Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

Nature Reviews Nephrology volume 5, pages 629–640 (2009)Cite this article

Abstract

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

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cascade of events during sepsis leading to acute kidney injury.

Similar content being viewed by others

References

  1. Teres, D., Rapoport, J., Lemeshow, S., Kim, S. & Akhras, K. Effects of severity of illness on resource use by survivors and nonsurvivors of severe sepsis at intensive care unit admission. Crit. Care Med. 30, 2413–2419 (2002).

    Article  PubMed  Google Scholar 

  2. Vincent, J. L. et al. Sepsis in European intensive care units: results of the SOAP study. Crit. Care Med. 34, 344–353 (2006).

    Article  PubMed  Google Scholar 

  3. Silva, E. et al. Brazilian Sepsis Epidemiological Study (BASES). Crit. Care 8, R251–R260 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Nguyen, H. B. et al. Severe sepsis and septic shock: review of the literature and emergency department management guidelines. Ann. Emerg. Med. 48, 28–54 (2006).

    PubMed  Google Scholar 

  5. Chertow, G. M. et al. Mortality after acute renal failure: models for prognostic stratification and risk adjustment. Kidney Int. 70, 1120–1126 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Ronco, C., Kellum, J. A., Bellomo, R. & House, A. A. Potential interventions in sepsis-related acute kidney injury. Clin. J. Am. Soc. Nephrol. 3, 531–544 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bagshaw, S. M. et al. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin. J. Am. Soc. Nephrol. 2, 431–439 (2007).

    Article  PubMed  Google Scholar 

  8. Bellomo, R., Ronco, C., Kellum, J. A., Mehta, R. L. & Palevsky, P. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit. Care 8, R204–R212 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Mehta, R. L. et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit. Care 11, R31 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lopes, J. A. et al. Acute kidney injury in patients with sepsis: a contemporary analysis. Int. J. Infect. Dis. 13, 176–181 (2009).

    Article  PubMed  Google Scholar 

  11. Bagshaw, S. M. et al. Acute kidney injury in septic shock: clinical outcomes and impact of duration of hypotension prior to initiation of antimicrobial therapy. Intensive Care Med. 35, 871–881 (2009).

    Article  PubMed  Google Scholar 

  12. Neveu, H., Kleinknecht, D., Brivet, F., Loirat, P. & Landais, P. Prognostic factors in acute renal failure due to sepsis. Results of a prospective multicentre study. The French Study Group on Acute Renal Failure. Nephrol. Dial. Transplant. 11, 293–299 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Wan, L. et al. Pathophysiology of septic acute kidney injury: what do we really know? Crit. Care Med. 36, S198–S203 (2008).

    Article  PubMed  Google Scholar 

  14. Lopes, J. A. et al. Acute renal failure in patients with sepsis. Crit. Care 11, 411 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Opal, S. M. et al. Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock. J. Infect. Dis. 180, 1584–1589 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Marshall, J. C. Lipopolysaccharide: an endotoxin or an exogenous hormone? Clin. Infect. Dis. 41 (Suppl. 7), S470–S480 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Braude, A. I., Carey, F. J. & Zalesky, M. Studies with radioactive endotoxin. II. Correlation of physiologic effects with distribution of radioactivity in rabbits injected with radioactive sodium chromate. J. Clin. Invest. 34, 858–866 (1955).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. de Haas, C. J., van Leeuwen, H. J., Verhoef, J., van Kessel, K. P. & van Strijp, J. A. Analysis of lipopolysaccharide (LPS)-binding characteristics of serum components using gel filtration of FITC-labeled LPS. J. Immunol. Methods 242, 79–89 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Triantafilou, M. & Triantafilou, K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends Immunol. 23, 301–304 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Chowdhury, P., Sacks, S. H. & Sheerin, N. S. Toll-like receptors TLR2 and TLR4 initiate the innate immune response of the renal tubular epithelium to bacterial products. Clin. Exp. Immunol. 145, 346–356 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lopez-Bojorquez, L. N., Dehesa, A. Z. & Reyes-Teran, G. Molecular mechanisms involved in the pathogenesis of septic shock. Arch. Med. Res. 35, 465–479 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Dear, J. W. et al. Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: acute renal failure is dependent on MyD88 but not renal cell apoptosis. Kidney Int. 69, 832–836 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cohen, J. The immunopathogenesis of sepsis. Nature 420, 885–891 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Al-Lamki, R. S. et al. Expression of tumor necrosis factor receptors in normal kidney and rejecting renal transplants. Lab. Invest. 81, 1503–1515 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Thiemermann, C. Nitric oxide and septic shock. Gen. Pharmacol. 29, 159–166 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Schrier, R. W. & Wang, W. Acute renal failure and sepsis. N. Engl. J. Med. 351, 159–169 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Knotek, M. et al. Endotoxemic renal failure in mice: role of tumor necrosis factor independent of inducible nitric oxide synthase. Kidney Int. 59, 2243–2249 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Millar, C. G. & Thiemermann, C. Intrarenal haemodynamics and renal dysfunction in endotoxaemia: effects of nitric oxide synthase inhibition. Br. J. Pharmacol. 121, 1824–1830 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chvojka, J. et al. Renal haemodynamic, microcirculatory, metabolic and histopathological responses to peritonitis-induced septic shock in pigs. Crit. Care 12, R164 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Johannes, T. et al. Low-dose dexamethasone-supplemented fluid resuscitation reverses endotoxin-induced acute renal failure and prevents cortical microvascular hypoxia. Shock 31, 521–528 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Chawla, L. S. et al. Elevated plasma concentrations of IL-6 and elevated APACHE II score predict acute kidney injury in patients with severe sepsis. Clin. J. Am. Soc. Nephrol. 2, 22–30 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Traylor, L. A. & Mayeux, P. R. Nitric oxide generation mediates lipid-A-induced oxidant injury in renal proximal tubules. Arch. Biochem. Biophys. 338, 129–135 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Furchgott, R. F. & Zawadzki, J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288, 373–376 (1980).

