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

• Published in: Oxidative Medicine and Cellular Longevity Vol. 2019; no. 2019; pp. 1 - 15
• Main Authors: Winklhofer-Roob, Brigitte M., Roob, Johannes M., Rabbani, Naila, Thornalley, Paul J., Tiran, Beate, Rajpoot, Kashif, Grabher, Johanna, Rajpoot, Nasir, Hafner-Giessauf, Hildegard, Anwar, Attia, Faustmann, Gernot, Masania, Jinit, Obermayer-Pietsch, Barbara
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Publishing Corporation 2019; Hindawi; Hindawi Limited; John Wiley & Sons, Inc
• Subjects: Adult; Age; Algorithms; Amino acids; Amino Acids, Branched-Chain; Amino Acids, Branched-Chain - metabolism; Amino Acids, Branched-Chain - urine; Analysis; Biomarkers; Biomarkers - urine; Body Mass Index; Branched chain amino acids; Cardiovascular disease; Cardiovascular diseases; Case-Control Studies; Chromatography, High Pressure Liquid; Chronic illnesses; Chronic kidney failure; Crosslinked polymers; Diabetes; Diagnosis; Epidemiology; Ethylenediaminetetraacetic acid; Female; Food; Glucose; Glycation End Products, Advanced; Glycation End Products, Advanced - urine; Glycosylation; Humans; Insulin resistance; Kidney; Kidney - metabolism; Kidney diseases; Liquid chromatography; Lysine; Lysine - analogs & derivatives; Lysine - urine; Machine learning; Male; Mass spectrometry; Medical screening; Metabolic Diseases; Metabolic Diseases - metabolism; Metabolic Diseases - pathology; Metabolism; Metabolites; Nitration; Oxidation-Reduction; Oxidation-reduction reaction; Proteins; Proteolysis; Research Article; Scientific imaging; Severity of Illness Index; Tandem Mass Spectrometry; Type 2 diabetes; Tyrosine; Tyrosine - analogs & derivatives; Tyrosine - urine; Urine; Vascular Diseases; Vascular Diseases - metabolism; Vascular Diseases - pathology; United Kingdom; Austria
• ISSN: 1942-0900; 1942-0994; 1942-0994
• DOI: 10.1155/2019/4851323

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.