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Urinary proteomic biomarkers for diagnosis and risk stratification of autosomal dominant polycystic kidney disease: a multicentric study


Kistler, Andreas D; Serra, Andreas L; Siwy, Justyna; Poster, Diane; Krauer, Fabienne; Torres, Vicente E; Mrug, Michal; Grantham, Jared J; Bae, Kyongtae T; Bost, James E; Mullen, William; Wüthrich, Rudolf P; Mischak, Harald; Chapman, Arlene B (2013). Urinary proteomic biomarkers for diagnosis and risk stratification of autosomal dominant polycystic kidney disease: a multicentric study. PLoS ONE, 8(1):e53016.

Abstract

Treatment options for autosomal dominant polycystic kidney disease (ADPKD) will likely become available in the near future, hence reliable diagnostic and prognostic biomarkers for the disease are strongly needed. Here, we aimed to define urinary proteomic patterns in ADPKD patients, which aid diagnosis and risk stratification. By capillary electrophoresis online coupled to mass spectrometry (CE-MS), we compared the urinary peptidome of 41 ADPKD patients to 189 healthy controls and identified 657 peptides with significantly altered excretion, of which 209 could be sequenced using tandem mass spectrometry. A support-vector-machine based diagnostic biomarker model based on the 142 most consistent peptide markers achieved a diagnostic sensitivity of 84.5% and specificity of 94.2% in an independent validation cohort, consisting of 251 ADPKD patients from five different centers and 86 healthy controls. The proteomic alterations in ADPKD included, but were not limited to markers previously associated with acute kidney injury (AKI). The diagnostic biomarker model was highly specific for ADPKD when tested in a cohort consisting of 481 patients with a variety of renal and extrarenal diseases, including AKI. Similar to ultrasound, sensitivity and specificity of the diagnostic score depended on patient age and genotype. We were furthermore able to identify biomarkers for disease severity and progression. A proteomic severity score was developed to predict height adjusted total kidney volume (htTKV) based on proteomic analysis of 134 ADPKD patients and showed a correlation of r = 0.415 (p<0.0001) with htTKV in an independent validation cohort consisting of 158 ADPKD patients. In conclusion, the performance of peptidomic biomarker scores is superior to any other biochemical markers of ADPKD and the proteomic biomarker patterns are a promising tool for prognostic evaluation of ADPKD.

Abstract

Treatment options for autosomal dominant polycystic kidney disease (ADPKD) will likely become available in the near future, hence reliable diagnostic and prognostic biomarkers for the disease are strongly needed. Here, we aimed to define urinary proteomic patterns in ADPKD patients, which aid diagnosis and risk stratification. By capillary electrophoresis online coupled to mass spectrometry (CE-MS), we compared the urinary peptidome of 41 ADPKD patients to 189 healthy controls and identified 657 peptides with significantly altered excretion, of which 209 could be sequenced using tandem mass spectrometry. A support-vector-machine based diagnostic biomarker model based on the 142 most consistent peptide markers achieved a diagnostic sensitivity of 84.5% and specificity of 94.2% in an independent validation cohort, consisting of 251 ADPKD patients from five different centers and 86 healthy controls. The proteomic alterations in ADPKD included, but were not limited to markers previously associated with acute kidney injury (AKI). The diagnostic biomarker model was highly specific for ADPKD when tested in a cohort consisting of 481 patients with a variety of renal and extrarenal diseases, including AKI. Similar to ultrasound, sensitivity and specificity of the diagnostic score depended on patient age and genotype. We were furthermore able to identify biomarkers for disease severity and progression. A proteomic severity score was developed to predict height adjusted total kidney volume (htTKV) based on proteomic analysis of 134 ADPKD patients and showed a correlation of r = 0.415 (p<0.0001) with htTKV in an independent validation cohort consisting of 158 ADPKD patients. In conclusion, the performance of peptidomic biomarker scores is superior to any other biochemical markers of ADPKD and the proteomic biomarker patterns are a promising tool for prognostic evaluation of ADPKD.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nephrology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2013
Deposited On:14 Feb 2014 13:19
Last Modified:03 Aug 2017 16:20
Publisher:Public Library of Science (PLoS)
ISSN:1932-6203
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1371/journal.pone.0053016
PubMed ID:23326375

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