    Article  CAS  PubMed  Google Scholar 

  34. Beckman, J. S. & Koppenol, W. H. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am. J. Physiol. 271, C1424–C1437 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Lundberg, J. O. & Weitzberg, E. NO generation from nitrite and its role in vascular control. Arterioscler. Thromb. Vasc. Biol. 25, 915–922 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Bultinck, J., Sips, P., Vakaet, L., Brouckaert, P. & Cauwels, A. Systemic NO production during (septic) shock depends on parenchymal and not on hematopoietic cells: in vivo iNOS expression pattern in (septic) shock. FASEB J. 20, 2363–2365 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Wang, W. et al. Endotoxemia-related acute kidney injury in transgenic mice with endothelial overexpression of GTP cyclohydrolase-1. Am. J. Physiol. Renal Physiol. 294, F571–F576 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Ortiz, P. A. & Garvin, J. L. Cardiovascular and renal control in NOS-deficient mouse models. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R628–R638 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Ahn, K. Y., Mohaupt, M. G., Madsen, K. M. & Kone, B. C. In situ hybridization localization of mRNA encoding inducible nitric oxide synthase in rat kidney. Am. J. Physiol. 267, F748–F757 (1994).

    CAS  PubMed  Google Scholar 

  40. Markewitz, B. A., Michael, J. R. & Kohan, D. E. Cytokine-induced expression of a nitric oxide synthase in rat renal tubule cells. J. Clin. Invest. 91, 2138–2143 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kone, B. C. & Baylis, C. Biosynthesis and homeostatic roles of nitric oxide in the normal kidney. Am. J. Physiol. 272, F561–F578 (1997).

    CAS  PubMed  Google Scholar 

  42. Heemskerk, S. et al. Up-regulation of renal iNOS during human endotoxemia and sepsis is associated with proximal tubule injury. Clin. J. Am. Soc. Nephrol. 1, 853–862 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Heemskerk, S. et al. Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. Crit. Care Med. 37, 417e1–423e1 (2009).

    Article  CAS  Google Scholar 

  44. Vallance, P. & Leiper, J. Blocking NO synthesis: how, where and why? Nat. Rev. Drug Discov. 1, 939–950 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Delles, C. et al. The role of nitric oxide in the regulation of glomerular haemodynamics in humans. Nephrol. Dial. Transplant. 19, 1392–1397 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Brown, R., Ollerstam, A. & Persson, A. E. Neuronal nitric oxide synthase inhibition sensitizes the tubuloglomerular feedback mechanism after volume expansion. Kidney Int. 65, 1349–1356 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Hu, L. & Manning, R. D. Jr. Role of nitric oxide in regulation of long-term pressure-natriuresis relationship in Dahl rats. Am. J. Physiol. 268, H2375–H2383 (1995).

    CAS  PubMed  Google Scholar 

  48. Majid, D. S., Williams, A. & Navar, L. G. Inhibition of nitric oxide synthesis attenuates pressure-induced natriuretic responses in anesthetized dogs. Am. J. Physiol. 264, F79–F87 (1993).

