Use of Biomarkers to Identify Acute Kidney Injury to Help Detect Sepsis in Patients With Infection

John A Kellum, Antonio Artigas, Kyle J Gunnerson, Patrick M Honore, J Patrick Kampf, Thomas Kwan, Paul McPherson, H Bryant Nguyen, Thomas Rimmelé, Nathan I Shapiro, Jing Shi, Jean-Louis Vincent, Lakhmir S Chawla, Sapphire Investigators, John A Kellum, Antonio Artigas, Kyle J Gunnerson, Patrick M Honore, J Patrick Kampf, Thomas Kwan, Paul McPherson, H Bryant Nguyen, Thomas Rimmelé, Nathan I Shapiro, Jing Shi, Jean-Louis Vincent, Lakhmir S Chawla, Sapphire Investigators

Abstract

Objectives: Although early recognition of sepsis is vital to improving outcomes, the diagnosis may be missed or delayed in many patients. Acute kidney injury is one of the most common organ failures in patients with sepsis but may not be apparent on presentation. Novel biomarkers for acute kidney injury might improve organ failure recognition and facilitate earlier sepsis care.

Design: Retrospective, international, Sapphire study.

Setting: Academic Medical Center.

Patients: Adults admitted to the ICU without evidence of acute kidney injury at time of enrollment.

Interventions: None.

Measurements and main results: We stratified patients enrolled in the Sapphire study into three groups-those with a clinical diagnosis of sepsis (n = 216), those with infection without sepsis (n = 120), and those without infection (n = 387) at enrollment. We then examined 30-day mortality stratified by acute kidney injury within each group. Finally, we determined the operating characteristics for kidney stress markers (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) for prediction of acute kidney injury as a sepsis-defining organ failure in patients with infection without a clinical diagnosis of sepsis at enrollment. Combining all groups, 30-day mortality was 23% for patients who developed stage 2-3 acute kidney injury within the first 3 days compared with 14% without stage 2-3 acute kidney injury. However, this difference was greatest in the infection without sepsis group (34% vs 11%; odds ratio, 4.09; 95% CI, 1.53-11.12; p = 0.005). Using a (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) cutoff of 2.0 units, 14 patients (11.7%), in the infection/no sepsis group, tested positive of which 10 (71.4%) developed stage 2-3 acute kidney injury. The positive test result occurred a median of 19 hours (interquartile range, 0.8-34.0 hr) before acute kidney injury manifested by serum creatinine or urine output. Similar results were obtained using a cutoff of 1.0 for any stage of acute kidney injury.

Conclusions: Use of the urinary (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) test could identify acute kidney injury in patients with infection, possibly helping to detect sepsis, nearly a day before acute kidney injury is apparent by clinical criteria.

Trial registration: ClinicalTrials.gov NCT01209169.

Conflict of interest statement

Dr. Kellum’s institution received funding from Astute Medical and bioMerieux. Drs. Kellum, Rimmelé, Shi, and Chawla received funding from Astute Medical. Drs. Kampf, Kwan, and McPherson are employees of Astute Medical/bioMerieux; Drs. Kellum, Rimmelé, Shi, and Chawla are paid consultants of Astute Medical/bioMerieux; and Dr. Kellum has received grant support from Astute Medical/bioMerieux apart from the current work. Dr. Artigas’s institution received funding from Lilly Foundation, and he received funding from Grifols, Fisher & Paykel. Drs. Kampf, Kwan, and McPherson received funding from Astute Medical (employee). Drs. Nguyen’s and Shapiro’s institutions received funding from Astute Medical. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.

Figures

Figure 1.
Figure 1.
Thirty-day mortality by acute kidney injury (AKI) status. A, Shows mortality for stage 2–3 AKI versus no-AKI, and stage 1 stratified by no infection, infection only, and sepsis. B, Shows mortality for stage 1–3 AKI versus no-AKI stratified by the same three patient groups. *p < 0.05.
Figure 2.
Figure 2.
Mortality curves out to 9 mo stratified by the both urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) × insulin-like growth factor binding protein 7 (IGFBP7) and acute kidney injury (AKI). A, Shows results for the 2.0 cutoff and stage 2–3 AKI. Using no-AKI or stage 1 and (TIMP-2) × (IGFBP7) less than or equal to 2 as reference, the individual hazard ratios (95% CI) for each group were as follows: 1.27 (0.64–2.49), p = 0.49 for no-AKI/stage 1 and (TIMP-2) × (IGFBP7) greater than 2; 1.61 (1.16–2.24), p = 0.005 for stage 2–3 AKI and (TIMP-2) × (IGFBP7) less than or equal to 2; and 2.32 (1.46–3.67), p < 0.001 stage 2–3 AKI and (TIMP-2) × (IGFBP7) greater than 2 (ng/mL)2/1,000. B, Shows the 1.0 cutoff and stage 1–3 AKI. Using no-AKI and (TIMP-2) × (IGFBP7) less than or equal to 1 as reference, the individual hazard ratios (95% CI) for each group were as follows: 0.56 (0.20–1.54), p = 0.26 for no-AKI and (TIMP-2) × (IGFBP7) greater than 1; 1.55 (1.12–2.14), p = 0.008 for AKI and (TIMP-2) × (IGFBP7) less than or equal to 1; and 2.44 (1.68–3.54), p < 0.001 for AKI and (TIMP-2) × (IGFBP7) greater than 1 (ng/mL)2/1,000.

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Source: PubMed

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