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Abstract: FR-PO1020

CKD Induces Endotoxin-Related Activation of the Innate Immune System and Is Associated with Overall Mortality

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms

Authors

  • Meijers, Björn Ki, Katholieke Universiteit Leuven Groep Biomedische Wetenschappen, Leuven, Belgium
  • Dejongh, Sander, Katholieke Universiteit Leuven Groep Biomedische Wetenschappen, Leuven, Flanders, Belgium
  • Lauriola, Mara, Katholieke Universiteit Leuven Groep Biomedische Wetenschappen, Leuven, Flanders, Belgium
  • Evenepoel, Pieter, Katholieke Universiteit Leuven Groep Biomedische Wetenschappen, Leuven, Belgium
  • Farre, Ricard, Katholieke Universiteit Leuven Groep Biomedische Wetenschappen, Leuven, Flanders, Belgium
Background

Chronic inflammation is associated with poor outcome. The gut-kidney axis is considered an important contributor via the leaky gut. Lipopolysaccharide (LPS) is a pyrogen found in the exterior cell membrane of most gram-negative bacteria. When absorbed through the intestinal epithelium, LPS induces inflammation by activating macrophages and monocytes. Due to short half-life direct quantification of LPS is a poor marker of innate immune system activation. Lipoprotein binding protein (LBP) is an essential component of the innate immune response to LPS. Circulating LBP significantly enhances the sensitivity of CD14+ cells (mostly monocytes and macrophages) to stimulation by LPS. Levels of LBP peak in serum shortly after endotoxemia, and remain increased up to 72 hours later. We hypothesized that CKD increases levels of LBP and is associated with an increased risk of mortality.

Methods

We analyzed plasma LBP (species-specific ELISA,HycultBiotech, The Netherlands) in the Leuven mild-to-moderate CKD cohort (NCT00441623). To study causality, we used animal models of experimentally induced CKD. To exclude model-related bias, two different rat models of CKD, i.e. 5/6th nephrectomy and 0.25% w/w adenine supplementation, were used. We analysed the association between LBP and overall mortality using Cox proportional hazards analysis.

Results

In a cohort of 460 patients with CKD, LBP is significantly inversely correlated with eGFR (p <0,0001; Spearman r: -0,2209). In two different rat models, induction of CKD resulted in a significant increase of LBP. In these animals, we observed a significant inverse association between eGFR (and measured creatinine clearance) and LBP concentrations (P<0.0001). In univariate Cox proportional hazard analysis, plasma LBP was significantly associated with mortality (p <0.01). This association remained significant in multivariate models adjusted for the systematic coronary risk evaluation (score) model.

Conclusion

Patients with CKD have higher levels of LBP. Experimental CKD leads to elevation of LBP, indicative of a causal relationship. Higher LBP associates with increased risk of overall mortality. Combined with functional data on increased gut permeability our data strengthen the hypothesis of the gut-kidney axis as a source of chronic inflammation.

Funding

  • Government Support – Non-U.S.