    CAS  PubMed  Google Scholar 

  49. De Nicola, L., Blantz, R. C. & Gabbai, F. B. Nitric oxide and angiotensin II. Glomerular and tubular interaction in the rat. J. Clin. Invest. 89, 1248–1256 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Schwartz, D. et al. Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. J. Clin. Invest. 100, 439–448 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chauhan, S. D. et al. Protection against lipopolysaccharide-induced endothelial dysfunction in resistance and conduit vasculature of iNOS knockout mice. FASEB J. 17, 773–775 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Schwartz, D. & Blantz, R. C. Nitric oxide, sepsis, and the kidney. Semin. Nephrol. 19, 272–276 (1999).

    CAS  PubMed  Google Scholar 

  53. Cohen, R. I. et al. Renal effects of nitric oxide in endotoxemia. Am. J. Respir. Crit. Care Med. 164, 1890–1895 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Shultz, P. J. & Raij, L. Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis. J. Clin. Invest. 90, 1718–1725 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Szabo, C. Multiple pathways of peroxynitrite cytotoxicity. Toxicol. Lett. 140–141, 105–112 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Harrois, A., Huet, O. & Duranteau, J. Alterations of mitochondrial function in sepsis and critical illness. Curr. Opin. Anaesthesiol. 22, 143–149 (2009).

    Article  PubMed  Google Scholar 

  57. Lancaster, J. R. Jr. Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc. Natl Acad. Sci. USA 91, 8137–8141 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yu, L., Gengaro, P. E., Niederberger, M., Burke, T. J. & Schrier, R. W. Nitric oxide: a mediator in rat tubular hypoxia/reoxygenation injury. Proc. Natl Acad. Sci. USA 91, 1691–1695 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ling, H. et al. Effect of hypoxia on proximal tubules isolated from nitric oxide synthase knockout mice. Kidney Int. 53, 1642–1646 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Peresleni, T., Noiri, E., Bahou, W. F. & Goligorsky, M. S. Antisense oligodeoxynucleotides to inducible NO synthase rescue epithelial cells from oxidative stress injury. Am. J. Physiol. 270, F971–F977 (1996).

    CAS  PubMed  Google Scholar 

  61. Greenacre, S. A. & Ischiropoulos, H. Tyrosine nitration: localisation, quantification, consequences for protein function and signal transduction. Free Radic. Res. 34, 541–581 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Wu, L., Gokden, N. & Mayeux, P. R. Evidence for the role of reactive nitrogen species in polymicrobial sepsis-induced renal peritubular capillary dysfunction and tubular injury. J. Am. Soc. Nephrol. 18, 1807–1815 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Wu, Y. T., Chou, Y. C., Guo, W. Y., Yeh, T. C. & Hsieh, J. C. Classification of spatiotemporal hemodynamics from brain perfusion MR images using expectation-maximization estimation with finite mixture of multivariate Gaussian distributions. Magn. Reson. Med. 57, 181–191 (2007).

    Article  PubMed  Google Scholar 

  64. Wolin, M. S., Ahmad, M. & Gupte, S. A. The sources of oxidative stress in the vessel wall. Kidney Int. 67, 1659–1661 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Molitoris, B. A. & Sutton, T. A. Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int. 66, 496–499 (2004).

    Article  PubMed  Google Scholar 

  66. Yuan, H. T., Li, X. Z., Pitera, J. E., Long, D. A. & Woolf, A. S. Peritubular capillary loss after mouse acute nephrotoxicity correlates with down-regulation of vascular endothelial growth factor-A and hypoxia-inducible factor-1α. Am. J. Pathol. 163, 2289–2301 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tiwari, M. M., Brock, R. W., Megyesi, J. K., Kaushal, G. P. & Mayeux, P. R. Disruption of renal peritubular blood flow in lipopolysaccharide-induced renal failure: role of nitric oxide and caspases. Am. J. Physiol. Renal Physiol. 289, F1324–F1332 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Cuzzocrea, S. et al. A role for nitric oxide-mediated peroxynitrite formation in a model of endotoxin-induced shock. J. Pharmacol. Exp. Ther. 319, 73–81 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Bian, K., Davis, K., Kuret, J., Binder, L. & Murad, F. Nitrotyrosine formation with endotoxin-induced kidney injury detected by immunohistochemistry. Am. J. Physiol. 277, F33–F40 (1999).

    CAS  PubMed  Google Scholar 

  70. Heemskerk, S. et al. Nitric oxide differentially regulates renal ATP binding cassette transporters during endotoxemia. Pflugers Archiv. Eur. J. Physiol. 454, 321–334 (2007).

