title: Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides.
abstract: Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.
authors.affiliation: Institute of Cardiovascular and Metabolic Disease, French Institute of Health and Medical Research U1048, Toulouse, France; Paul Sabatier University (Toulouse III), Toulouse, France;
authors.forename: Joost P
authors.initials: JP
authors.lastname: Schanstra
authors.affiliation: mosaiques diagnostics GmbH, Hanover, Germany; zuerbig@mosaiques-diagnostics.com.
authors.forename: Petra
authors.initials: P
authors.lastname: Zürbig
authors.affiliation: University Medical Center Groningen and University of Groningen, Groningen, The Netherlands;
authors.forename: Alaa
authors.initials: A
authors.lastname: Alkhalaf
authors.affiliation: RD Néphrologie, Montpellier, France;
authors.forename: Angel
authors.initials: A
authors.lastname: Argiles
authors.affiliation: University Medical Center Groningen and University of Groningen, Groningen, The Netherlands;
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
authors.affiliation: KfH Renal Unit, Department Nephrology, Leipzig and Martin-Luther-University, Halle/Wittenberg, Germany;
authors.forename: Joachim
authors.initials: J
authors.lastname: Beige
authors.affiliation: University Medical Center Groningen and University of Groningen, Groningen, The Netherlands; Diabetes Centre, Isala Clinics, Zwolle, The Netherlands;
authors.forename: Henk J G
authors.initials: HJ
authors.lastname: Bilo
authors.affiliation: Department of Nephrology and Hypertension, University Hospital of Magdeburg, Magdeburg, Germany;
authors.forename: Christos
authors.initials: C
authors.lastname: Chatzikyrkou
authors.affiliation: mosaiques diagnostics GmbH, Hanover, Germany;
authors.forename: Mohammed
authors.initials: M
authors.lastname: Dakna
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Jesse
authors.initials: J
authors.lastname: Dawson
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Christian
authors.initials: C
authors.lastname: Delles
authors.affiliation: Department of Nephrology and Hypertension, Medical School of Hanover, Hanover, Germany;
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.affiliation: Department of Nephrology, Klinikum Fulda gAG, Fulda, Germany;
authors.forename: Marion
authors.initials: M
authors.lastname: Haubitz
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Holger
authors.initials: H
authors.lastname: Husi
authors.affiliation: Institute for Molecular Cardiovascular Research, RWTH Aachen University Hospital, Aachen, Germany; Department of Internal Medicine IV, Charity Medical University of Berlin, Berlin, Germany;
authors.forename: Joachim
authors.initials: J
authors.lastname: Jankowski
authors.affiliation: Austin Health, University of Melbourne, Heidelberg, Australia;
authors.forename: George
authors.initials: G
authors.lastname: Jerums
authors.affiliation: University Medical Center Groningen and University of Groningen, Groningen, The Netherlands; Diabetes Centre, Isala Clinics, Zwolle, The Netherlands;
authors.forename: Nanne
authors.initials: N
authors.lastname: Kleefstra
authors.affiliation: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; Faculty of Health, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kuznetsova
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado;
authors.forename: David M
authors.initials: DM
authors.lastname: Maahs
authors.affiliation: Department of Nephrology and Hypertension, Medical School of Hanover, Hanover, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Menne
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
authors.forename: William
authors.initials: W
authors.lastname: Mullen
authors.affiliation: School of Medicine, Jimenez Diaz Foundation Institute for Health Research, Autonomous University of Madrid, Madrid, Spain;
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark;
authors.forename: Frederik
authors.initials: F
authors.lastname: Persson
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark; Faculty of Health, University of Aarhus, Aarhus, Denmark; Faculty of Health, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
authors.affiliation: Mario Negri Institute of Pharmacology Research, Bergamo, Italy;
authors.forename: Piero
authors.initials: P
authors.lastname: Ruggenenti
authors.affiliation: Second Department of Internal Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic;
authors.forename: Ivan
authors.initials: I
authors.lastname: Rychlik
authors.affiliation: Division of Nephrology, University Hospital, and Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Switzerland;
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Serra
authors.affiliation: mosaiques diagnostics GmbH, Hanover, Germany; Department of Internal Medicine IV, Charity Medical University of Berlin, Berlin, Germany;
authors.forename: Justyna
authors.initials: J
authors.lastname: Siwy
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado;
authors.forename: Janet
authors.initials: J
authors.lastname: Snell-Bergeon
authors.affiliation: University Department of Nephrology, Medical Faculty, University of Skopje, Skopje, Macedonia;
authors.forename: Goce
authors.initials: G
authors.lastname: Spasovski
authors.affiliation: Faculty of Health, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Jan A
authors.initials: JA
authors.lastname: Staessen
authors.affiliation: Division of Biotechnology, Biomedical Research Foundation, Academy of Athens, Athens, Greece; School of Biomedical and Healthcare Sciences, Plymouth University, Plymouth, United Kingdom; and.
authors.forename: Antonia
authors.initials: A
authors.lastname: Vlahou
authors.affiliation: Faculty of Health, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Harald
authors.initials: H
authors.lastname: Mischak
authors.affiliation: Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Raymond
authors.initials: R
authors.lastname: Vanholder
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000652:urine; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000652:urine*; D051436:Renal Insufficiency, Chronic / Q000652:urine*
chemical_list: D015415:Biomarkers; D010455:Peptides
keywords: CKD; albuminuria; biomarker; extracellular matrix; fibrosis; renal progression