title: Circulating Modified Metabolites and a Risk of ESRD in Patients With Type 1 Diabetes and Chronic Kidney Disease.
abstract: Patients with type 1 diabetes (T1D) with impaired renal function are at increased risk for end-stage renal disease (ESRD). Although the rate of progression varies, determinants and mechanisms of this variation are unknown.
  
  
  
  We examined serum metabolomic profiles associated with variation in renal function decline in participants with T1D (the Joslin Kidney Study prospective cohort). One hundred fifty-eight patients with proteinuria and chronic kidney disease stage 3 were followed for a median of 11 years to determine estimated glomerular filtration rate slopes from serial measurements of serum creatinine and to ascertain time to onset of ESRD. Baseline serum samples were subjected to global metabolomic profiling.
  
  
  
  One hundred ten amino acids and purine and pyrimidine metabolites were detected in at least 80% of participants. Serum levels of seven modified metabolites (C-glycosyltryptophan, pseudouridine, O-sulfotyrosine, N-acetylthreonine, N-acetylserine, N6-carbamoylthreonyladenosine, and N6-acetyllysine) were associated with renal function decline and time to ESRD (P< 0.001) independent of the relevant clinical covariates. The significant metabolites correlated with one another and with the indices of tubular injury.
  
  
  
  This prospective cohort study in participants with T1D, proteinuria, and impaired renal function at baseline demonstrated that patients with increased circulating levels of certain modified metabolites experience faster renal function decline, leading to ESRD. Whether some of these candidate metabolites are risk factors or just prognostic biomarkers of progression to ESRD in T1D needs to be determined.
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA monika.niewczas@joslin.harvard.edu.|Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Monika A
authors.initials: MA
authors.lastname: Niewczas
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Mathew
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Croall
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
authors.forename: Jaeman
authors.initials: J
authors.lastname: Byun
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Major
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, MA.
authors.forename: Venkatta S
authors.initials: VS
authors.lastname: Sabisetti
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA.
authors.forename: Adam
authors.initials: A
authors.lastname: Smiles
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA.|Renal Division, Brigham and Women's Hospital, Boston, MA.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA.|Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Krolewski
mesh_terms: D000328:Adult; D003404:Creatinine / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000150:complications; D003928:Diabetic Nephropathies / Q000097:blood / Q000209:etiology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000209:etiology; D007677:Kidney Function Tests; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011507:Proteinuria / Q000097:blood / Q000209:etiology; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000150:complications; D012307:Risk Factors; D055815:Young Adult
chemical_list: D003404:Creatinine