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Discovery, validation and sequencing of urinary peptides for diagnosis of liver fibrosis-A multicentre study.

Abstract：

BACKGROUND:Liver fibrosis is a consequence of chronic inflammation and is associated with protein changes within the hepatocytes structure. In this study, we aimed to investigate if this is reflected by the urinary proteome and can be explored to diagnose liver fibrosis in patients with chronic liver disease. METHODS:In a multicentre combined cross-sectional and prospective diagnostic test validation study, 129 patients with varying degrees of liver fibrosis and 223 controls without liver fibrosis were recruited. Additionally, 41 patients with no liver, but kidney fibrosis were included to evaluate interference with expressions of kidney fibrosis. Urinary low molecular weight proteome was analysed by capillary electrophoresis coupled to mass spectrometry (CE-MS) and a support vector machine marker model was established by integration of peptide markers for liver fibrosis. FINDINGS:CE-MS enabled identification of 50 urinary peptides associated with liver fibrosis. When combined into a classifier, LivFib-50, it separated patients with liver fibrosis (N = 31) from non-liver disease controls (N = 123) in cross-sectional diagnostic phase II evaluation with an area under the curve (AUC) of 0.94 (95% confidence intervals (CI): 0.89-0.97, p<0.0001). When adjusted for age, LivFib-50 demonstrated an AUC of 0.94 (95% CI: 0.89-0.97, p<0.0001) in chronic liver disease patients with (N = 19) or without (N = 17) liver fibrosis progression. In this prospective diagnostic phase III validation set, age-adjusted LivFib-50 showed 84.2% sensitivity (95% CI: 60.4-96.6) and 82.4% specificity (95% CI: 56.6-96.2) for detection of liver fibrosis. The sequence-identified peptides are mainly fragments of collagen chains, uromodulin and Na/K-transporting ATPase subunit γ. We also identified ten putative proteolytic cleavage sites, eight were specific for matrix metallopeptidases and two for cathepsins. INTERPRETATION:In liver fibrosis, urinary peptides profiling offers potential diagnostic markers and leads to discovery of proteolytic sites that could be targets for developing anti-fibrotic therapy.

journal_name

EBioMedicine

journal_title

EBioMedicine

authors

Bannaga AS,Metzger J,Kyrou I,Voigtländer T,Book T,Melgarejo J,Latosinska A,Pejchinovski M,Staessen JA,Mischak H,Manns MP,Arasaradnam RP

doi

10.1016/j.ebiom.2020.103083

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

103083

issn

2352-3964

pii

S2352-3964(20)30459-X

journal_volume

62

pub_type

杂志文章

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