Association of Urinary CCL14 with Host-Response and Outcomes in Critically Ill Sepsis Patients with Persistent AKI

Background: Urinary concentrations of CC chemokine ligand 14 (CCL14) have recently been identified as a strong predictor of acute kidney injury (AKI) persistence. Whether CCL14 plays a role in the pathogenesis of AKI is still unknown. We postulated that looking at the host-response could help determine a correlation of CCL14 with specific AKI pathophysiologic pathways. Methods: Critically ill patients with sepsis associated (SA) AKI were included from the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) prospective cohort (N=92). They were grouped by high (>1.3ng/ml) and low CCL14. Plasma levels of 15 biomarkers reflective of: systemic inflammation and cytokine responses, endothelial cell activation, and coagulation activation were quantified. In a subset of 24 SA-AKI patients, whole-blood leukocyte genome-wide transcriptomes were determined. Results: High CCL14 (n=26, 28.3%) was associated with more severe and persistent renal injury, skin and urinary tract infections compared with low CCL14 (n= 66, 71.7%). Adjusted for disesease severity, age and source of infection High CCL14 was associated with endothelial barrier dysfunction and platelet use (Figure), but also with a heightened transcription of neutrophil degranulation pathways, a dampened response in interferon signaling pathways, upregulated cellular stress response pathways, and a net upregulation of leukocyte activation pathways. Conclusion: These findings suggest that urinary CCL14 can be used to distinguish a specific subtype of severe AKI with more prominent endothelial activation and barrier disruption, and might be a useful guide for future therapeutic strategies. Funding: Private Foundation SupportDifferences in plasma markers of endothelial activation and coagulation in plasma of AKI patients with high (orange) and low (green) urinary CCL14.