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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

BMC Nephrology 1/2017

Early urinary biomarkers of diabetic nephropathy in type 1 diabetes mellitus show involvement of kallikrein-kinin system

BMC Nephrology > Ausgabe 1/2017
Lenka Vitova, Zdenek Tuma, Jiri Moravec, Milan Kvapil, Martin Matejovic, Jan Mares
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Electronic supplementary material

The online version of this article (doi:10.​1186/​s12882-017-0519-4) contains supplementary material, which is available to authorized users.



Additional urinary biomarkers for diabetic nephropathy (DN) are needed, providing early and reliable diagnosis and new insights into its mechanisms. Rigorous selection criteria and homogeneous study population may improve reproducibility of the proteomic approach.


Long-term type 1 diabetes patients without metabolic comorbidities were included, 11 with sustained microalbuminuria (MA) and 14 without MA (nMA). Morning urine proteins were precipitated and resolved by 2D electrophoresis. Principal component analysis (PCA) and Projection to latent structures discriminatory analysis (PLS-DA) were adopted to assess general data validity, to pick protein fractions for identification with mass spectrometry (MS), and to test predictive value of the resulting model.


Proteins (n = 113) detected in more than 90% patients were considered representative. Unsupervised PCA showed excellent natural data clustering without outliers. Protein spots reaching Variable Importance in Projection score above 1 in PLS (n = 42) were subjected to MS, yielding 33 positive identifications. The PLS model rebuilt with these proteins achieved accurate classification of all patients (R2X = 0.553, R2Y = 0.953, Q2 = 0.947). Thus, multiple earlier recognized biomarkers of DN were confirmed and several putative new biomarkers suggested. Among them, the highest significance was met in kininogen-1. Its activation products detected in nMA patients exceeded by an order of magnitude the amount found in MA patients.


Reducing metabolic complexity of the diseased and control groups by meticulous patients’ selection allows to focus the biomarker search in DN. Suggested new biomarkers, particularly kininogen fragments, exhibit the highest degree of correlation with MA and substantiate validation in larger and more varied cohorts.
Additional file 1: Principal component analysis of protein spot intensities – composite projection of cases into the factor plane defined by the first two principal components (PC)”. (DOCX 23 kb)
Additional file 2: Variable importance in projection (VIP) scores for the 113 spots entering the PLS-DA model”. (DOCX 84 kb)
Additional file 3: Combined MS and MS/MS sequence coverage of detected cleavage fragments”. (DOCX 22 kb)
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