Inflammation-induced renal injury subsides when endotoxin tolerance develops in humans as measured by urine proteomics

Introduction

A prominent role of inflammatory mediators such as cytokines is increasingly recognized to play a prominent role in the development of renal injury during sepsis. Because of its high mortality rates, early detection of renal injury is of the utmost importance and the discovering of renal biomarkers seems promising in achieving this goal.

Methods

We induced endotoxin tolerance to accomplish an attenuated proinflammatory state by intravenous injection of 2 ng/kg/day lipopolysaccharide (LPS) on 5 consecutive days in five healthy male volunteers. Renal function was monitored and urinary proteome research was performed before and after LPS administrations on days 1 and 5.

Results

Repeated LPS administrations induced an increase in serum creatinine of 11 ± 3% (P = 0.002) and a diminished glomerular filtration rate of 33 ± 7% (P = 0.02) on day 3, which was associated with the appearance of 15 peak intensities and an increase in β₂-microglobulin levels (P = 0.04) 6 hours after the first LPS administration. Four of the 15 peak intensities correlated with serum creatinine levels; namely, 3,950 (r = 0.91, r² = 0.84, P = 0.03), 4,445 (r = 0.97, r² = 0.94, P = 0.01), 6,723 (r = 0.94, r² = 0.88, P = 0.02) and 7,735 mass per charge (r = 0.87, r² = 0.75, P = 0.05). During day 5 of the repeated LPS administrations, endotoxin tolerance developed and renal function was restored, reflected by serum creatinine levels of 70 ± 6 μmol/l (P = 0.2, day 1 compared with day 5) and by attenuated peak intensities on the urinary proteome profiles (P < 0.0001 for all measured 15 peak intensities) and levels β₂-microglobulin comparable with baseline on the first day (P = 0.35).

Conclusion

Renal injury occurs on day 3 during repeated endotoxemia, as adequately predicted by urinary proteome research on day 1. A significant correlation was found between four markers and the extent of renal injury, which may act as potential new biomarkers for renal injury at an early stage of inflammation. The inflammation-induced renal injury subsided when LPS tolerance developed after 5 consecutive days of LPS administrations.