title: Systems Biology-Derived Biomarkers to Predict Progression of Renal Function Decline in Type 2 Diabetes.
abstract: Chronic kidney disease (CKD) in diabetes has a complex molecular and likely multifaceted pathophysiology. We aimed to validate a panel of biomarkers identified using a systems biology approach to predict the individual decline of estimated glomerular filtration rate (eGFR) in a large group of patients with type 2 diabetes and CKD at various stages.
  
  
  
  We used publicly available "omics" data to develop a molecular process model of CKD in diabetes and identified a representative parsimonious set of nine molecular biomarkers: chitinase 3-like protein 1, growth hormone 1, hepatocyte growth factor, matrix metalloproteinase (MMP) 2, MMP7, MMP8, MMP13, tyrosine kinase, and tumor necrosis factor receptor-1. These biomarkers were measured in baseline serum samples from 1,765 patients recruited into two large clinical trials. eGFR decline was predicted based on molecular markers, clinical risk factors (including baseline eGFR and albuminuria), and both combined, and these predictions were evaluated using mixed linear regression models for longitudinal data.
  
  
  
  The variability of annual eGFR loss explained by the biomarkers, indicated by the adjustedR2value, was 15% and 34% for patients with eGFR ≥60 and <60 mL/min/1.73 m2, respectively; variability explained by clinical predictors was 20% and 31%, respectively. A combination of molecular and clinical predictors increased the adjustedR2to 35% and 64%, respectively. Calibration analysis of marker models showed significant (allP< 0.0001) but largely irrelevant deviations from optimal calibration (calibration-in-the-large: -1.125 and 0.95; calibration slopes: 1.07 and 1.13 in the two groups, respectively).
  
  
  
  A small set of serum protein biomarkers identified using a systems biology approach, combined with clinical variables, enhances the prediction of renal function loss over a wide range of baseline eGFR values in patients with type 2 diabetes and CKD.
authors.affiliation: Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Gert
authors.initials: G
authors.lastname: Mayer
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Hiddo J L
authors.initials: HJ
authors.lastname: Heerspink
authors.affiliation: Department of Nephrology, Medical University of Vienna, Vienna, Austria.
authors.forename: Constantin
authors.initials: C
authors.lastname: Aschauer
authors.affiliation: emergentec biodevelopment GmbH, Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinzel
authors.affiliation: Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Section for Clinical Biometrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Heinze
authors.affiliation: Department of Nephrology, Medical University of Vienna, Vienna, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kainz
authors.affiliation: Department of Nephrology, Medical University of Vienna, Vienna, Austria.
authors.forename: Judith
authors.initials: J
authors.lastname: Sunzenauer
authors.affiliation: emergentec biodevelopment GmbH, Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Perco
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
authors.affiliation: Steno Diabetes Center, Gentofte, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Michelle
authors.initials: M
authors.lastname: Pena
authors.affiliation: Department of Nephrology, Medical University of Vienna, Vienna, Austria rainer.oberbauer@meduniwien.ac.at.
authors.forename: Rainer
authors.initials: R
authors.lastname: Oberbauer
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D001786:Blood Glucose / Q000378:metabolism; D000071451:Chitinase-3-Like Protein 1 / Q000097:blood / Q000235:genetics; D003404:Creatinine / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D013006:Growth Hormone / Q000097:blood / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D020782:Matrix Metalloproteinases / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000097:blood / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood / Q000235:genetics; D051436:Renal Insufficiency, Chronic / Q000097:blood*; D012307:Risk Factors; D049490:Systems Biology
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D000071451:Chitinase-3-Like Protein 1; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D017228:Hepatocyte Growth Factor; D013006:Growth Hormone; D003404:Creatinine; D011505:Protein-Tyrosine Kinases; D020782:Matrix Metalloproteinases