title: Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes.
abstract: OBJECTIVE
  Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) contribute to experimental diabetic kidney disease, a condition with substantially increased cardiovascular risk when present in patients. Therefore, we aimed to explore the levels of sTNFRs, and their association with prevalent kidney disease, incident cardiovascular disease, and risk of mortality independently of baseline kidney function and microalbuminuria in a cohort of patients with type 2 diabetes. In pre-defined secondary analyses we also investigated whether the sTNFRs predict adverse outcome in the absence of diabetic kidney disease.
  
  
  METHODS
  The CARDIPP study, a cohort study of 607 diabetes patients [mean age 61 years, 44 % women, 45 cardiovascular events (fatal/non-fatal myocardial infarction or stroke) and 44 deaths during follow-up (mean 7.6 years)] was used.
  
  
  RESULTS
  Higher sTNFR1 and sTNFR2 were associated with higher odds of prevalent kidney disease [odd ratio (OR) per standard deviation (SD) increase 1.60, 95 % confidence interval (CI) 1.32-1.93, p < 0.001 and OR 1.54, 95 % CI 1.21-1.97, p = 0.001, respectively]. In Cox regression models adjusting for age, sex, glomerular filtration rate and urinary albumin/creatinine ratio, higher sTNFR1 and sTNFR2 predicted incident cardiovascular events [hazard ratio (HR) per SD increase, 1.66, 95 % CI 1.29-2.174, p < 0.001 and HR 1.47, 95 % CI 1.13-1.91, p = 0.004, respectively]. Results were similar in separate models with adjustments for inflammatory markers, HbA1c, or established cardiovascular risk factors, or when participants with diabetic kidney disease at baseline were excluded (p < 0.01 for all). Both sTNFRs were associated with mortality.
  
  
  CONCLUSIONS
  Higher circulating sTNFR1 and sTNFR2 are associated with diabetic kidney disease, and predicts incident cardiovascular disease and mortality independently of microalbuminuria and kidney function, even in those without kidney disease. Our findings support the clinical utility of sTNFRs as prognostic markers in type 2 diabetes.
authors.affiliation: Division of Family Medicine, Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. axelcefam@hotmail.com.|Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. axelcefam@hotmail.com.
authors.forename: Axel C
authors.initials: AC
authors.lastname: Carlsson
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, Sweden. carl.johan.ostgren@liu.se.
authors.forename: Carl Johan
authors.initials: CJ
authors.lastname: Östgren
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, Sweden. fredrik.nystrom@regionostergotland.se.
authors.forename: Fredrik H
authors.initials: FH
authors.lastname: Nystrom
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, Sweden. toste.lanne@liu.se.
authors.forename: Toste
authors.initials: T
authors.lastname: Länne
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, Sweden. par.jennersjo@liu.se.
authors.forename: Pär
authors.initials: P
authors.lastname: Jennersjö
authors.affiliation: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. anders.larsson@akademiska.se.
authors.forename: Anders
authors.initials: A
authors.lastname: Larsson
authors.affiliation: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. johan.arnlov@medsci.uu.se.|School of Health and Social Studies, Dalarna University, Falun, Sweden. johan.arnlov@medsci.uu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Ärnlöv
mesh_terms: D000419:Albuminuria / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D003928:Diabetic Nephropathies / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D015994:Incidence; D018836:Inflammation Mediators / Q000097:blood; D016015:Logistic Models; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D011237:Predictive Value of Tests; D015995:Prevalence; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D006442:Glycated Hemoglobin; D018836:Inflammation Mediators; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506235:TNFRSF1A protein, human; C415902:TNFRSF1B protein, human; C517652:hemoglobin A1c protein, human