compensate through increased nitric oxide production.1Spina S. Lei C. Pinciroli R. Berra L. Hemolysis and kidney injury in cardiac surgery: the protective role of nitric oxide therapy.Semin Nephrol. 2019; 39: 484-495Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar On the other hand, dysfunctional endothelium is unable to mount an appropriate response and the endogenous pool of nitric oxide is compromised.1Spina S. Lei C. Pinciroli R. Berra L. Hemolysis and kidney injury in cardiac surgery: the protective role of nitric oxide therapy.Semin Nephrol. 2019; 39: 484-495Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Adult patients undergoing cardiac surgery may have worse baseline endothelium function due to the common risk factors of atherosclerosis, peripheral vascular disease, obesity, and diabetes.1Spina S. Lei C. Pinciroli R. Berra L. Hemolysis and kidney injury in cardiac surgery: the protective role of nitric oxide therapy.Semin Nephrol. 2019; 39: 484-495Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Consequently, these patients may experience a greater relative benefit from nitric oxide supplementation. Although it remains to be seen whether or not intraoperative nitric oxide supplementation will gain traction in the prevention of CPB-associated AKI in either population, the results of this ovine study are encouraging and argue that further investigation is warranted. Exogenous nitric oxide delivery protects against cardiopulmonary bypass–associated acute kidney injury: Histologic and serologic evidence from an ovine modelThe Journal of Thoracic and Cardiovascular SurgeryPreviewSeveral human studies have associated nitric oxide administration via the cardiopulmonary bypass circuit with decreased incidence of cardiopulmonary bypass–associated acute kidney injury, but histopathologic and serologic evidence of nitric oxide efficacy for acute kidney injury attenuation are lacking. Full-Text PDF