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Urinary Metabolomic Markers of Protein Glycation, Oxidation, and Nitration in Early-Stage Decline in Metabolic, Vascular, and Renal Health

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submitted on 2023-03-15, 11:52 and posted on 2023-07-13, 08:49 authored by Jinit Masania, Gernot Faustmann, Attia Anwar, Hildegard Hafner-Giessauf, Nasir Rajpoot, Johanna Grabher, Kashif Rajpoot, Beate Tiran, Barbara Obermayer-Pietsch, Brigitte M. Winklhofer-Roob, Johannes M. Roob, Naila Rabbani, Paul J. Thornalley

Glycation, oxidation, nitration, and crosslinking of proteins are implicated in the pathogenic mechanisms of type 2 diabetes, cardiovascular disease, and chronic kidney disease. Related modified amino acids formed by proteolysis are excreted in urine. We quantified urinary levels of these metabolites and branched-chain amino acids (BCAAs) in healthy subjects and assessed changes in early-stage decline in metabolic, vascular, and renal health and explored their diagnostic utility for a noninvasive health screen. We recruited 200 human subjects with early-stage health decline and healthy controls. Urinary amino acid metabolites were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Machine learning was applied to optimise and validate algorithms to discriminate between study groups for potential diagnostic utility. Urinary analyte changes were as follows: impaired metabolic health—increased Nε-carboxymethyl-lysine, glucosepane, glutamic semialdehyde, and pyrraline; impaired vascular health—increased glucosepane; and impaired renal health—increased BCAAs and decreased Nε-(γ-glutamyl)lysine. Algorithms combining subject age, BMI, and BCAAs discriminated between healthy controls and impaired metabolic, vascular, and renal health study groups with accuracy of 84%, 72%, and 90%, respectively. In 2-step analysis, algorithms combining subject age, BMI, and urinary Nε-fructosyl-lysine and valine discriminated between healthy controls and impaired health (any type), accuracy of 78%, and then between types of health impairment with accuracy of 69%-78% (cf. random selection 33%). From likelihood ratios, this provided small, moderate, and conclusive evidence of early-stage cardiovascular, metabolic, and renal disease with diagnostic odds ratios of 6 – 7, 26 – 28, and 34 – 79, respectively. We conclude that measurement of urinary glycated, oxidized, crosslinked, and branched-chain amino acids provides the basis for a noninvasive health screen for early-stage health decline in metabolic, vascular, and renal health. 

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Published in: Oxidative Medicine and Cellular Longevity
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  • English



Publication Year

  • 2019

Institution affiliated with

  • Qatar Biomedical Research Institute
  • Hamad Bin Khalifa University

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