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Renal Effects of Nitric Oxide during Sepsis: Another Two-Edged Sword?

We appreciate the comments by Heemskerk and colleagues regarding our recent article (1). By our study methods, we are not able to distinguish causation from correlation in terms of nitric oxide (NO) levels and clinical outcomes. Hence, we provided several potential explanations including a direct beneficial effect of NO or a role for NO as a marker of less severe injury in certain organs. In specifically evaluating the kidney, we calculated an estimated glomerular filtration rate (GFR) (2) in these critically ill patients as a measure of kidney function. We included GFR in our multivariate analyses and found that higher urine NO levels remained predictive of better clinical outcomes, suggesting that our results were independent of measured impairment in kidney function. We cannot rule out that NO may be damaging to the kidney during acute lung injury (ALI) given that inducible NO synthase (iNOS)–related NO production has been shown to be detrimental to the kidney in experimental models of sepsis (3, 4). If so, a unifying explanation would be that the detrimental effect of NO in the kidneys of our patients is overwhelmed by the beneficial effects of NO in other organs during ALI.

An alternate explanation, offered by Heemskerk and coworkers, is that NO generated by iNOS is detrimental to the kidney during sepsis-related ALI, but not in other conditions predisposing to ALI. If so, a negative effect in septic patients would be diluted by beneficial results in the majority of patients who did not have sepsis predisposing to ALI. As requested by these authors, we ran additional analyses to examine if there was a correlation between NOx levels and renal damage in patients specifically with sepsis as the primary condition predisposing to ALI.

In our first analysis, we determined Spearman correlation coefficients for (1) urine NO/creatinine (Cr) levels and serum Cr and (2) urine NO/Cr and GFR in the 141 patients with sepsis predisposing to ALI. We found significant correlations within this population subset. There was a negative correlation between urine NO/Cr and serum Cr (r = –0.22, p = 0.008) and a positive correlation between urine NO/Cr and estimated GFR (r = 0.21, p = 0.01). The same correlations run for our whole study population showed similar findings (r = –0.27, p < 0.001, and r = 0.26, p < 0.001, respectively). These analyses show that higher NO levels are significantly associated with markers of better renal function—that is, lower serum creatinine and higher GFR.

In addition, we ran a linear regression analysis to assess the interaction between sepsis and Cr. As expected from the Spearman correlations, serum Cr and urine NO/Cr are inversely related (p < 0.0001), but there is no evidence that the impact of serum Cr on urine NO/Cr levels differs for septic versus nonseptic patients (p = 0.94 for serum Cr vs. sepsis interaction). While we cannot rule out a local negative effect for NO in the kidney of our septic ALI patients, we also cannot prove that one exists within this study.

Dana McClintock, Mark Eisner and Michael A. Matthay

University of California, San Francisco, San Francisco, California

FOOTNOTES

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

1. McClintock DE, Ware LB, Eisner MD, Wickersham N, Thompson BT, Matthay MA; National Heart, Lung, and Blood Institute ARDS Network. Higher urine nitric oxide is associated with improved outcomes in patients with acute lung injury. Am J Respir Crit Care Med 2007;175:256–262.[Abstract/Free Full Text]
2. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461–470.[Abstract/Free Full Text]
3. Heemskerk S, Pickkers P, Bouw MPWJM, Draisma A, van der Hoeven JG, Peters WHM, Smits P, Russel FG, Masereeuw R. Upregulation of inducible nitric oxide synthase during human endotoxemia and sepsis is associated with proximal tubule njury. Clin J Am Soc Nephrol 2006;1:853–862.[CrossRef]
4. Heemskerk S, van Koppen A, van den Broek L, Poelen GJ, Wouterse AC, Dijkman HB, Russel FG, Masereeuw R. Nitric oxide differentially regulates renal ATP-binding cassette transporters during endotoxemia. Pflugers Arch 2007;454:321–334.[CrossRef][Medline]

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