    Article  CAS  Google Scholar 

  71. Zhang, C., Walker, L. M. & Mayeux, P. R. Role of nitric oxide in lipopolysaccharide-induced oxidant stress in the rat kidney. Biochem. Pharmacol. 59, 203–209 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Fukuyama, N. et al. Clinical evidence of peroxynitrite formation in chronic renal failure patients with septic shock. Free Radic. Biol. Med. 22, 771–774 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Groeneveld, P. H., Kwappenberg, K. M., Langermans, J. A., Nibbering, P. H. & Curtis, L. Nitric oxide (NO) production correlates with renal insufficiency and multiple organ dysfunction syndrome in severe sepsis. Intensive Care Med. 22, 1197–1202 (1996).

    Article  CAS  PubMed  Google Scholar 

  74. Evans, T., Carpenter, A., Kinderman, H. & Cohen, J. Evidence of increased nitric oxide production in patients with the sepsis syndrome. Circ. Shock 41, 77–81 (1993).

    CAS  PubMed  Google Scholar 

  75. Werra, I. D. et al. Cytokines, nitrite/nitrate, soluble tumor necrosis factor receptors and procalcitonin concentrations: comparisons in patients with septic shock, cardiogenic shock, and bacterial pneumonia. Crit. Care Med. 25, 607–613 (1997).

    Article  PubMed  Google Scholar 

  76. Ochoa, J. B. et al. Nitrogen oxide levels in patients after trauma and during sepsis. Ann. Surg. 214, 621–626 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang, H. D., Lu, D. X. & Qi, R. B. Therapeutic strategies targeting the LPS signaling and cytokines. Pathophysiology 16, 291–296 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Ianaro, A., Tersigni, M. & D'Acquisto, F. New insight in LPS antagonist. Mini Rev. Med. Chem. 9, 306–317 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Lorente, J. A. & Marshall, J. C. Neutralization of tumor necrosis factor in preclinical models of sepsis. Shock 24 (Suppl. 1), 107–119 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Radomski, M. W., Palmer, R. M. & Moncada, S. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc. Natl Acad. Sci. USA 87, 10043–10047 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tsao, C. M. et al. Low-dose dexamethasone ameliorates circulatory failure and renal dysfunction in conscious rats with endotoxemia. Shock 21, 484–491 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Miyaji, T. et al. Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice. Kidney Int. 64, 1620–1631 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Chiao, C. W., Lee, S. S., Wu, C. C. & Su, M. J. N-Allylsecoboldine as a novel agent prevents acute renal failure during endotoxemia. Eur. J. Pharmacol. 535, 291–300 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Liaw, W. J. et al. Effects of a membrane-permeable radical scavenger, Tempol, on intraperitoneal sepsis-induced organ injury in rats. Shock 23, 88–96 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Kadkhodaee, M. & Qasemi, A. Inhibition of inducible nitric oxide synthase reduces lipopolysaccharide-induced renal injury in the rat. Clin. Exp. Pharmacol. Physiol. 31, 842–846 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Rees, D. D., Palmer, R. M., Schulz, R., Hodson, H. F. & Moncada, S. Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br. J. Pharmacol. 101, 746–752 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Southan, G. J. & Szabo, C. Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. Biochem. Pharmacol. 51, 383–394 (1996).

    Article  CAS  PubMed  Google Scholar 

  88. Thiemermann, C., Szabo, C., Mitchell, J. A. & Vane, J. R. Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide. Proc. Natl Acad. Sci. USA 90, 267–271 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bolton, W. K. et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am. J. Nephrol. 24, 32–40 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Ruetten, H., Southan, G. J., Abate, A. & Thiemermann, C. Attenuation of endotoxin-induced multiple organ dysfunction by 1-amino-2-hydroxy-guanidine, a potent inhibitor of inducible nitric oxide synthase. Br. J. Pharmacol. 118, 261–270 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Szabo, C. et al. Mercaptoethylguanidine and guanidine inhibitors of nitric-oxide synthase react with peroxynitrite and protect against peroxynitrite-induced oxidative damage. J. Biol. Chem. 272, 9030–9036 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Boer, R. et al. The inhibitory potency and selectivity of arginine substrate site nitric-oxide synthase inhibitors is solely determined by their affinity toward the different isoenzymes. Mol. Pharmacol. 58, 1026–1034 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Garvey, E. P. et al. Potent and selective inhibition of human nitric oxide synthases. Inhibition by non-amino acid isothioureas. J. Biol. Chem. 269, 26669–26676 (1994).

