title: Urine and plasma metabolites predict the development of diabetic nephropathy in individuals with Type 2 diabetes mellitus.
abstract: OBJECTIVE
  Early detection of individuals with Type 2 diabetes mellitus or hypertension at risk for micro- or macroalbuminuria may facilitate prevention and treatment of renal disease. We aimed to discover plasma and urine metabolites that predict the development of micro- or macroalbuminuria.
  
  
  METHODS
  Patients with Type 2 diabetes (n = 90) and hypertension (n = 150) were selected from the community-cohort 'Prevention of REnal and Vascular End-stage Disease' (PREVEND) and the Steno Diabetes Center for this case-control study. Cases transitioned in albuminuria stage (from normo- to microalbuminuria or micro- to macroalbuminuria). Controls, matched for age, gender, and baseline albuminuria stage, remained in normo- or microalbuminuria stage during follow-up. Median follow-up was 2.9 years. Metabolomics were performed on plasma and urine. The predictive performance of a metabolite for albuminuria transition was assessed by the integrated discrimination index.
  
  
  RESULTS
  In patients with Type 2 diabetes with normoalbuminuria, no metabolites discriminated cases from controls. In patients with Type 2 diabetes with microalbuminuria, plasma histidine was lower (fold change = 0.87, P = 0.02) and butenoylcarnitine was higher (fold change = 1.17, P = 0.007) in cases vs. controls. In urine, hexose, glutamine and tyrosine were lower in cases vs. controls (fold change = 0.20, P < 0.001; 0.32, P < 0.001; 0.51, P = 0.006, respectively). Adding the metabolites to a model of baseline albuminuria and estimated glomerular filtration rate metabolites improved risk prediction for macroalbuminuria transition (plasma integrated discrimination index = 0.28, P < 0.001; urine integrated discrimination index = 0.43, P < 0.001). These metabolites did not differ between hypertensive cases and controls without Type 2 diabetes.
  
  
  CONCLUSIONS
  Type 2 diabetes-specific plasma and urine metabolites were discovered that predict the development of macroalbuminuria beyond established renal risk markers. These results should be confirmed in a large, prospective cohort.
authors.affiliation: Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Pena
authors.forename: H J
authors.initials: HJ
authors.lastname: Lambers Heerspink
authors.forename: M E
authors.initials: ME
authors.lastname: Hellemons
authors.forename: T
authors.initials: T
authors.lastname: Friedrich
authors.forename: G
authors.initials: G
authors.lastname: Dallmann
authors.forename: M
authors.initials: M
authors.lastname: Lajer
authors.forename: S J L
authors.initials: SJ
authors.lastname: Bakker
authors.forename: R T
authors.initials: RT
authors.lastname: Gansevoort
authors.forename: P
authors.initials: P
authors.lastname: Rossing
authors.forename: D
authors.initials: D
authors.lastname: de Zeeuw
authors.forename: S S
authors.initials: SS
authors.lastname: Roscioni
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000378:metabolism* / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000503:physiopathology; D042241:Early Diagnosis; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies
chemical_list: D015415:Biomarkers