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Molecular & Cellular Proteomics 8:2296-2307, 2009.
© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Identification and Validation of Urinary Biomarkers for Differential Diagnosis and Evaluation of Therapeutic Intervention in Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis^*,

From the ^aDepartment of Nephrology, Hannover Medical School, D-30625 Hannover, Germany,
Departments of ^dChemistry and
ⁱBiomolecular Chemistry, University of Wisconsin Madison, Wisconsin 53706,
^fDepartment of Nephrology, Ludwig Maximilians University, D-80336 Munich, Germany,
^gDepartment of Urology, University of Virginia, Charlottesville, Virginia 22908, and
^hMosaiques Diagnostics GmbH, D-30625 Hannover, Germany

Renal activity and smoldering disease is difficult to assess in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) because of renal scarring. Even repeated biopsies suffer from sampling errors in this focal disease especially in patients with chronic renal insufficiency. We applied capillary electrophoresis coupled to mass spectrometry toward urine samples from patients with active renal AAV to identify and validate urinary biomarkers that enable differential diagnosis of disease and assessment of disease activity. The data were compared with healthy individuals, patients with other renal and non-renal diseases, and patients with AAV in remission. 113 potential biomarkers were identified that differed significantly between active renal AAV and healthy individuals and patients with other chronic renal diseases. Of these, 58 could be sequenced. Sensitivity and specificity of models based on 18 sequenced biomarkers were validated using blinded urine samples of 40 patients with different renal diseases. Discrimination of AAV from other renal diseases in blinded samples was possible with 90% sensitivity and 86.7–90% specificity depending on the model. 10 patients with active AAV were followed for 6 months after initiation of treatment. Immunosuppressive therapy led to a change of the proteome toward "remission." 47 biomarkers could be sequenced that underwent significant changes during therapy together with regression of clinical symptoms, normalization of C-reactive protein, and improvement of renal function. Proteomics analysis with capillary electrophoresis-MS represents a promising tool for fast identification of patients with active AAV, indication of renal relapses, and monitoring for ongoing active renal disease and remission without renal biopsy.

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