title: Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study.
abstract: Here we studied plasma metabolomic profiles as determinants of progression to end-stage renal disease (ESRD) in patients with type 2 diabetes (T2D). This nested case-control study evaluated 40 cases who progressed to ESRD during 8-12 years of follow-up and 40 controls who remained alive without ESRD from the Joslin Kidney Study cohort. Controls were matched with cases for baseline clinical characteristics, although controls had slightly higher eGFR and lower levels of urinary albumin excretion than cases. Plasma metabolites at baseline were measured by mass spectrometry-based global metabolomic profiling. Of the named metabolites in the library, 262 were detected in at least 80% of the study patients. The metabolomic platform recognized 78 metabolites previously reported to be elevated in ESRD (uremic solutes). Sixteen were already elevated in the baseline plasma of our cases years before ESRD developed. Other uremic solutes were either not different or not commonly detectable. Essential amino acids and their derivatives were significantly depleted in the cases, whereas certain amino acid-derived acylcarnitines were increased. All findings remained statistically significant after adjustment for differences between study groups in albumin excretion rate, eGFR, or HbA1c. Uremic solute differences were confirmed by quantitative measurements. Thus, abnormal plasma concentrations of putative uremic solutes and essential amino acids either contribute to progression to ESRD or are a manifestation of an early stage(s) of the disease process that leads to ESRD in T2D.
authors.affiliation: 1] Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachussetts, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachussetts, USA.
authors.forename: Monika A
authors.initials: MA
authors.lastname: Niewczas
authors.affiliation: Renal Division, Department of Medicine, Stanford School of Medicine, Stanford, California, USA.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Sirich
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Mathew
authors.affiliation: 1] Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachussetts, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachussetts, USA [3] Department of Metabolic Diseases, Jagiellonian University, Krakow, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Skupien
authors.affiliation: Metabolon Inc, Durham, North Carolina, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.affiliation: 1] Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachussetts, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachussetts, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Warram
authors.affiliation: Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachussetts, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Smiles
authors.affiliation: Metabolism Program, Boston Childrens Hospital, Boston, Massachussetts, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Huang
authors.affiliation: Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachussetts, USA.
authors.forename: Walker
authors.initials: W
authors.lastname: Walker
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jaeman
authors.initials: J
authors.lastname: Byun
authors.affiliation: Metabolon Inc, Durham, North Carolina, USA.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.affiliation: Metabolon Inc, Durham, North Carolina, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Kensicki
authors.affiliation: 1] Department of Medicine, Harvard Medical School, Boston, Massachussetts, USA [2] Metabolism Program, Boston Childrens Hospital, Boston, Massachussetts, USA.
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Berry
authors.affiliation: 1] Department of Medicine, Harvard Medical School, Boston, Massachussetts, USA [2] Renal Division, Brigham and Women's Hospital, Boston, Massachussetts, USA.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.affiliation: Renal Division, Department of Medicine, Stanford School of Medicine, Stanford, California, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Meyer
authors.affiliation: 1] Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachussetts, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachussetts, USA.
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Krolewski
mesh_terms: D000368:Aged; D000601:Amino Acids, Essential / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D001900:Boston; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000175:diagnosis; D003928:Diabetic Nephropathies / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D013997:Time Factors; D014511:Uremia / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology
chemical_list: D000601:Amino Acids, Essential; D015415:Biomarkers; D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human