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A novel urinary biomarker predicts 1-year mortality after discharge from intensive care

Authors
  • Nkuipou-Kenfack, Esther1
  • Latosinska, Agnieszka1
  • Yang, Wen-Yi2, 3
  • Fournier, Marie-Céline4
  • Blet, Alice4, 5
  • Mujaj, Blerim2
  • Thijs, Lutgarde2
  • Feliot, Elodie4
  • Gayat, Etienne4, 5, 6
  • Mischak, Harald1
  • Staessen, Jan A.2, 7
  • Mebazaa, Alexandre4, 5, 6
  • Zhang, Zhen-Yu2
  • Deye, N.
  • Fauvaux, C.
  • Mebazaa, A.
  • Damoisel, C.
  • Payen, D.
  • Azoulay, E.
  • Moreau, A. S.
  • And 41 more
  • 1 Mosaiques Diagnostics GmbH, Hannover, Germany , Hannover (Germany)
  • 2 University of Leuven, Campus Sint Rafaël, Kapucijnenvoer 35, Box 7001, Leuven, 3000, Belgium , Leuven (Belgium)
  • 3 Shanghai Jiao Tong University School of Medicine, Shanghai, China , Shanghai (China)
  • 4 Saint Louis-Lariboisière – Fernand Widal University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France , Paris (France)
  • 5 Université de Paris, Paris, France , Paris (France)
  • 6 INSERM UMR-S 942 – MASCOT, Paris, France , Paris (France)
  • 7 Maastricht University, Maastricht, the Netherlands , Maastricht (Netherlands)
Type
Published Article
Journal
Critical Care
Publisher
BioMed Central
Publication Date
Jan 09, 2020
Volume
24
Issue
1
Identifiers
DOI: 10.1186/s13054-019-2686-0
Source
Springer Nature
Keywords
License
Green

Abstract

RationaleThe urinary proteome reflects molecular drivers of disease.ObjectivesTo construct a urinary proteomic biomarker predicting 1-year post-ICU mortality.MethodsIn 1243 patients, the urinary proteome was measured on ICU admission, using capillary electrophoresis coupled with mass spectrometry along with clinical variables, circulating biomarkers (BNP, hsTnT, active ADM, and NGAL), and urinary albumin. Methods included support vector modeling to construct the classifier, Cox regression, the integrated discrimination (IDI), and net reclassification (NRI) improvement, and area under the curve (AUC) to assess predictive accuracy, and Proteasix and protein-proteome interactome analyses.Measurements and main resultsIn the discovery (deaths/survivors, 70/299) and test (175/699) datasets, the new classifier ACM128, mainly consisting of collagen fragments, yielding AUCs of 0.755 (95% CI, 0.708–0.798) and 0.688 (0.656–0.719), respectively. While accounting for study site and clinical risk factors, hazard ratios in 1243 patients were 2.41 (2.00–2.91) for ACM128 (+ 1 SD), 1.24 (1.16–1.32) for the Charlson Comorbidity Index (+ 1 point), and ≥ 1.19 (P ≤ 0.022) for other biomarkers (+ 1 SD). ACM128 improved (P ≤ 0.0001) IDI (≥ + 0.50), NRI (≥ + 53.7), and AUC (≥ + 0.037) over and beyond clinical risk indicators and other biomarkers. Interactome mapping, using parental proteins derived from sequenced peptides included in ACM128 and in silico predicted proteases, including/excluding urinary collagen fragments (63/35 peptides), revealed as top molecular pathways protein digestion and absorption, lysosomal activity, and apoptosis.ConclusionsThe urinary proteomic classifier ACM128 predicts the 1-year post-ICU mortality over and beyond clinical risk factors and other biomarkers and revealed molecular pathways potentially contributing to a fatal outcome.

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