SUBCLINICAL KIDNEY INJURY IS CAUSED BY A MODERATE SINGLE INFLAMMATORY EVENT

Abstract

Background: Current means of diagnosis of acute kidney injury (AKI) based on serum creatinine have poor sensitivity and may miss possible therapeutic windows in subclinical kidney injury, especially in septic AKI. Kidney injury molecule-1 (KIM-1) may be a valuable biomarker to improve diagnostic algorithms for AKI. The understanding of septic AKI is still insufficient, and knowledge about KIM-1 kinetics in inflammation is scarce. The aim of this study was to investigate the possible effect of lipopolysaccharide (LPS) on KIM-1 as a marker of structural kidney injury in healthy volunteers. Methods: A single-blinded, placebo-controlled cross-over study using the human endotoxin model (LPS administration) was performed in 10 healthy men. Kidney injury molecule-1 and serum creatinine were measured repetitively for 48 hours. Results: We observed a significant elevation of serum KIM-1 levels after the administration of LPS ( P < 0.001). Furthermore, LPS caused a significant elevation of serum creatinine at an early time point ( P = 0.013) as compared with placebo. Conclusion: Even a relatively small inflammatory stimulus is sufficient to cause subclinical structural kidney injury with elevated KIM-1 and serum creatinine in healthy volunteers. This outlines the insufficiency of the current diagnostic approach regarding AKI and the urgency to develop novel diagnostic algorithms including markers of kidney injury. Clinical Trial Registration:www.clinicaltrials.gov . Unique identifier: NCT03392701 (August 1, 2018).

Conflict of interest statement

The authors report no conflict of interests.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.

Figures

Fig. 1

Serum KIM-1 levels after administration of placebo and LPS. Statistical analysis using RM-ANOVA revealed a significant difference (P < 0.001) with sKIM-1 concentrations rising from 6 hours after LPS administration. In secondary analysis, paired t tests revealed significant differences at 24 hours (P = 0.011) and 48 hours (P = 0.016). Of note, the NPX format is an arbitrary log2 unit; thus, the depicted values do not reflect actual concentrations. For better graphical depiction, the log2-logarithmic NPX values were transformed into linear scale by calculating 2(respective NPX value). Statistical analysis was performed using the original NPX values.

Fig. 2

Area under the curve of serum KIM-1 levels after administration of LPS and placebo. Statistical analysis using AUCs calculation with the trapezoidal method over the observation period of 48 hours showed significantly higher AUC for serum KIM-1 after LPS compared with placebo (median difference, 64,789 NPX2 × min; **P = 0.0039).

Fig. 3

Serum creatinine concentrations after administration of placebo and LPS. Statistical analysis using RM-ANOVA revealed a significant difference (P = 0.013) over 48 hours. In secondary analysis, serum creatinine concentrations showed significantly elevated at 60 minutes (*P = 0.024) and 120 minutes (*P = 0.013) in comparison with placebo using paired t test. There was no significant difference at baseline (P = 0.282). The decrease of serum creatinine after placebo infusion may be due to the fasting state of subjects at the beginning of the study day.

Fig. 4

Area under the curve of serum creatinine after administration of LPS and placebo. Statistical analysis using AUCs calculation with the trapezoidal method over 6 hours after infusion showed significantly higher AUC for serum creatinine after LPS compared with placebo (median difference, 10.40 mg/dL × min; *P = 0.0273).