title: Soluble tumor necrosis factor receptor 1 and 2 predict outcomes in advanced chronic kidney disease: a prospective cohort study.
abstract: BACKGROUND
  Soluble tumor necrosis factor receptors 1 (sTNFR1) and 2 (sTNFR2) have been associated to progression of renal failure, end stage renal disease and mortality in early stages of chronic kidney disease (CKD), mostly in the context of diabetic nephropathy. The predictive value of these markers in advanced stages of CKD irrespective of the specific causes of kidney disease has not yet been defined. In this study, the relationship between sTNFR1 and sTNFR2 and the risk for adverse cardiovascular events (CVE) and all-cause mortality was investigated in a population with CKD stage 4-5, not yet on dialysis, to minimize the confounding by renal function.
  
  
  METHODS
  In 131 patients, CKD stage 4-5, sTNFR1, sTNFR2 were analysed for their association to a composite endpoint of all-cause mortality or first non-fatal CVE by univariate and multivariate Cox proportional hazards models. In the multivariate models, age, gender, CRP, eGFR and significant comorbidities were included as covariates.
  
  
  RESULTS
  During a median follow-up of 33 months, 40 events (30.5%) occurred of which 29 deaths (22.1%) and 11 (8.4%) first non-fatal CVE. In univariate analysis, the hazard ratios (HR) of sTNFR1 and sTNFR2 for negative outcome were 1.49 (95% confidence interval (CI): 1.28-1.75) and 1.13 (95% CI: 1.06-1.20) respectively. After adjustment for clinical covariables (age, CRP, diabetes and a history of cardiovascular disease) both sTNFRs remained independently associated to outcomes (HR: sTNFR1: 1.51, 95% CI: 1.30-1.77; sTNFR2: 1.13, 95% CI: 1.06-1.20). A subanalysis of the non-diabetic patients in the study population confirmed these findings, especially for sTNFR1.
  
  
  CONCLUSIONS
  sTNFR1 and sTNFR2 are independently associated to all-cause mortality or an increased risk for cardiovascular events in advanced CKD irrespective of the cause of kidney disease.
authors.affiliation: Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Neirynck
authors.affiliation: Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Griet
authors.initials: G
authors.lastname: Glorieux
authors.affiliation: Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Schepers
authors.affiliation: Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Francis
authors.initials: F
authors.lastname: Verbeke
authors.affiliation: Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Raymond
authors.initials: R
authors.lastname: Vanholder
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II
references.citation: J Exp Med. 1992 Feb 1;175(2):323-9
references.pmid: 1310100
references.citation: Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4845-9
references.pmid: 1317575
references.citation: J Immunol. 1994 Apr 15;152(8):4036-43
references.pmid: 8144970
references.citation: Cytokine. 1994 Nov;6(6):608-15
references.pmid: 7893969
references.citation: J Immunol. 1997 Apr 15;158(8):3869-73
references.pmid: 9103455
references.citation: J Clin Invest. 1998 Feb 1;101(3):650-9
references.pmid: 9449699
references.citation: Circulation. 2005 Feb 22;111(7):863-70
references.pmid: 15699251
references.citation: JAMA. 2005 Apr 13;293(14):1737-45
references.pmid: 15827312
references.citation: J Am Soc Nephrol. 2005 Mar;16 Suppl 1:S83-8
references.pmid: 15938042
references.citation: Kidney Int. 2005 Jul;68(1):237-45
references.pmid: 15954913
references.citation: J Am Coll Cardiol. 2005 Dec 6;46(11):2018-21
references.pmid: 16325035
references.citation: Clin Nephrol. 2007 Jun;67(6):352-7
references.pmid: 17598370
references.citation: J Biol Chem. 2008 May 23;283(21):14177-81
references.pmid: 18385130
references.citation: Ann Intern Med. 2009 May 5;150(9):604-12
references.pmid: 19414839
references.citation: Am J Pathol. 2009 Aug;175(2):696-705
references.pmid: 19628765
references.citation: Kidney Int. 2010 Mar;77(6):550-6
references.pmid: 20016471
references.citation: Nephrol Dial Transplant. 2011 Apr;26(4):1313-8
references.pmid: 20846939
references.citation: J Am Soc Nephrol. 2012 Mar;23(3):507-15
references.pmid: 22266663
references.citation: J Am Soc Nephrol. 2012 Mar;23(3):516-24
references.pmid: 22266664
references.citation: Cell Signal. 2012 Jun;24(6):1297-305
references.pmid: 22374304
references.citation: Ren Fail. 2012;34(8):1002-9
references.pmid: 22746155
references.citation: PLoS One. 2013;8(2):e55477
references.pmid: 23405158
references.citation: Age Ageing. 2013 May;42(3):385-90
references.pmid: 23321203
references.citation: Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1728-33
references.pmid: 23640499
references.citation: Diabetes Care. 2014 May;37(5):1425-31
references.pmid: 24623026
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1297-302
references.pmid: 14745008
references.citation: J Am Soc Nephrol. 2004 May;15(5):1307-15
references.pmid: 15100371
references.citation: Nephrol Dial Transplant. 2004 May;19(5):1154-60
references.pmid: 14993508
references.citation: J Am Soc Nephrol. 2004 Jul;15(7):1897-903
references.pmid: 15213279
references.citation: J Exp Med. 2004 Aug 2;200(3):367-76
references.pmid: 15289505
references.citation: Proc Natl Acad Sci U S A. 1990 Nov;87(21):8331-5
references.pmid: 2172983