#5569 ASSOCIATION OF URINARY CCL14 WITH PLASMA PROTEIN BIOMARKERS IN CRITICALLY ILL SEPSIS PATIENTS WITH PERSISTENT ACUTE KIDNEY INJURY
Authors: Peters-Sengers H , Steenvoorden Thei , van Vught Lonneke , Vogt Liffert , Schultz Marcus , van der Poll Tom 
Published: June 2023

Abstract

Background and Aims
The urinary concentration of CC chemokine ligand 14 (CCL14) – a chemoattractant for T-cells and monocytes – has recently been identified as a strong predictor of persistence of severe acute kidney injury (AKI). The mechanisms by which CCL14 mediates persistent severe AKI are not yet completely understood. With sepsis being the most frequent cause of AKI, we wanted to externally validate whether urinary CCL14 concentration can differentiate sepsis patients with and without persistence of AKI, and its association with plasma protein biomarkers reflective of three pathophysiological pathways.

Method
Patients admitted with sepsis to the intensive care unit (ICU) were categorized according to the evolution of AKI (no-AKI, transient-AKI, and persistent-AKI, defined as lasting &gt; 48h), and matched to a 1:1:1 ratio. AKI was assessed prospectively and daily, using the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) classification. Transient- and persistent-AKI patients had at least injury or failure (severe) RIFLE stages. Urine samples collected at ICU admission were analyzed for CCL14 level; in the same patient cohort we measured 9 plasma biomarkers reflective of systemic inflammation and cytokine responses, endothelial cell activation, and loss of endothelial barrier function. We applied a recently proposed cutoff of 1.3 ng/mL for high CCL14 for the identification of patients at high risk for persistent severe AKI.

Results
of 211 sepsis patients enrolled, 72 patients did not have AKI, 71 had transient AKI and 68 had persistent AKI. Majority of patients with high CCL14 had a persistent AKI (23 out of 31; 74.2%). CCL14 showed good discrimination between persistent-AKI and no-AKI (Area Under the ROC Curve [AUC], 0.82, 95%CI 0.75-0.89), and moderate discrimination between persistent-AKI and transient-AKI (AUC 0.71, 95%CI 0.55-0.87). High CCL14 was associated with higher disease severity as measured by APACHE-IV score, and source of infection being the urinary tract, and skin. The plasma protein analysis revealed that high urinary CCL14 was associated with more prominent systemic (anti-)inflammatory and cytokine responses, and signs of disrupted endothelial barrier function (shown by elevated interleukin [IL]-8 and IL-10, and decreased angiopoietin-1 [P = .005; P = .004; P = .009, respectively]). Within the persistent-AKI group, baseline characteristics (age, chronic comorbidities, and disease severity) did not differ between CCL14 groups, and high CCL14 was only associated with decreased angiopoietin-1 (P = .003).

Conclusion
External validation of urinary CCL14 showed good discrimination in critically ill sepsis patients between persistent AKI and no-AKI, and moderate discriminative ability to separate transient-AKI. High urinary CCL14 identifies persistent-AKI sepsis patients with more profound dysregulation of inflammatory pathways coupled with loss of endothelial barrier function. This could guide future therapeutic strategies targeting subgroups within the AKI population.