title: A panel of novel biomarkers representing different disease pathways improves prediction of renal function decline in type 2 diabetes.
abstract: OBJECTIVE
  We aimed to identify a novel panel of biomarkers predicting renal function decline in type 2 diabetes, using biomarkers representing different disease pathways speculated to contribute to the progression of diabetic nephropathy.
  
  
  METHODS
  A systematic data integration approach was used to select biomarkers representing different disease pathways. Twenty-eight biomarkers were measured in 82 patients seen at an outpatient diabetes center in The Netherlands. Median follow-up was 4.0 years. We compared the cross-validated explained variation (R2) of two models to predict eGFR decline, one including only established risk markers, the other adding a novel panel of biomarkers. Least absolute shrinkage and selection operator (LASSO) was used for model estimation. The C-index was calculated to assess improvement in prediction of accelerated eGFR decline defined as <-3.0 mL/min/1.73m2/year.
  
  
  RESULTS
  Patients' average age was 63.5 years and baseline eGFR was 77.9 mL/min/1.73m2. The average rate of eGFR decline was -2.0 ± 4.7 mL/min/1.73m2/year. When modeled on top of established risk markers, the biomarker panel including matrix metallopeptidases, tyrosine kinase, podocin, CTGF, TNF-receptor-1, sclerostin, CCL2, YKL-40, and NT-proCNP improved the explained variability of eGFR decline (R2 increase from 37.7% to 54.6%; p=0.018) and improved prediction of accelerated eGFR decline (C-index increase from 0.835 to 0.896; p=0.008).
  
  
  CONCLUSIONS
  A novel panel of biomarkers representing different pathways of renal disease progression including inflammation, fibrosis, angiogenesis, and endothelial function improved prediction of eGFR decline on top of established risk markers in type 2 diabetes. These results need to be confirmed in a large prospective cohort.
authors.affiliation: Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Pena
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, Medical University of Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Heinze
authors.affiliation: Diabetes Centre, Isala Clinics, Zwolle, The Netherlands; Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Alaa
authors.initials: A
authors.lastname: Alkhalaf
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Tri Q
authors.initials: TQ
authors.lastname: Nguyen
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.affiliation: Diabetes Centre, Isala Clinics, Zwolle, The Netherlands; Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Henk J G
authors.initials: HJ
authors.lastname: Bilo
authors.affiliation: emergentec biodevelopment GmbH, Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Perco
authors.affiliation: emergentec biodevelopment GmbH, Vienna, Austria.
authors.forename: Bernd
authors.initials: B
authors.lastname: Mayer
authors.affiliation: Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
authors.affiliation: Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hiddo J
authors.initials: HJ
authors.lastname: Lambers Heerspink
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D054392:Adipokines / Q000097:blood; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D019485:Bone Morphogenetic Proteins / Q000097:blood; D018932:Chemokine CCL2 / Q000097:blood; D000071451:Chitinase-3-Like Protein 1; D055513:Connective Tissue Growth Factor / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000097:blood* / Q000175:diagnosis / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D005819:Genetic Markers; D005919:Glomerular Filtration Rate; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D037102:Lectins / Q000097:blood; D008297:Male; D053505:Matrix Metalloproteinases, Secreted / Q000097:blood; D008565:Membrane Proteins / Q000097:blood; D008875:Middle Aged; D020098:Natriuretic Peptide, C-Type / Q000097:blood; D010045:Outpatients; D011379:Prognosis; D011446:Prospective Studies; D011505:Protein-Tyrosine Kinases / Q000097:blood; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000175:diagnosis / Q000503:physiopathology; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054392:Adipokines; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; C111835:CCL2 protein, human; C526317:CCN2 protein, human; C084533:CHI3L1 protein, human; D018932:Chemokine CCL2; D000071451:Chitinase-3-Like Protein 1; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D008565:Membrane Proteins; C407223:NPHS2 protein; D047888:Receptors, Tumor Necrosis Factor, Type I; C422903:SOST protein, human; C480579:amino-terminal pro-C-type natriuretic peptide, human; D020098:Natriuretic Peptide, C-Type; D055513:Connective Tissue Growth Factor; D011505:Protein-Tyrosine Kinases; D053505:Matrix Metalloproteinases, Secreted