title: A prospective study of multiple protein biomarkers to predict progression in diabetic chronic kidney disease.
abstract: BACKGROUND
  Diabetic nephropathy imposes a substantial cardiovascular and renal burden contributing to both morbidity and excess mortality. Progression of chronic kidney disease (CKD) in diabetes mellitus is variable, and few biomarkers are available to predict progression accurately. Identification of novel predictive biomarkers may inform clinical care and assist in the design of clinical trials. We hypothesized that urinary and plasma protein biomarkers predict CKD progression independently of the known clinical markers such as albuminuria and estimated glomerular filtration rate (eGFR) in diabetic nephropathy.
  
  
  METHODS
  We studied 67 US veterans with CKD due to type 2 diabetes mellitus and 20 age-matched controls (no CKD, hypertension or cardiovascular disease). After clinical evaluation and the collection of blood and urine specimens for 24 biomarkers, we followed subjects prospectively for the next 2-6 years. CKD progression was defined in three ways: (i) clinically by examining eGFR versus time plots for each individual (slope progression), (ii) progression to end-stage renal disease (ESRD) and (iii) a composite outcome of ESRD or death.
  
  
  RESULTS
  Among 17 urinary and 7 plasma biomarkers evaluated, the relationship of the biomarkers with outcome was as follows: (i) for progression identified by eGFR plots, urinary C-terminal fibroblast growth factor (FGF)-23 emerged to have the strongest primary association (adjusted odds ratio [aOR] 2.08, P = 0.008); (ii) for ESRD, plasma vascular endothelial growth factor (VEGF) had an association (aOR: 1.44, P = 0.027) and (iii) for the composite outcome of death and ESRD, plasma C-terminal FGF-23 also had a robust direct association (aOR: 3.07, P = 0.008).
  
  
  CONCLUSIONS
  The relationship of biomarkers with future progression of CKD is complex and depends in part on how CKD progression is defined. Biomarkers in the FGF-23 and VEGF-A pathways predicted patient progression independently of albuminuria levels in this patient cohort. Additional studies in other cohorts will help further validate this pilot study.
authors.affiliation: Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Duffin
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Laska
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Voelker
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Mitchell
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000453:epidemiology / Q000378:metabolism* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D015995:Prevalence; D011379:Prognosis; D011446:Prospective Studies; D011506:Proteins / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000453:epidemiology / Q000378:metabolism* / Q000503:physiopathology; D014481:United States / Q000453:epidemiology
chemical_list: D015415:Biomarkers; C000717427:FGF23 protein, human; D011506:Proteins; D000089703:Fibroblast Growth Factor-23
keywords: albuminuria; biomarkers; chronic kidney disease