    CAS  PubMed  Google Scholar 

  94. Blasko, E. et al. Mechanistic studies with potent and selective inducible nitric-oxide synthase dimerization inhibitors. J. Biol. Chem. 277, 295–302 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Matejovic, M. et al. Selective inducible nitric oxide synthase inhibition during long-term hyperdynamic porcine bacteremia. Shock 21, 458–465 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Asakura, H. et al. Selective inducible nitric oxide synthase inhibition attenuates organ dysfunction and elevated endothelin levels in LPS-induced DIC model rats. J. Thromb. Haemost. 3, 1050–1055 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Wray, G. M., Millar, C. G., Hinds, C. J. & Thiemermann, C. Selective inhibition of the activity of inducible nitric oxide synthase prevents the circulatory failure, but not the organ injury/dysfunction, caused by endotoxin. Shock 9, 329–335 (1998).

    Article  CAS  PubMed  Google Scholar 

  98. Liaudet, L., Fishman, D., Markert, M., Perret, C. & Feihl, F. L-Canavanine improves organ function and tissue adenosine triphosphate levels in rodent endotoxemia. Am. J. Respir. Crit. Care Med. 155, 1643–1648 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Marzocco, S. et al. Effect of methylguanidine in a model of septic shock induced by LPS. Free Radic. Res. 38, 1143–1153 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Russell, J. A. Management of sepsis. N. Engl. J. Med. 355, 1699–1713 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. De Vriese, A. S. Prevention and treatment of acute renal failure in sepsis. J. Am. Soc. Nephrol. 14, 792–805 (2003).

    Article  PubMed  Google Scholar 

  102. Rivers, E. et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N. Engl. J. Med. 345, 1368–1377 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. van den Berghe, G. et al. Intensive insulin therapy in the critically ill patients. N. Engl. J. Med. 345, 1359–1367 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Schetz, M., Vanhorebeek, I., Wouters, P. J., Wilmer, A. & van den Berghe, G. Tight blood glucose control is renoprotective in critically ill patients. J. Am. Soc. Nephrol. 19, 571–578 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Griesdale, D. E. et al. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ 180, 821–827 (2009).

    Article  PubMed  Google Scholar 

  106. [No authors listed] Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N. Engl. J. Med. 342, 1301–1308 (2000).

  107. Bernard, G. R. et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N. Engl. J. Med. 336, 912–918 (1997).

    Article  CAS  PubMed  Google Scholar 

  108. Keh, D. & Sprung, C. L. Use of corticosteroid therapy in patients with sepsis and septic shock: an evidence-based review. Crit. Care Med. 32, S527–S533 (2004).

    Article  PubMed  Google Scholar 

  109. Annane, D. Glucocorticoids in the treatment of severe sepsis and septic shock. Curr. Opin. Crit. Care 11, 449–453 (2005).

    Article  PubMed  Google Scholar 

  110. Sprung, C. L. et al. Hydrocortisone therapy for patients with septic shock. N. Engl. J. Med. 358, 111–124 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Warren, H. S., Suffredini, A. F., Eichacker, P. Q. & Munford, R. S. Risks and benefits of activated protein C treatment for severe sepsis. N. Engl. J. Med. 347, 1027–1030 (2002).

    Article  PubMed  Google Scholar 

  112. Bernard, G. R. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344, 699–709 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Woodward, B. & Cartwright, M. Safety of drotrecogin alfa (activated) in severe sepsis: data from adult clinical trials and observational studies. J. Crit. Care doi:10.1016/j.jcrc.2008.11.011

  114. Martich, G. D., Boujoukos, A. J. & Suffredini, A. F. Response of man to endotoxin. Immunobiology 187, 403–416 (1993).

    Article  CAS  PubMed  Google Scholar 

  115. Taveira da Silva, A. M. et al. Brief report: shock and multiple-organ dysfunction after self-administration of Salmonella endotoxin. N. Engl. J. Med. 328, 1457–1460 (1993).

    Article  CAS  PubMed  Google Scholar 

  116. Baumgartner, J. D. et al. Association between protective efficacy of anti-lipopolysaccharide (LPS) antibodies and suppression of LPS-induced tumor necrosis factor α and interleukin 6. Comparison of O-side-chain-specific antibodies with core LPS antibodies. J. Exp. Med. 171, 889–896 (1990).

    Article  CAS  PubMed  Google Scholar 

  117. Bone, R. C. et al. A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. The E5 Sepsis Study Group. Crit. Care Med. 23, 994–1006 (1995).

    Article  CAS  PubMed  Google Scholar 

  118. Willatts, S. M., Radford, S. & Leitermann, M. Effect of the antiendotoxic agent, taurolidine, in the treatment of sepsis syndrome: a placebo-controlled, double-blind trial. Crit. Care Med. 23, 1033–1039 (1995).

    Article  CAS  PubMed  Google Scholar 

  119. Ziegler, E. J. et al. Treatment of Gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N. Engl. J. Med. 324, 429–436 (1991).

