Selective iNOS inhibition for the treatment of sepsis-induced acute kidney injury

• Published in: Nature reviews. Nephrology Vol. 5; no. 11; pp. 629 - 640
• Main Authors: Heemskerk, Suzanne, Masereeuw, Rosalinde, Russel, Frans G. M, Pickkers, Peter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2009; Nature Publishing Group
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - etiology; Animals; Complications and side effects; Cytokines; Drug therapy; Enzyme Inhibitors - therapeutic use; Health aspects; Hemodynamics; Humans; Inflammation; Intensive care; Kidney diseases; Kidneys; Medicine; Medicine & Public Health; Mortality; Nephrology; Nitric oxide; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; Physiological aspects; review-article; Risk factors; Sepsis; Sepsis - complications; Septic shock; Toxicology; Tumor necrosis factor-TNF; Netherlands
• ISSN: 1759-5061; 1759-507X
• DOI: 10.1038/nrneph.2009.155

The incidence and mortality of sepsis and the associated development of acute kidney injury (AKI) remain high, despite intense research into potential treatment strategies. Inducible nitric oxide synthase—which is constitutively expressed in the kidney but is not expressed in many other organs—has known importance in the pathogenesis of sepsis-induced AKI in humans. In this article, Heemskerk and colleagues discuss the selective inhibition of iNOS as a potential novel treatment for sepsis-induced AKI. The incidence and mortality of sepsis and the associated development of acute kidney injury (AKI) remain high, despite intense research into potential treatments. Targeting the inflammatory response and/or sepsis-induced alterations in the (micro)circulation are two therapeutic strategies. Another approach could involve modulating the downstream mechanisms that are responsible for organ system dysfunction. Activation of inducible nitric oxide (NO) synthase (iNOS) during sepsis leads to elevated NO levels that influence renal hemodynamics and cause peroxynitrite-related tubular injury through the local generation of reactive nitrogen species. In many organs iNOS is not constitutively expressed; however, it is constitutively expressed in the kidney and, in humans, a relationship between the upregulation of renal iNOS and proximal tubular injury during systemic inflammation has been demonstrated. For these reasons, the selective inhibition of renal iNOS might have important implications for the treatment of sepsis-induced AKI. Various animal studies have demonstrated that selective iNOS inhibition—in contrast to nonselective NOS inhibition—attenuates sepsis-induced renal dysfunction and improves survival, a finding that warrants investigation in clinical trials. In this Review, the selective inhibition of iNOS as a potential novel treatment for sepsis-induced AKI is discussed. Key Points Clinical studies rarely show an improvement of renal function in patients with severe sepsis or septic shock Although the pathogenesis of sepsis-induced acute kidney injury (AKI) is multifactorial and not well understood, nitric oxide (NO) is considered to have an important role in this process Inducible NO synthase (iNOS) is constitutively expressed in the kidney, which probably facilitates the rapid upregulation of its expression in the kidney during systemic inflammation Rather than being the result of hemodynamic effects, sepsis-induced AKI is more likely to be the consequence of a toxic state in which local effects of excessive NO release and peroxynitrite might have a role The deleterious effects of interventions with nonselective inhibitors of NOS might be explained by the physiological and protective actions of NO—produced by endothelial NOS—that need to be maintained The selective inhibition of iNOS has beneficial effects during systemic inflammation in animal and human experimental studies, a finding that could have important implications for the treatment of AKI in patients with sepsis