Urine proteomics for discovery of improved diagnos

Authors: Alex Kentsis Andrew Shulman Saima Ahmed Eileen Brennan Michael C Monuteaux Young‐Ho Lee Susan Lipsett Joao A Paulo Fatma Dedeoglu Robert Fuhlbrigge Richard Bachur Gary Bradwin Moshe Arditi Robert P Sundel Jane W Newburger Hanno Steen Susan Kim

Publish Date: 2013/02/04

Volume: 5, Issue: 2, Pages: 210-220

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Abstract

Kawasaki disease KD is a systemic vasculitis of unknown etiology Absence of definitive diagnostic markers limits the accuracy of clinical evaluations of suspected KD with significant increases in morbidity In turn incomplete understanding of its molecular pathogenesis hinders the identification of rational targets needed to improve therapy We used high‐accuracy mass spectrometry proteomics to analyse over 2000 unique proteins in clinical urine specimens of patients with KD We discovered that urine proteomes of patients with KD but not those with mimicking conditions were enriched for markers of cellular injury such as filamin and talin immune regulators such as complement regulator CSMD3 immune pattern recognition receptor muclin and immune cytokine protease meprin A Significant elevations of filamin C and meprin A were detected in both the serum and urine in two independent cohorts of patients with KD comprised of a total of 236 patients Meprin A and filamin C exhibited superior diagnostic performance as compared to currently used markers of disease in a blinded case‐control study of 107 patients with suspected KD with receiver operating characteristic areas under the curve of 098 95 confidence intervals CI of 097–1 and 095–1 respectively Notably meprin A was enriched in the coronary artery lesions of a mouse model of KD In all urine proteome profiles revealed novel candidate molecular markers of KD including filamin C and meprin A that exhibit excellent diagnostic performance These disease markers may improve the diagnostic accuracy of clinical evaluations of children with suspected KD lead to the identification of novel therapeutic targets and allow the development of a biological classification of Kawasaki diseaseIn spite of years of intensive study accurate diagnosis and understanding of the causes of Kawasaki disease remain elusive As a consequence delayed or inaccurate diagnosis causes significant complications and long‐term injury and hinders the development of improved therapiesUsing recently developed techniques for analysing thousands of protein molecules in the urine of patients with Kawasaki disease and those with conditions that routinely mimic Kawasaki disease we identified signatures of distinct biological processes that are associated with Kawasaki disease Using tests readily amenable for routine medical use we found that two discovered markers of Kawasaki disease meprin A and filamin C can be used to identify patients with Kawasaki disease with excellent accuracy

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