title: Prediction of Declining Renal Function and Albuminuria in Patients With Type 2 Diabetes by Metabolomics.
abstract: BACKGROUND
  Renal disease in type 2 diabetes mellitus (T2DM) is associated with excess morbidity/mortality. Although estimated glomerular filtration rate (eGFR) and albuminuria are routine for assessing renal impairment, novel biomarkers could improve risk stratification and prediction.
  
  
  OBJECTIVE
  To identify specific biomarkers of progression of renal dysfunction.
  
  
  METHODS
  Prospective observational.
  
  
  METHODS
  Academic diabetes clinics.
  
  
  METHODS
  A total of 286 T2DM patients (age, 62 ± 8 y; glycosylated hemoglobin, 7.2 ± 0.9%; eGFR, 85 ± 20 mL · min(-1) · 1.73 m(2)).
  
  
  METHODS
  None.
  
  
  METHODS
  Progression of eGFR and albuminuria.
  
  
  RESULTS
  We performed screening metabolomics in serum and urine samples by gas chromatography/mass spectroscopy (MS) and ultra-high performance liquid chromatography/MS/MS. Biomarker identification was performed by random forest using an eGFR cutoff of < 60 mL · min(-1) · 1.73 m(2) or an albumin/creatinine ratio (ACR) cutoff ≥ 30 mg/g as response variables. At follow-up, eGFR had declined by 16 [9] (median [interquartile ratio]) mL · min(-1) · 1.73 m(2), and ACR had increased by 41 [135] mg/g in patients in the respective top quartile of changes from baseline. Clinical parameters (gender, age, fasting glucose, and baseline eGFR) predicted outcome, with receiver operator characteristics curve (ROC) = 0.671. The five serum metabolites best correlated with either eGFR < 60 or ACR ≥ 30 at baseline were tested for their ability to improve clinical prediction. The sum of C-glycosyl tryptophan, pseudouridine, and N-acetylthreonine (MetIndex) raised the ROC to 0.739 (P < .0001). eGFR decline was predicted by the top MetIndex quartile (odds ratio = 5.48 [95% confidence interval, 2.23-14.47]). MetIndex also predicted an ACR increase with an odds ratio of 2.82 [1.20-7.03] and a ROC of 0.750. Top urine metabolites did not add significant predictivity.
  
  
  CONCLUSIONS
  A limited number of circulating intermediates of amino acid and nucleotide pathways carry clinically significant predictivity for deterioration of renal function in well-controlled T2DM.
authors.affiliation: Department of Clinical and Experimental Medicine (A.S., M.L.M., G.Pe., E.F.), and Department of Mathematics (M.L.M.), University of Pisa, 56126 Pisa, Italy; Department of Clinical and Molecular Medicine (G.Pu.), "La Sapienza" University, 00185 Rome, Italy; Metabolon, Inc (J.E.C.), Durham, North Carolina 27713; and National Research Council Institute of Clinical Physiology (E.F.), 56124 Pisa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Solini
authors.affiliation: Department of Clinical and Experimental Medicine (A.S., M.L.M., G.Pe., E.F.), and Department of Mathematics (M.L.M.), University of Pisa, 56126 Pisa, Italy; Department of Clinical and Molecular Medicine (G.Pu.), "La Sapienza" University, 00185 Rome, Italy; Metabolon, Inc (J.E.C.), Durham, North Carolina 27713; and National Research Council Institute of Clinical Physiology (E.F.), 56124 Pisa, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Manca
authors.affiliation: Department of Clinical and Experimental Medicine (A.S., M.L.M., G.Pe., E.F.), and Department of Mathematics (M.L.M.), University of Pisa, 56126 Pisa, Italy; Department of Clinical and Molecular Medicine (G.Pu.), "La Sapienza" University, 00185 Rome, Italy; Metabolon, Inc (J.E.C.), Durham, North Carolina 27713; and National Research Council Institute of Clinical Physiology (E.F.), 56124 Pisa, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Penno
authors.affiliation: Department of Clinical and Experimental Medicine (A.S., M.L.M., G.Pe., E.F.), and Department of Mathematics (M.L.M.), University of Pisa, 56126 Pisa, Italy; Department of Clinical and Molecular Medicine (G.Pu.), "La Sapienza" University, 00185 Rome, Italy; Metabolon, Inc (J.E.C.), Durham, North Carolina 27713; and National Research Council Institute of Clinical Physiology (E.F.), 56124 Pisa, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pugliese
authors.affiliation: Department of Clinical and Experimental Medicine (A.S., M.L.M., G.Pe., E.F.), and Department of Mathematics (M.L.M.), University of Pisa, 56126 Pisa, Italy; Department of Clinical and Molecular Medicine (G.Pu.), "La Sapienza" University, 00185 Rome, Italy; Metabolon, Inc (J.E.C.), Durham, North Carolina 27713; and National Research Council Institute of Clinical Physiology (E.F.), 56124 Pisa, Italy.
authors.forename: Jeff E
authors.initials: JE
authors.lastname: Cobb
authors.affiliation: Department of Clinical and Experimental Medicine (A.S., M.L.M., G.Pe., E.F.), and Department of Mathematics (M.L.M.), University of Pisa, 56126 Pisa, Italy; Department of Clinical and Molecular Medicine (G.Pu.), "La Sapienza" University, 00185 Rome, Italy; Metabolon, Inc (J.E.C.), Durham, North Carolina 27713; and National Research Council Institute of Clinical Physiology (E.F.), 56124 Pisa, Italy.
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000209:etiology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018570:Risk Assessment
chemical_list: D006442:Glycated Hemoglobin