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Nephrol Dial Transplant. 2017 Nov 1;32(11):1866-1873. doi: 10.1093/ndt/gfw292.

Urinary proteomics predict onset of microalbuminuria in normoalbuminuric type 2 diabetic patients, a sub-study of the DIRECT-Protect 2 study.

Author information

1
Steno Diabetes Center, Gentofte, Denmark.
2
Mosaiques Diagnostics GmbH, Hannover, Germany.
3
University of Glasgow, Glasgow, UK.
4
Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
5
Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
6
Department of Epidemiology, Medicine & Pediatrics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
7
Department of Medical Sciences, University of Turin, Torino, Italy.
8
Department of Epidemiology and Public Health, University College London, London, UK.
9
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
10
South Tees NHS Trust, Middlesbrough, UK.
11
Institute of Cardiovascular Sciences, University College London, London, UK.
12
Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
13
Faculty of Health Science, University of Aarhus, Aarhus, Denmark.
14
The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

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.

KEYWORDS:

albuminuria; clinical trial; diabetes mellitus; diabetic nephropathy; proteomics

PMID:
27507891
DOI:
10.1093/ndt/gfw292
[Indexed for MEDLINE]

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