A universal predictive and mechanistic urinary peptide signature in acute kidney injury
Alexis Piedrafita,
Justyna Siwy,
Julie Klein,
Amal Akkari,
Ana Amaya-garrido,
Alexandre Mebazaa,
Anna Belen Sanz,
Benjamin Breuil,
Laura Montero Herrero,
Bertrand Marcheix,
François Depret,
Lucie Fernandez,
Elsa Tardif,
Vincent Minville,
Melinda Alves,
Jochen Metzger,
Kidney Attack Study Group,
Julia Grossac,
Harald Mischak,
Alberto Ortiz,
Stéphane Gazut,
Joost P. Schanstra,
Stanislas Faguer,
Nicolas Mayeur,
Audrey Casemayou,
François Labaste
Affiliations
Alexis Piedrafita
Department of Nephrology and Organ Transplantation, University Hospital of Toulouse, and French Intensive Care Renal Network
Justyna Siwy
Mosaiques Diagnostics GmbH
Julie Klein
National Institute of Health and Medical Research (INSERM), UMR 1297, Institute of Cardiovascular and Metabolic Disease
Amal Akkari
Université Paris-Saclay, CEA, List
Ana Amaya-garrido
National Institute of Health and Medical Research (INSERM), UMR 1297, Institute of Cardiovascular and Metabolic Disease
Alexandre Mebazaa
Department of Anesthesiology, Critical Care and Burn Unit, Hôpitaux Universitaires Saint Louis-Lariboisière, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot-Paris 7, Sorbonne Paris Cité, UMR-S 942, INSERM, France, INI-CRCT
Anna Belen Sanz
School of Medicine, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, FRIAT and REDINREN
Benjamin Breuil
National Institute of Health and Medical Research (INSERM), UMR 1297, Institute of Cardiovascular and Metabolic Disease
Laura Montero Herrero
School of Medicine, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, FRIAT and REDINREN
Bertrand Marcheix
University Paul Sabatier
François Depret
Department of Anesthesiology, Critical Care and Burn Unit, Hôpitaux Universitaires Saint Louis-Lariboisière, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot-Paris 7, Sorbonne Paris Cité, UMR-S 942, INSERM, France, INI-CRCT
Lucie Fernandez
National Institute of Health and Medical Research (INSERM), UMR 1297, Institute of Cardiovascular and Metabolic Disease
Elsa Tardif
Department of Anesthesiology and Critical Care Medicine, University Hospital of Toulouse
Vincent Minville
University Paul Sabatier
Melinda Alves
National Institute of Health and Medical Research (INSERM), UMR 1297, Institute of Cardiovascular and Metabolic Disease
Jochen Metzger
Mosaiques Diagnostics GmbH
Kidney Attack Study Group
Julia Grossac
Department of Anesthesiology and Critical Care Medicine, University Hospital of Toulouse
Harald Mischak
Mosaiques Diagnostics GmbH
Alberto Ortiz
School of Medicine, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, FRIAT and REDINREN
Stéphane Gazut
Université Paris-Saclay, CEA, List
Joost P. Schanstra
National Institute of Health and Medical Research (INSERM), UMR 1297, Institute of Cardiovascular and Metabolic Disease
Stanislas Faguer
Department of Nephrology and Organ Transplantation, University Hospital of Toulouse, and French Intensive Care Renal Network
Nicolas Mayeur
Department of Anesthesiology and Critical Care Medicine, University Hospital of Toulouse
Audrey Casemayou
Institute for Metabolic and Cardiovascular Disease, National Institute of Health and Medical Research
François Labaste
Department of Anesthesiology and Critical Care Medicine, University Hospital of Toulouse
Abstract Background The delayed diagnosis of acute kidney injury (AKI) episodes and the lack of specificity of current single AKI biomarkers hamper its management. Urinary peptidome analysis may help to identify early molecular changes in AKI and grasp its complexity to identify potential targetable molecular pathways. Methods In derivation and validation cohorts totalizing 1170 major cardiac bypass surgery patients and in an external cohort of 1569 intensive care unit (ICU) patients, a peptide-based score predictive of AKI (7-day KDIGO classification) was developed, validated, and compared to the reference biomarker urinary NGAL and NephroCheck and clinical scores. Results A set of 204 urinary peptides derived from 48 proteins related to hemolysis, inflammation, immune cells trafficking, innate immunity, and cell growth and survival was identified and validated for the early discrimination (< 4 h) of patients according to their risk to develop AKI (OR 6.13 [3.96–9.59], p < 0.001) outperforming reference biomarkers (urinary NGAL and [IGFBP7].[TIMP2] product) and clinical scores. In an external cohort of 1569 ICU patients, performances of the signature were similar (OR 5.92 [4.73–7.45], p < 0.001), and it was also associated with the in-hospital mortality (OR 2.62 [2.05–3.38], p < 0.001). Conclusions An overarching AKI physiopathology-driven urinary peptide signature shows significant promise for identifying, at an early stage, patients who will progress to AKI and thus to develop tailored treatments for this frequent and life-threatening condition. Performance of the urine peptide signature is as high as or higher than that of single biomarkers but adds mechanistic information that may help to discriminate sub-phenotypes of AKI offering new therapeutic avenues.
