A novel urinary biomarker predicts 1-year mortality after discharge from intensive care
Esther Nkuipou-Kenfack,
Agnieszka Latosinska,
Wen-Yi Yang,
Marie-Céline Fournier,
Alice Blet,
Blerim Mujaj,
Lutgarde Thijs,
Elodie Feliot,
Etienne Gayat,
Harald Mischak,
Jan A. Staessen,
Alexandre Mebazaa,
Zhen-Yu Zhang,
The French and European Outcome Registry in Intensive Care Unit Investigators
Affiliations
Esther Nkuipou-Kenfack
Mosaiques Diagnostics GmbH
Agnieszka Latosinska
Mosaiques Diagnostics GmbH
Wen-Yi Yang
Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven
Marie-Céline Fournier
Department of Anesthesiology and Intensive Care, Saint Louis-Lariboisière – Fernand Widal University Hospital, Assistance Publique Hôpitaux de Paris
Alice Blet
Department of Anesthesiology and Intensive Care, Saint Louis-Lariboisière – Fernand Widal University Hospital, Assistance Publique Hôpitaux de Paris
Blerim Mujaj
Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven
Lutgarde Thijs
Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven
Elodie Feliot
Department of Anesthesiology and Intensive Care, Saint Louis-Lariboisière – Fernand Widal University Hospital, Assistance Publique Hôpitaux de Paris
Etienne Gayat
Department of Anesthesiology and Intensive Care, Saint Louis-Lariboisière – Fernand Widal University Hospital, Assistance Publique Hôpitaux de Paris
Harald Mischak
Mosaiques Diagnostics GmbH
Jan A. Staessen
Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven
Alexandre Mebazaa
Department of Anesthesiology and Intensive Care, Saint Louis-Lariboisière – Fernand Widal University Hospital, Assistance Publique Hôpitaux de Paris
Zhen-Yu Zhang
Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven
The French and European Outcome Registry in Intensive Care Unit Investigators
Abstract Rationale The urinary proteome reflects molecular drivers of disease. Objectives To construct a urinary proteomic biomarker predicting 1-year post-ICU mortality. Methods In 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 results In 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. Conclusions The 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.
