Abstract
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 s2-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 s2-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.
Highlights
Renal injury is a common clinical problem in the critically ill patient, and is associated with poor outcome [1,2]
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 LPS tolerance
Serum creatinine levels increased from 73 ± 5 μmol/L, before the first LPS administration to a peak concentration of 82 ± 6 μmol/L, after 3 consecutive days of LPS administrations (p=0.01), which returned to baseline levels of 70 ± 6 μmol/L on day 5,when LPS tolerance developed (p=0.2 between baseline levels on day 1 compared to day 5, Figure 1)
Summary
Renal injury is a common clinical problem in the critically ill patient, and is associated with poor outcome [1,2]. Critically ill patients who develop renal injury and require renal replacement therapy, have mortality rates of 50-80% [2]. Despite many advances in therapeutic and research techniques in the past 20 years, fundamental changes in the outcome of patients with renal injury have not occurred. This limited progression may be related to many factors, including the lack of early diagnostic tests, that indicate the onset of renal injury. The diagnosis of renal injury is based on either the elevation of serum creatinine, or the occurrence of oliguria, whilst this is fraught with imprecision [16]
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