title: Changes in urinary metabolomic profile during relapsing renal vasculitis.
abstract: Current biomarkers of renal disease in systemic vasculitis lack predictive value and are insensitive to early damage. To identify novel biomarkers of renal vasculitis flare, we analysed the longitudinal urinary metabolomic profile of a rat model of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. Wistar-Kyoto (WKY) rats were immunised with human myeloperoxidase (MPO). Urine was obtained at regular intervals for 181 days, after which relapse was induced by re-challenge with MPO. Urinary metabolites were assessed in an unbiased fashion using nuclear magnetic resonance (NMR) spectroscopy, and analysed using partial least squares discriminant analysis (PLS-DA) and partial least squares regression (PLS-R). At 56 days post-immunisation, we found that rats with vasculitis had a significantly different urinary metabolite profile than control animals; the observed PLS-DA clusters dissipated between 56 and 181 days, and re-emerged with relapse. The metabolites most altered in rats with active or relapsing vasculitis were trimethylamine N-oxide (TMAO), citrate and 2-oxoglutarate. Myo-inositol was also moderately predictive. The key urine metabolites identified in rats were confirmed in a large cohort of patients using liquid chromatography-mass spectrometry (LC-MS). Hypocitraturia and elevated urinary myo-inositol remained associated with active disease, with the urine myo-inositol:citrate ratio being tightly correlated with active renal vasculitis.
authors.affiliation: Renal Immunobiology Group, School of Infection, Immunology and Inflammation, University of Birmingham, UK.
authors.forename: Bahjat
authors.initials: B
authors.lastname: Al-Ani
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Fitzpatrick
authors.affiliation: Renal Immunobiology Group, School of Infection, Immunology and Inflammation, University of Birmingham, UK.
authors.forename: Hamad
authors.initials: H
authors.lastname: Al-Nuaimi
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Ireland.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Coughlan
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Ireland.
authors.forename: Fionnuala B
authors.initials: FB
authors.lastname: Hickey
authors.affiliation: Renal Section, Imperial College London, London, UK.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.affiliation: Renal Immunobiology Group, School of Infection, Immunology and Inflammation, University of Birmingham, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Savage
authors.affiliation: Agilent Technologies Ltd, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Benton
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Ireland.
authors.forename: Eóin C
authors.initials: EC
authors.lastname: O'Brien
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Ireland.
authors.forename: Declan
authors.initials: D
authors.lastname: O'Toole
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Ireland.
authors.forename: Ken H
authors.initials: KH
authors.lastname: Mok
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Young
authors.affiliation: Trinity Health Kidney Centre, Trinity Centre for Health Sciences, Tallaght Hospital, Dublin 24. Ireland.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Little
mesh_terms: D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000652:urine*; D019343:Citric Acid / Q000652:urine; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007114:Immunization; D007656:Ketoglutaric Acids / Q000652:urine; D007674:Kidney Diseases / Q000652:urine*; D016018:Least-Squares Analysis; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008744:Methylamines / Q000652:urine; D009195:Peroxidase / Q000008:administration & dosage* / Q000276:immunology; D051381:Rats; D011921:Rats, Inbred WKY; D012008:Recurrence
chemical_list: D007656:Ketoglutaric Acids; D008744:Methylamines; D019343:Citric Acid; D009195:Peroxidase; C005855:trimethyloxamine