title: Urinary proteomics predict onset of microalbuminuria in normoalbuminuric type 2 diabetic patients, a sub-study of the DIRECT-Protect 2 study.
abstract: BACKGROUND
  Early prevention of diabetic nephropathy is not successful as early interventions have shown conflicting results, partly because of a lack of early and precise indicators of disease development. Urinary proteomics has shown promise in this regard and could identify those at high risk who might benefit from treatment. In this study we investigate its utility in a large type 2 diabetic cohort with normoalbuminuria.
  
  
  METHODS
  We performed a post hoc analysis in the Diabetic Retinopathy Candesartan Trials (DIRECT-Protect 2 study), a multi centric randomized clinical controlled trial. Patients were allocated to candesartan or placebo, with the aim of slowing the progression of retinopathy. The secondary endpoint was development of persistent microalbuminuria (three of four samples). We used a previously defined chronic kidney disease risk score based on proteomic measurement of 273 urinary peptides (CKD273-classifier). A Cox regression model for the progression of albuminuria was developed and evaluated with integrated discrimination improvement (IDI), continuous net reclassification index (cNRI) and receiver operating characteristic curve statistics.
  
  
  RESULTS
  Seven hundred and thirty-seven patients were analysed and 89 developed persistent microalbuminuria (12%) with a mean follow-up of 4.1 years. At baseline the CKD273-classifier predicted development of microalbuminuria during follow-up, independent of treatment (candesartan/placebo), age, gender, systolic blood pressure, urine albumin excretion rate, estimated glomerular filtration rate, HbA1c and diabetes duration, with hazard ratio 2.5 [95% confidence interval (CI) 1.4-4.3; P = 0.002] and area under the curve 0.79 (95% CI 0.75-0.84; P < 0.0001). The CKD273-classifier improved the risk prediction (relative IDI 14%, P = 0.002; cNRI 0.10, P = 0.043).
  
  
  CONCLUSIONS
  In this cohort of patients with type 2 diabetes and normoalbuminuria from a large intervention study, the CKD273-classifier was an independent predictor of microalbuminuria. This may help identify high-risk normoalbuminuric patients for preventive strategies for diabetic nephropathy.
authors: Steno Diabetes Center, Gentofte, Denmark.
authors: Morten
authors: M
authors: Lindhardt
authors: Steno Diabetes Center, Gentofte, Denmark.
authors: Frederik
authors: F
authors: Persson
authors: Mosaiques Diagnostics GmbH, Hannover, Germany.
authors: Petra
authors: P
authors: Zürbig
authors: University of Glasgow, Glasgow, UK.
authors: Angelique
authors: A
authors: Stalmach
authors: Mosaiques Diagnostics GmbH, Hannover, Germany.|University of Glasgow, Glasgow, UK.
authors: Harald
authors: H
authors: Mischak
authors: Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Dick
authors: D
authors: de Zeeuw
authors: Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Hiddo
authors: H
authors: Lambers Heerspink
authors: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: Ronald
authors: R
authors: Klein
authors: Department of Epidemiology, Medicine & Pediatrics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Trevor
authors: T
authors: Orchard
authors: Department of Medical Sciences, University of Turin, Torino, Italy.
authors: Massimo
authors: M
authors: Porta
authors: Department of Epidemiology and Public Health, University College London, London, UK.
authors: John
authors: J
authors: Fuller
authors: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|South Tees NHS Trust, Middlesbrough, UK.
authors: Rudolf
authors: R
authors: Bilous
authors: Institute of Cardiovascular Sciences, University College London, London, UK.
authors: Nish
authors: N
authors: Chaturvedi
authors: Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors: Hans-Henrik
authors: HH
authors: Parving
authors: Steno Diabetes Center, Gentofte, Denmark.|Faculty of Health Science, University of Aarhus, Aarhus, Denmark.|The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors: Peter
authors: P
authors: Rossing
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology / Q000652:urine*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use; D015415:Biomarkers / Q000652:urine; D001713:Biphenyl Compounds; D001794:Blood Pressure; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology / Q000652:urine*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control / Q000652:urine*; D003930:Diabetic Retinopathy; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D016032:Randomized Controlled Trials as Topic; D013777:Tetrazoles / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D015415:Biomarkers; D001713:Biphenyl Compounds; D020543:Proteome; D013777:Tetrazoles; C081643:candesartan
keywords: albuminuria; clinical trial; diabetes mellitus; diabetic nephropathy; proteomics