Performance of a Standardized Clinical Assay for Urinary C-C Motif Chemokine Ligand 14 (CCL14) for Persistent Severe Acute Kidney Injury

Abstract

Background: Clinical use of biomarkers requires the development of standardized assays and establishment of cutoffs. Urinary C-C motif chemokine ligand 14 (CCL14) has been validated to predict persistent severe AKI in critically ill patients with established AKI. We now report on the performance of standardized cutoffs using a clinical assay.

Methods: A second aim of the multicenter RUBY Study was to establish two cutoffs for the prediction of persistent severe AKI (defined as KDIGO stage 3 AKI for at least 72 consecutive hours). Patients who received renal replacement therapy (RRT) or died before achieving 72 hours in stage 3 AKI were also considered to have reached the end point.

Results: A cutoff value for urinary CCL14 of 1.3 ng/ml was determined to achieve high sensitivity (91%; 95% CI, 84% to 96%), and 13 ng/ml achieved high specificity (93%; 95% CI, 89% to 96%). The cutoff of 1.3 ng/ml identifies the majority (91%) of patients who developed persistent severe AKI with a negative predictive value of 92%. The cutoff at 13 ng/ml had a positive predictive value of 72% (with a negative predictive value of 75%). In multivariable adjusted analyses, a CCL14 concentration between 1.3 and 13 ng/ml had an adjusted odds ratio (aOR) of 3.82 (95% CI, 1.73 to 9.12; P=0.001) for the development of persistent severe AKI compared with those with a CCL14 ≤1.3 ng/ml, whereas a CCL14 >13 ng/ml had an aOR of 10.4 (95% CI, 3.89 to 29.9; P<0.001).

Conclusions: Using a clinical assay, these standardized cutoffs (1.3 and 13 ng/ml) allow for the identification of patients at high risk for the development of persistent severe AKI. These results have immediate utility in helping to guide AKI patient care and may facilitate future clinical trials.Clinical Trial registry name and registration number: Identification and Validation of Biomarkers of Acute Kidney Injury Recovery, NCT01868724.

Keywords: acute kidney injury; acute kidney injury and ICU nephrology; assay validation; biomarkers; chemokines; critical care nephrology; dialysis; ligands; mortality; outcomes.

Conflict of interest statement

L.S. Chawla reports current employment by Silver Creek Pharmaceuticals; ownership interest in Exthera Medical, Lowell Therapeutics, and Stavro Medical; and patents and inventions with George Washington University. S. Demirjian reports research funding from National Institute of Diabetes and Digestive and Kidney Diseases (UO1 DK129980-01); honoraria from Outset Medical; patents or royalties with Cleveland Clinic Innovation and the holder of US patent no. 10281455; and participating in a speakers’ bureau for Outset Medical. K.J. Gunnerson reports research funding from Spectral Medical. J.P. Kampf reports employment by Astute Medical, Inc. (a bioMérieux company) and ownership interest in bioMérieux. J.A. Kellum reports current employment by Spectral Medical; consultancy agreements with AM Pharma, Astellas, Astute Medical, Baxter, bioMérieux, Cytosorbents, Grifols, Klotho, Mallinckrodt, NxStage, PhotoPhage, Potrero, and RenalSense; ownership interest with J3RM, Klotho, Photophage, and Spectral Medical; research funding from Astellas, Astute Medical, Atox Bio, Baxter, bioMérieux, Bioporto, Cytosorbents, Grifols, and RenalSense; patents and inventions with Astute Medical, Cytosorbents, J3RM, Klotho, and Photophage; and is the editor of Critical Care Clinics of North America and on the editorial boards of Nephrology Dialysis Transplantation, Critical Care, Critical Care Medicine, and Blood Purification. J.L. Koyner reports consultancy for Astute Medical/bioMérieux, Baxter, Mallinckrodt, Novartis, and SeaStar; research funding from Astute Medical, Fresenius Medical, the National Institutes of Health, and Nxstage Medical; honoraria from Acute Disease Quality Initiative (ADQI), the American Society of Nephrology, CSCTR, and ISICEM; being listed on a patent for Pi GST to detect severe AKI following cardiac surgery with Argutus Medical; is on the editorial board of Clinical Journal of American Society of Nephrology (CJASN), American Journal of Nephrology, and Kidney360; is on the scientific advisory board for Guard Therapeutics, the NKF-National, and Novartis; and participated in a speakers’ bureau for NxStage Medical. T. Kwan reports current employment by Astute Medical, Inc. (a bioMérieux company). P. McPherson reports employment by Astute Medical, Inc. (a bioMérieux company) and ownership interest in bioMérieux. S.T. Wilber reports ownership interest in Merck & Co., Inc. All remaining authors have nothing to disclose.

Copyright © 2022 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Comparison of C-C motif chemokine ligand 14 (CCL14) concentrations in four populations: healthy (n=378), chronic conditions without acute illness (n=366), RUBY—did not develop persistent severe AKI (n=225), and RUBY—developed persistent severe AKI (n=110). Bottom and top whiskers represent the 10th and 90th percentiles of the CCL14 concentrations in that group, respectively. Bottom and top boxes represent the 1st and 3rd quartiles, respectively. Middle bar is the median. The horizontal dashed lines correspond to the 1.3 and 13 ng/ml cutoffs. P value computed using the Kruskal–Wallis test <0.001.

Figure 2.

Risk of the primary end point of persistent severe AKI stratified by CCL14 level below, between, and above 1.3 and 13 ng/ml. Within each CCL14 stratum, the individual components of the composite end point are displayed. End point components are shown on the basis of the first criterion (e.g., serum creatinine or urine output) that was met. The end point was ascertained within 5 days of enrollment (see text for details).

Figure 3.

Cumulative incidence of RRT, death and RRT, or death within 90 days of enrollment in the RUBY Study stratified by CCL14 concentrations below, between, and above 1.3 and 13 ng/ml. The number of patients with CCL14 concentrations below, between, and above 1.3 and 13 ng/ml are 124, 157, and 54, respectively. The log-rank test for trend was used to compute the P value for differences among the strata.