title: Added value of soluble tumor necrosis factor-α receptor 1 as a biomarker of ESRD risk in patients with type 1 diabetes.
abstract: OBJECTIVE
  Recent studies have suggested that circulating levels of the tumor necrosis factor-α receptor 1 (sTNFαR1) may be a useful predictor for the risk of end-stage renal disease (ESRD) in patients with diabetes. However, its potential utility as a biomarker has not been formally quantified.
  
  
  METHODS
  Circulating levels of sTNFαR1 were assessed in 429 patients with type 1 diabetes and overt nephropathy from the Finnish Diabetic Nephropathy (FinnDiane) cohort study. Predictors of incident ESRD over a median of 9.4 years of follow-up were determined by Cox regression and Fine-Gray competing risk analyses. The added value of sTNFαR1 was estimated via time-dependent receiver operating characteristic curves, net reclassification index (NRI), and integrated discrimination improvement (IDI) for survival data.
  
  
  RESULTS
  A total of 130 individuals developed ESRD (28%; ESRD incidence rate of 3.4% per year). In cause-specific modeling, after adjusting for baseline renal status, predictors of increased incidence of ESRD in patients with overt nephropathy were an elevated HbA1c, shorter duration of diabetes, and circulating levels of sTNFαR1. Notably, sTNFαR1 outperformed estimated glomerular filtration rate in terms of R(2). Circulating levels of the sTNFαR1 also remained associated with ESRD after adjusting for the competing risk of death. A prediction model including sTNFαR1 (as a -0.5 fractional polynomial) was superior to a model without it, as demonstrated by better global fit, an increment of R(2), the C index, and area under the curve. Estimates of IDI and NRI(>0) were 0.22 (95% CI 0.16-0.28; P < 0.0001) and 0.98 (0.78-1.23; P < 0.0001), respectively. The median increment in the risk score after including sTNFαR1 in the prediction model was 0.18 (0.12-0.30; P < 0.0001).
  
  
  CONCLUSIONS
  Circulating levels of sTNFαR1 are independently associated with the cumulative incidence of ESRD. This association is both significant and biologically plausible and appears to provide added value as a biomarker, based on the absolute values of NRI and IDI.
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, FinlandDepartment of Nephrology, Department of Medicine, Helsinki University Central Hospital, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.affiliation: Department of Intensive Care Medicine, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Moran
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, FinlandDepartment of Nephrology, Department of Medicine, Helsinki University Central Hospital, Biomedicum Helsinki, Helsinki, FinlandDiabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Valma
authors.initials: V
authors.lastname: Harjutsalo
authors.affiliation: EKF Diagnostics, London, U.K.
authors.forename: Tony
authors.initials: T
authors.lastname: Loughman
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, FinlandDepartment of Nephrology, Department of Medicine, Helsinki University Central Hospital, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Johan
authors.initials: J
authors.lastname: Wadén
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, FinlandDepartment of Nephrology, Department of Medicine, Helsinki University Central Hospital, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Tolonen
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, FinlandDepartment of Nephrology, Department of Medicine, Helsinki University Central Hospital, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Lena
authors.initials: L
authors.lastname: Thorn
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, FinlandDepartment of Nephrology, Department of Medicine, Helsinki University Central Hospital, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Saraheimo
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, FinlandDepartment of Nephrology, Department of Medicine, Helsinki University Central Hospital, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gordin
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, FinlandDepartment of Nephrology, Department of Medicine, Helsinki University Central Hospital, Biomedicum Helsinki, Helsinki, FinlandBaker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia per-henrik.groop@helsinki.fi.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, FinlandBaker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Merlin C
authors.initials: MC
authors.lastname: Thomas
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000150:complications* / Q000453:epidemiology; D003928:Diabetic Nephropathies / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology / Q000209:etiology; D005260:Female; D006801:Humans; D015994:Incidence; D007676:Kidney Failure, Chronic / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D015415:Biomarkers; D014409:Tumor Necrosis Factor-alpha