title: High levels of circulating TNFR1 increase the risk of all-cause mortality and progression of renal disease in type 2 diabetic nephropathy.
abstract: BACKGROUND
  Several studies have demonstrated that levels of circulating inflammatory markers such as tumour necrosis factorα (TNFα), are associated with early progression of diabetic nephropathy (DN). The aim of this study was to investigate whether there is an association between circulating TNFα receptor and disease progression in patients with advanced type 2 DN and severe proteinuria.
  
  
  METHODS
  Between 2006 and 2011, we measured levels of circulating soluble TNFα receptor 1 (TNFR1) and soluble TNFα receptor 2 (TNFR2) at baseline and 4 and 12 months in 101 patients included in a multicenter randomized controlled trial to compare the effect of optimal doses of renin-angiotensin system blockers in monotherapy or in combination (dual blockade) to slow progression of established type 2 DN. The primary composite endpoint was a >50% increase in baseline serum creatinine, end-stage renal disease, or death.
  
  
  RESULTS
  The median follow-up was 32 months (IQR, 18-48), during which time 28 patients (22.7%) achieved the primary endpoint. The TNFR1 level, but not the TNFR2 level, was correlated with other inflammatory markers. Cox regression analysis showed that the highest TNFR1 levels (HR, 2.60; 95%CI, 1.11-86.34) and baseline proteinuria (HR 1.32; 95%CI 1.15-1.52) were associated with the primary endpoint. The mixed model analysis revealed that TNFR1 and the TNFR2 levels did not change after starting treatment with renin-angiotensin system blockers.
  
  
  CONCLUSIONS
  Our results show that the highest levels of TNFR1 are independently associated with progression of renal disease and death in type 2 DN. The renin angiotensin blockers have no effect on these inflammatory markers.
authors.affiliation: Hospital Universitario Fundacion Alcorcón, Spain.
authors.forename: Gema
authors.identifier: http://orcid.org/0000-0001-6641-7763
authors.initials: G
authors.lastname: Fernández-Juárez
authors.affiliation: Hospital Universitario Fundacion Alcorcón, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Villacorta Perez
authors.affiliation: Nephrology Department, Hospital Universitario Gregorio Marañón, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Luño Fernández
authors.affiliation: Hospital Universitario Gregorio Marañón, Spain.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Martinez-Martinez
authors.affiliation: Hospital Universitario Gregorio Marañón, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Cachofeiro
authors.affiliation: Complutense University, Medicine Faculty, Physiology Department, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Barrio Lucia
authors.affiliation: Hospital Universitario Fundacion Alcorcón, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Tato Ribera
authors.affiliation: Hospital Universitario Fundacion Alcorcón, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Mendez Abreu
authors.affiliation: Hospital Universitario Fundacion Alcorcón, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cordon
authors.affiliation: National Epidemiolgy Center, Instituto de Salud Carlos III, Spain.
authors.forename: Jesus Angel
authors.initials: JA
authors.lastname: Oliva Dominguez
authors.affiliation: Nephrology Department, Hospital Universitario Doce Octubre, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Praga Terente
mesh_terms: D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002423:Cause of Death; D003404:Creatinine / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications* / Q000401:mortality; D003928:Diabetic Nephropathies / Q000097:blood* / Q000188:drug therapy / Q000209:etiology / Q000401:mortality; D018450:Disease Progression; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000097:blood / Q000209:etiology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011507:Proteinuria / Q000097:blood / Q000209:etiology / Q000401:mortality; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects; D012307:Risk Factors; D013030:Spain; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; 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; D003404:Creatinine
keywords: ACE inhibitos; Inflammation; angiotensin II receptor blockers; diabetic nephropathy; nephropathy progression