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Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

Joost P. Schanstra, Petra Zürbig, Alaa Alkhalaf, Angel Argiles, Stephan J.L. Bakker, Joachim Beige, Henk J.G. Bilo, Christos Chatzikyrkou, Mohammed Dakna, Jesse Dawson, Christian Delles, Hermann Haller, Marion Haubitz, Holger Husi, Joachim Jankowski, George Jerums, Nanne Kleefstra, Tatiana Kuznetsova, David M. Maahs, Jan Menne, William Mullen, Alberto Ortiz, Frederik Persson, Peter Rossing, Piero Ruggenenti, Ivan Rychlik, Andreas L. Serra, Justyna Siwy, Janet Snell-Bergeon, Goce Spasovski, Jan A. Staessen, Antonia Vlahou, Harald Mischak and Raymond Vanholder
JASN August 2015, 26 (8) 1999-2010; DOI: https://doi.org/10.1681/ASN.2014050423
Joost P. Schanstra
Institute of Cardiovascular and Metabolic Disease, French Institute of Health and Medical Research U1048, Toulouse, France;Paul Sabatier University (Toulouse III), Toulouse, France;
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Petra Zürbig
mosaiques diagnostics GmbH, Hanover, Germany;
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Alaa Alkhalaf
University Medical Center Groningen and University of Groningen, Groningen, The Netherlands;
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Angel Argiles
RD Néphrologie, Montpellier, France;
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Stephan J.L. Bakker
University Medical Center Groningen and University of Groningen, Groningen, The Netherlands;
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Joachim Beige
KfH Renal Unit, Department Nephrology, Leipzig and Martin-Luther-University, Halle/Wittenberg, Germany;
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Henk J.G. Bilo
University Medical Center Groningen and University of Groningen, Groningen, The Netherlands;Diabetes Centre, Isala Clinics, Zwolle, The Netherlands;
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Christos Chatzikyrkou
Department of Nephrology and Hypertension, University Hospital of Magdeburg, Magdeburg, Germany;
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Mohammed Dakna
mosaiques diagnostics GmbH, Hanover, Germany;
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Jesse Dawson
BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
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Christian Delles
BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
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Hermann Haller
Department of Nephrology and Hypertension, Medical School of Hanover, Hanover, Germany;
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Marion Haubitz
Department of Nephrology, Klinikum Fulda gAG, Fulda, Germany;
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Holger Husi
BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
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Joachim Jankowski
Institute for Molecular Cardiovascular Research, RWTH Aachen University Hospital, Aachen, Germany;Department of Internal Medicine IV, Charity Medical University of Berlin, Berlin, Germany;
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George Jerums
Austin Health, University of Melbourne, Heidelberg, Australia;
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Nanne Kleefstra
University Medical Center Groningen and University of Groningen, Groningen, The Netherlands;Diabetes Centre, Isala Clinics, Zwolle, The Netherlands;
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Tatiana Kuznetsova
Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium;Faculty of Health, University of Copenhagen, Copenhagen, Denmark;
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David M. Maahs
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado;
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Jan Menne
Department of Nephrology and Hypertension, Medical School of Hanover, Hanover, Germany;
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William Mullen
BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
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Alberto Ortiz
School of Medicine, Jimenez Diaz Foundation Institute for Health Research, Autonomous University of Madrid, Madrid, Spain;
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Frederik Persson
Steno Diabetes Center, Gentofte, Denmark;
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Peter Rossing
Steno Diabetes Center, Gentofte, Denmark;Faculty of Health, University of Aarhus, Aarhus, Denmark;Faculty of Health, University of Copenhagen, Copenhagen, Denmark;
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Piero Ruggenenti
Mario Negri Institute of Pharmacology Research, Bergamo, Italy;
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Ivan Rychlik
Second Department of Internal Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic;
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Andreas L. Serra
Division of Nephrology, University Hospital, and Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Switzerland;
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Justyna Siwy
mosaiques diagnostics GmbH, Hanover, Germany;Department of Internal Medicine IV, Charity Medical University of Berlin, Berlin, Germany;
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Janet Snell-Bergeon
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado;
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Goce Spasovski
University Department of Nephrology, Medical Faculty, University of Skopje, Skopje, Macedonia;
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Jan A. Staessen
Faculty of Health, University of Copenhagen, Copenhagen, Denmark;
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Antonia Vlahou
Division of Biotechnology, Biomedical Research Foundation, Academy of Athens, Athens, Greece;School of Biomedical and Healthcare Sciences, Plymouth University, Plymouth, United Kingdom; and
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Harald Mischak
Faculty of Health, University of Copenhagen, Copenhagen, Denmark;
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Raymond Vanholder
Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium
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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.

  • CKD
  • renal progression
  • fibrosis
  • extracellular matrix
  • albuminuria
  • biomarker
  • Copyright © 2015 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 26 (8)
Journal of the American Society of Nephrology
Vol. 26, Issue 8
August 2015
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Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides
Joost P. Schanstra, Petra Zürbig, Alaa Alkhalaf, Angel Argiles, Stephan J.L. Bakker, Joachim Beige, Henk J.G. Bilo, Christos Chatzikyrkou, Mohammed Dakna, Jesse Dawson, Christian Delles, Hermann Haller, Marion Haubitz, Holger Husi, Joachim Jankowski, George Jerums, Nanne Kleefstra, Tatiana Kuznetsova, David M. Maahs, Jan Menne, William Mullen, Alberto Ortiz, Frederik Persson, Peter Rossing, Piero Ruggenenti, Ivan Rychlik, Andreas L. Serra, Justyna Siwy, Janet Snell-Bergeon, Goce Spasovski, Jan A. Staessen, Antonia Vlahou, Harald Mischak, Raymond Vanholder
JASN Aug 2015, 26 (8) 1999-2010; DOI: 10.1681/ASN.2014050423

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Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides
Joost P. Schanstra, Petra Zürbig, Alaa Alkhalaf, Angel Argiles, Stephan J.L. Bakker, Joachim Beige, Henk J.G. Bilo, Christos Chatzikyrkou, Mohammed Dakna, Jesse Dawson, Christian Delles, Hermann Haller, Marion Haubitz, Holger Husi, Joachim Jankowski, George Jerums, Nanne Kleefstra, Tatiana Kuznetsova, David M. Maahs, Jan Menne, William Mullen, Alberto Ortiz, Frederik Persson, Peter Rossing, Piero Ruggenenti, Ivan Rychlik, Andreas L. Serra, Justyna Siwy, Janet Snell-Bergeon, Goce Spasovski, Jan A. Staessen, Antonia Vlahou, Harald Mischak, Raymond Vanholder
JASN Aug 2015, 26 (8) 1999-2010; DOI: 10.1681/ASN.2014050423
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Keywords

  • CKD
  • renal progression
  • fibrosis
  • extracellular matrix
  • albuminuria
  • biomarker

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