© 2007 American Thoracic Society
Renal Effects of Nitric Oxide during Sepsis: Another Two-Edged Sword?To the Editor:Nitric oxide (NO) has been considered an important contributory factor to the pathogenesis of septic shock. Although physiological concentrations of NO exert beneficial effects in several organs, sustained, high-output generation of NO by inducible NO synthase (iNOS) reacts with superoxide ions to form peroxynitrite, which can cause tissue damage (1). In contrast to these detrimental effects of NO, McClintock and colleagues in their recent article reported that higher urine NO metabolites (NOx) at baseline were associated with lower mortality and more organ-failure–free days, in patients with acute lung injury (ALI) (2). This article comprises the first large-scale, multicenter investigation of the role of endogenous NO in ALI, for which we congratulate the authors. In contrast to prior experimental and clinical work that correlated higher levels of NOx with adverse outcomes in ALI (3, 4), this clinical trial demonstrated a possible protective role of NO in other organs during ALI. Apparently, NO produced in the most affected organ in these patients (the lung) improves oxygen and nutrient delivery to other tissues, decreases platelet and leukocyte adhesion to the endothelium, and thereby decreases renal failure (2). Nevertheless, we disagree with the suggestion that a higher urinary NOx level is a biomarker of less severe organ injury, especially during systemic inflammation. We previously demonstrated that iNOS, which is constitutively expressed in renal proximal tubules (5), is up-regulated in renal cells isolated from urine of septic patients and during experimental endotoxemia (6). The urinary excretion of NOx significantly correlated with the excretion of a proximal tubular injury marker during systemic inflammation (r = 0.7, p < 0.01). Recently, we administered the LPS detoxifying enzyme, alkaline phosphatase, to 15 patients with severe sepsis and septic shock in a phase IIa study (S. Heemskerk and coworkers, unpublished data). Alkaline phosphatase inhibited the activity of renal iNOS and, subsequently, reduced NOx production, which was associated with renal function improvement. According to McClintock and coworkers, 27% of the ARDS Network patients suffered from sepsis, and we are interested in whether or not there was also a negative correlation between NOx levels and renal damage in this subset. Our results, combined with those of McClintock and coworkers, suggest that extrarenal production of NO (e.g., in the lung during ARDS) may exert beneficial effects in the kidney, whereas induction of renal iNOS during systemic inflammation results in local accumulation of NO in the proximal tubule, leading to renal damage. Especially during sepsis, this delicate balance of NO-related effects in the kidney appears to be disturbed.
Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands FOOTNOTES Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest if the subject of this manuscript. REFERENCES
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