    Article  CAS  PubMed  Google Scholar 

  120. Angus, D. C. et al. E5 murine monoclonal antiendotoxin antibody in Gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. JAMA 283, 1723–1730 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Warren, H. S. et al. Assessment of ability of murine and human anti-lipid A monoclonal antibodies to bind and neutralize lipopolysaccharide. J. Exp. Med. 177, 89–97 (1993).

    Article  CAS  PubMed  Google Scholar 

  122. Gustafson, G. L. & Rhodes, M. J. A rationale for the prophylactic use of monophosphoryl lipid A in sepsis and septic shock. Biochem. Biophys. Res. Commun. 182, 269–275 (1992).

    Article  CAS  PubMed  Google Scholar 

  123. Poelstra, K., Bakker, W. W., Klok, P. A., Hardonk, M. J. & Meijer, D. K. A physiologic function for alkaline phosphatase: endotoxin detoxification. Lab. Invest. 76, 319–327 (1997).

    CAS  PubMed  Google Scholar 

  124. Dinarello, C. A. Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. Chest 112, 321S–329S (1997).

    Article  CAS  PubMed  Google Scholar 

  125. Cavaillon, J. M., Adib-Conquy, M., Fitting, C., Adrie, C. & Payen, D. Cytokine cascade in sepsis. Scand. J. Infect. Dis. 35, 535–544 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Cunningham, P. N., Wang, Y., Guo, R., He, G. & Quigg, R. J. Role of Toll-like receptor 4 in endotoxin-induced acute renal failure. J. Immunol. 172, 2629–2635 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Fiedler, V. B. et al. Monoclonal antibody to tumor necrosis factor-α prevents lethal endotoxin sepsis in adult rhesus monkeys. J. Lab. Clin. Med. 120, 574–588 (1992).

    CAS  PubMed  Google Scholar 

  128. Opal, S. M. et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit. Care Med. 25, 1115–1124 (1997).

    Article  CAS  PubMed  Google Scholar 

  129. Reinhart, K. & Karzai, W. Anti-tumor necrosis factor therapy in sepsis: update on clinical trials and lessons learned. Crit. Care Med. 29, S121–S125 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Abraham, E. et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet 351, 929–933 (1998).

    Article  CAS  PubMed  Google Scholar 

  131. Cohen, J. & Carlet, J. INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-α in patients with sepsis. International Sepsis Trial Study Group. Crit. Care Med. 24, 1431–1440 (1996).

    Article  CAS  PubMed  Google Scholar 

  132. Angelo, D. J. Nitric oxide scavengers in the treatment of shock associated with systemic inflammatory response syndrome. Expert Opin. Pharmacother. 1, 19–29 (1999).

    Article  PubMed  Google Scholar 

  133. Yamada, M. et al. Discovery of novel and potent small-molecule inhibitors of NO and cytokine production as antisepsis agents: synthesis and biological activity of alkyl 6-(N-substituted sulfamoyl)cyclohex-1-ene-1-carboxylate. J. Med. Chem. 48, 7457–7467 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Kinasewitz, G. T. et al. Multicenter, randomized, placebo-controlled study of the nitric oxide scavenger pyridoxalated hemoglobin polyoxyethylene in distributive shock. Crit. Care Med. 36, 1999–2007 (2008).

    Article  CAS  PubMed  Google Scholar 

  135. Zacharowski, K. et al. The selective guanylate cyclase inhibitor ODQ reduces multiple organ injury in rodent models of Gram-positive and Gram-negative shock. Crit. Care Med. 29, 1599–1608 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Iwamoto, J., Yoshinaga, M., Yang, S. P., Krasney, E. & Krasney, J. Methylene blue inhibits hypoxic cerebral vasodilation in awake sheep. J. Appl. Physiol. 73, 2226–2232 (1992).

    Article  CAS  PubMed  Google Scholar 

  137. Mayer, B., Brunner, F. & Schmidt, K. Inhibition of nitric oxide synthesis by methylene blue. Biochem. Pharmacol. 45, 367–374 (1993).

    Article  CAS  PubMed  Google Scholar 

  138. Marczin, N., Ryan, U. S. & Catravas, J. D. Methylene blue inhibits nitrovasodilator- and endothelium-derived relaxing factor-induced cyclic GMP accumulation in cultured pulmonary arterial smooth muscle cells via generation of superoxide anion. J. Pharmacol. Exp. Ther. 263, 170–179 (1992).

    CAS  PubMed  Google Scholar 

  139. Heemskerk, S. et al. Short-term beneficial effects of methylene blue on kidney damage in septic shock patients. Intensive Care Med. 34, 350–354 (2008).

