title: Urinary peptidomics in a rodent model of diabetic nephropathy highlights epidermal growth factor as a biomarker for renal deterioration in patients with type 2 diabetes.
abstract: Many diabetic patients suffer from declining renal function without developing albuminuria. To identify alternative biomarkers for diabetic nephropathy (DN) we performed urinary peptidomic analysis in a rodent model in which hyperglycemia and hypertension synergize to promote renal pathologic changes consistent with human DN. We identified 297 increased and 15 decreased peptides in the urine of rats with DN compared with controls, including peptides derived from proteins associated with DN and novel candidate biomarkers. We confirmed by ELISA that one of the parent proteins, urinary epidermal growth factor (uEGF), was more than 2-fold reduced in rats with DN in comparison with controls. To assess the clinical utility of uEGF we examined renal outcomes in 642 participants from the Edinburgh Type 2 Diabetes Study who were normoalbuminuric and had preserved renal function at baseline. After adjustment for established renal risk factors, a lower uEGF to creatinine ratio was associated with new-onset estimated glomerular filtration rate less than 60 ml/min per 1.73m(2) (odds ratio 0.48; 95% confidence interval, 0.26-0.90), rapid (over 5% per annum) decline in renal function (odds ratio 0.44; 95% confidence interval, 0.27-0.72) or the composite of both outcomes (odds ratio 0.38; 95% confidence interval, 0.24-0.62). Thus, the utility of a low uEGF to creatinine ratio as a biomarker of progressive decline in renal function in normoalbuminuric patients should be assessed in additional populations.
authors.affiliation: Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK; Institute of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Thuringia, Germany.
authors.forename: Boris B
authors.initials: BB
authors.lastname: Betz
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Jenks
authors.affiliation: Proteomics Facility, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cronshaw
authors.affiliation: Proteomics Facility, College of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Lamont
authors.affiliation: University of Edinburgh/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: Carolynn
authors.initials: C
authors.lastname: Cairns
authors.affiliation: Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Manning
authors.affiliation: Department of Renal Medicine, Royal Infirmary, Edinburgh, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Goddard
authors.affiliation: University of Edinburgh/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK; Clinical Pharmacology Unit, University of Edinburgh, Edinburgh, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.affiliation: University of Edinburgh/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.affiliation: Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK; Department of Renal Medicine, Royal Infirmary, Edinburgh, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hughes
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Stela
authors.initials: S
authors.lastname: McLachlan
authors.affiliation: Metabolic Unit, Western General Hospital, Edinburgh, UK.
authors.forename: Mark W J
authors.initials: MWJ
authors.lastname: Strachan
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Jackie F
authors.initials: JF
authors.lastname: Price
authors.affiliation: University of Edinburgh/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK; Department of Renal Medicine, Royal Infirmary, Edinburgh, UK. Electronic address: bryan.conway@ed.ac.uk.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Conway
mesh_terms: D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000652:urine; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D003404:Creatinine / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000175:diagnosis; D003928:Diabetic Nephropathies / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology / Q000652:urine*; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000652:urine*; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D006973:Hypertension / Q000150:complications; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000503:physiopathology; D016015:Logistic Models; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011507:Proteinuria / Q000652:urine*; D040901:Proteomics / Q000379:methods; D055647:Rats, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000652:urine*; D012307:Risk Factors; D012606:Scotland; D016482:Urinalysis
chemical_list: D015415:Biomarkers; D003404:Creatinine; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C483803:Egfr protein, rat
keywords: diabetic nephropathy; epidermal growth factor; peptidomics