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New markers of inflammation-induced renal injury subside when endotoxin tolerance develops in humans as measured by urine proteomics


Sepsis has been identified as the most common cause of renal injury in ICUs although the pathophysiology is not well understood. No large clinical studies are available that show an improvement of renal function in patients with sepsis and this may be related to the lack of early diagnostic tests that indicate the onset of renal injury. The aim of the current study was to search for potential new early markers of renal injury during acute endotoxemia and to investigate whether renal injury can be ameliorated by the induction of lipopolysaccharide (LPS) tolerance.


Five healthy males received intravenous bolus injections of 2 ng/kg/day Escherichia coli LPS for 5 consecutive days. We used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (Seldi-TOF MS). This approach allows for rapid high-throughput profiling of multiple urine samples and detects low molecular weight biomarkers.


Repeated LPS administrations induced a diminished glomerular filtration rate of 33 ± 7% (P = 0.02) on day 2 and an increase in serum creatinine of 11 ± 3% (P = 0.002) on day 3, which was associated with the appearance of 15 peak intensities in the urinary protein profile including an increase in β-microglobulin levels (P = 0.04) 6 hours after the first LPS administration. Four of the 15 peak intensities on day 1 correlated with serum creatinine levels on day 3; 3,950, 4,445, 6,723 and 7,735 m/z(P = 0.03; 0.01; 0.02 and 0.05, respectively). With the development of LPS tolerance, renal function was restored, reflected by a decrease in serum creatinine and β-microglobulin levels to baseline (P = 0.2 and 0.4, respectively, between days 1 and 5), and by attenuated peak intensities in the urinary protein profile (P < 0.0001 for all 15 peak intensities).


In conclusion, renal injury occurs during repeated endotoxemia and can be predicted by new urinary markers using proteome research. The four markers that correlated with the extent of renal injury may represent potential new biomarkers for renal injury and need further identification. The inflammation-induced renal injury subsided when LPS tolerance developed after 5 consecutive days of LPS administrations.

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Correspondence to S Heemskerk.

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Heemskerk, S., Draisma, A., Laarakkers, C. et al. New markers of inflammation-induced renal injury subside when endotoxin tolerance develops in humans as measured by urine proteomics. Crit Care 14, P511 (2010).

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  • Serum Creatinine
  • Glomerular Filtration
  • Renal Injury
  • Intravenous Bolus Injection
  • Urinary Marker