    Article  CAS  PubMed  Google Scholar 

  140. Vallance, P., Leone, A., Calver, A., Collier, J. & Moncada, S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339, 572–575 (1992).

    Article  CAS  PubMed  Google Scholar 

  141. Nijveldt, R. J. et al. Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotoxaemia. Nephrol. Dial. Transplant. 18, 2542–2550 (2003).

    Article  CAS  PubMed  Google Scholar 

  142. Onozato, M. L. et al. Expression of NG, NG-dimethylarginine dimethylaminohydrolase and protein arginine, N-methyltransferase isoforms in diabetic rat kidney: effects of angiotensin II receptor blockers. Diabetes 57, 172–180 (2008).

    Article  CAS  PubMed  Google Scholar 

  143. O'Dwyer, M. J. et al. Septic shock is correlated with asymmetrical dimethyl arginine levels, which may be influenced by a polymorphism in the dimethylarginine dimethylaminohydrolase II gene: a prospective observational study. Crit. Care 10, R139 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Dijkhorst-Oei, L. T. & Koomans, H. A. Effects of a nitric oxide synthesis inhibitor on renal sodium handling and diluting capacity in humans. Nephrol. Dial. Transplant. 13, 587–593 (1998).

    Article  CAS  PubMed  Google Scholar 

  145. Haynes, W. G. et al. Physiological role of nitric oxide in regulation of renal function in humans. Am. J. Physiol. 272, F364–F371 (1997).

    CAS  PubMed  Google Scholar 

  146. Lopez, A. et al. Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit. Care Med. 32, 21–30 (2004).

    Article  CAS  PubMed  Google Scholar 

  147. Petros, A. et al. Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc. Res. 28, 34–39 (1994).

    Article  CAS  PubMed  Google Scholar 

  148. Schilling, J., Cakmakci, M., Battig, U. & Geroulanos, S. A new approach in the treatment of hypotension in human septic shock by NG-monomethyl-L-arginine, an inhibitor of the nitric oxide synthetase. Intensive Care Med. 19, 227–231 (1993).

    Article  CAS  PubMed  Google Scholar 

  149. Ou, P. & Wolff, S. P. Aminoguanidine: a drug proposed for prophylaxis in diabetes inhibits catalase and generates hydrogen peroxide in vitro. Biochem. Pharmacol. 46, 1139–1144 (1993).

    Article  CAS  PubMed  Google Scholar 

  150. Beehler, C. J. et al. Toxic effects of dimethylthiourea in rats. J. Lab. Clin. Med. 123, 73–80 (1994).

    CAS  PubMed  Google Scholar 

  151. Qi, S. et al. Effect of a novel inducible nitric oxide synthase inhibitor, FR260330, in prevention of renal ischemia/reperfusion injury in vervet monkeys. Transplantation 81, 627–631 (2006).

    Article  CAS  PubMed  Google Scholar 

  152. Chatterjee, P. K. et al. GW274150, a potent and highly selective inhibitor of iNOS, reduces experimental renal ischemia/reperfusion injury. Kidney Int. 63, 853–865 (2003).

    Article  CAS  PubMed  Google Scholar 

  153. Le, B. B. et al. Discovery of a series of aminopiperidines as novel iNOS inhibitors. Bioorg. Med. Chem. Lett. 18, 336–343 (2008).

    Article  CAS  Google Scholar 

  154. Thiemermann, C., Ruetten, H., Wu, C. C. & Vane, J. R. The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. Br. J. Pharmacol. 116, 2845–2851 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Gero, D. & Szabo, C. Poly(ADP-ribose) polymerase: a new therapeutic target? Curr. Opin. Anaesthesiol. 21, 111–121 (2008).

    Article  PubMed  Google Scholar 

  156. van de Water, F. M. et al. Intravenously administered short interfering RNA accumulates in the kidney and selectively suppresses gene function in renal proximal tubules. Drug Metab. Dispos. 34, 1393–1397 (2006).

    Article  CAS  PubMed  Google Scholar 

  157. Schramm, L. et al. Endotoxin-induced acute renal failure in rats: effects of L-arginine and nitric oxide synthase inhibition on renal function. J. Nephrol. 18, 374–381 (2005).

    CAS  PubMed  Google Scholar 

  158. Hinder, F. et al. Nitric oxide synthase inhibition during experimental sepsis improves renal excretory function in the presence of chronically increased atrial natriuretic peptide. Crit. Care Med. 24, 131–136 (1996).

