Potential new markers of inflammation-induced renal injury subside when endotoxin tolerance develops in humans

Purpose: Cytokines play an important role in the development of renal injury during sepsis. Because of its high mortality rate, early detection of inflammation-induced renal injury is of critical importance. Methods: We used Surface enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI--TOF MS), to search for new biomarkers for early renal injury during acute systemic inflammation, and after development of endotoxin tolerance in humans in vivo. Results: Repeated LPS administrations induced a 33 ± 7% decrease in glomerular filtration rate (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 β2-microglobuline 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; 3950, 4445, 6723 and 7735 m/z (r=0.91, 0.97, 0.94, 0.87; p=0.03; 0.01; 0.02 and 0.05, respectively). With the development of LPS tolerance, renal function restored, reflected by a decrease in serum creatinine and ß2-microglobuline to baseline levels (p=0.2 and 0.4, respectively, between day 1 and 5), and by attenuated peak intensities in the urinary protein profile (p<0.0001 for all 15 peak intensities). 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.