Abstract
Diabetic nephropathy (DN) is the main reason for end-stage renal disease. Microalbuminuria as the non-invasive available diagnosis marker lacks specificity and gives high false positive rates. To identify and validate biomarkers for DN, we used in the present study urine samples from four patient groups: diabetes without nephropathy, diabetes with microalbuminuria, diabetes with macroalbuminuria and proteinuria without diabetes. For the longitudinal validation, we recruited 563 diabetic patients and collected 1363 urine samples with the clinical data during a follow-up of 6 years. Comparative urinary proteomics identified four proteins Apolipoprotein A-I (APOA1), Beta-2-microglobulin (B2M), E-cadherin (CDH1) and Lithostathine-1-alpha (REG1A), which differentiated with high statistical strength (p < 0.05) between DN patients and the other groups. Label-free mass spectrometric quantification of the candidates confirmed the discriminatory value of E-cadherin and Lithostathine-1-alpha (p < 0.05). Immunological validation highlighted E-cadherin as the only marker able to differentiate significantly between the different DN stages with an area under the curve (AUC) of 0.85 (95%-CI: [0.72, 0.97]). The analysis of the samples from the longitudinal study confirmed the prognostic value of E-cadherin, the critical increase in urinary E-cadherin level was measured 20 ± 12.5 months before the onset of microalbuminuria and correlated significantly (p < 0.05) with the glomerular filtration rate measured by estimated glomerular filtration rate (eGFR).
Highlights
Diabetic nephropathy (DN) is a common complication of diabetes and the leading cause of chronic kidney disease
We identified in a discovery phase four potential biomarkers for diabetic nephropathy, we validated the identified biomarkers with independent methods, and we proved the prognostic value of one of the makers in a longitudinal study
The increasing number of diabetic patients is directly reflected in the number of patients with DN with a prevalence of 20–40%
Summary
Diabetic nephropathy (DN) is a common complication of diabetes and the leading cause of chronic kidney disease. Intervention in high-risk diabetes patients for the development of nephropathy is an attractive option, and a new meta-analysis shows the benefit of blocking of the renin-angiotensin-aldosterone system even in normo-albuminuric type 2 diabetic patients [6]. Despite this tremendous progress, the high intra-individual variability of urinary albuminuria and the lack of sensitive tests that can detect diabetic nephropathy prior to the onset of microalbuminuria still hinder early intervention [7,8,9,10,11]. We suggest a concentration threshold of this marker as risk predictor for nephropathy in diabetic patients
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