    Article  CAS  PubMed  Google Scholar 

  159. Mitaka, C. et al. S-Methylisothiourea sulfate improves renal, but not hepatic dysfunction in canine endotoxic shock model. Intensive Care Med. 26, 117–124 (2000).

    Article  CAS  PubMed  Google Scholar 

  160. Rosselet, A. et al. Selective iNOS inhibition is superior to norepinephrine in the treatment of rat endotoxic shock. Am. J. Respir. Crit. Care Med. 157, 162–170 (1998).

    Article  CAS  PubMed  Google Scholar 

  161. Szabo, C., Southan, G. J. & Thiemermann, C. Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. Proc. Natl Acad. Sci. USA 91, 12472–12476 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Levy, B. et al. Comparative effects of vasopressin, norepinephrine, and L-canavanine, a selective inhibitor of inducible nitric oxide synthase, in endotoxic shock. Am. J. Physiol. Heart Circ. Physiol. 287, H209–H215 (2004).

    Article  CAS  PubMed  Google Scholar 

  163. Mitaka, C., Hirata, Y., Yokoyama, K., Makita, K. & Imai, T. A selective inhibitor for inducible nitric oxide synthase improves hypotension and lactic acidosis in canine endotoxic shock. Crit. Care Med. 29, 2156–2161 (2001).

    Article  CAS  PubMed  Google Scholar 

  164. Wu, C. C., Ruetten, H. & Thiemermann, C. Comparison of the effects of aminoguanidine and Nω-nitro-L-arginine methyl ester on the multiple organ dysfunction caused by endotoxaemia in the rat. Eur. J. Pharmacol. 300, 99–104 (1996).

    Article  CAS  PubMed  Google Scholar 

  165. Wang, L., Fan, X. M. & Tang, H. X. Effects of aminoguanidine in different dosages on renal function in endotoxin induced rabbits shock model [Chinese]. Zhonghua Er Ke Za Zhi 42, 206–209 (2004).

    PubMed  Google Scholar 

  166. Ziegler, E. J. et al. Treatment of Gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. N. Engl. J. Med. 307, 1225–1230 (1982).

    Article  CAS  PubMed  Google Scholar 

  167. Calandra, T., Glauser, M. P., Schellekens, J. & Verhoef, J. Treatment of Gram-negative septic shock with human IgG antibody to Escherichia coli J5: a prospective, double-blind, randomized trial. J. Infect. Dis. 158, 312–319 (1988).

    Article  CAS  PubMed  Google Scholar 

  168. Greenman, R. L. et al. A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of Gram-negative sepsis. The XOMA Sepsis Study Group. JAMA 266, 1097–1102 (1991).

    Article  CAS  PubMed  Google Scholar 

  169. McCloskey, R. V., Straube, R. C., Sanders, C., Smith, S. M. & Smith, C. R. Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group. Ann. Intern. Med. 121, 1–5 (1994).

    Article  CAS  PubMed  Google Scholar 

  170. Levin, M. et al. Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group. Lancet 356, 961–967 (2000).

    Article  CAS  PubMed  Google Scholar 

  171. Werdan, K. et al. Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit. Care Med. 35, 2693–2701 (2007).

    Article  CAS  PubMed  Google Scholar 

  172. Abraham, E. et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor α in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-α MAb Sepsis Study Group. JAMA 273, 934–941 (1995).

    Article  CAS  PubMed  Google Scholar 

  173. Panacek, E. A. et al. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit. Care Med. 32, 2173–2182 (2004).

    Article  CAS  PubMed  Google Scholar 

  174. Fisher, C. J. Jr et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1Ra Sepsis Syndrome Study Group. JAMA 271, 1836–1843 (1994).

    Article  PubMed  Google Scholar 

  175. Kirov, M. Y. et al. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit. Care Med. 29, 1860–1867 (2001).

    Article  CAS  PubMed  Google Scholar 

  176. Andresen, M. et al. Use of methylene blue in patients with refractory septic shock: impact on hemodynamics and gas exchange. J. Crit. Care 13, 164–168 (1998).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Intensive Care Medicine and the Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Suzanne Heemskerk

  2. Department of Pharmacology and Toxicology, Center for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Rosalinde Masereeuw & Frans G. M. Russel

  3. Department of Intensive Care Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Peter Pickkers

Authors
  1. Suzanne Heemskerk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rosalinde Masereeuw
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frans G. M. Russel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Pickkers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suzanne Heemskerk.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heemskerk, S., Masereeuw, R., Russel, F. et al. Selective iNOS inhibition for the treatment of sepsis-induced acute kidney injury. Nat Rev Nephrol 5, 629–640 (2009). https://doi.org/10.1038/nrneph.2009.155

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2009.155

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing