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 Dépret, Lucie Fernandez, Elsa Tardif, Vincent Minville, Mélinda Alvès, Jochen Metzger, Kidney Attack Study Group, E. Grünenwald, Guylène Feuillet, Marie Buléon, Manon Brunet, Nicolas Mayeur, Audrey Casemayou, François Labaste, Julia Grossac, Harald Mischak, Alberto Ortíz, Stéphane Gazut, Joost P. Schanstra, Stanislas Faguer
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.