title: Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes.
abstract: Elevated plasma concentrations of TNF receptors 1 and 2 (TNFR1 and TNFR2) predict development of ESRD in patients with type 2 diabetes without proteinuria, suggesting these markers may contribute to the pathogenesis of renal decline. We investigated whether circulating markers of the TNF pathway determine GFR loss among patients with type 1 diabetes. We followed two cohorts comprising 628 patients with type 1 diabetes, normal renal function, and no proteinuria. Over 12 years, 69 patients developed estimated GFR less than 60 mL/min per 1.73 m(2) (16 per 1000 person-years). Concentrations of TNFR1 and TNFR2 were strongly associated with risk for early renal decline. Renal decline was associated only modestly with total TNFα concentration and appeared unrelated to free TNFα. The cumulative incidence of estimated GFR less than 60 mL/min per 1.73 m(2) for patients in the highest TNFR2 quartile was 60% after 12 years compared with 5%-19% in the remaining quartiles. In Cox proportional hazards analysis, patients with TNFR2 values in the highest quartile were threefold more likely to experience renal decline than patients in the other quartiles (hazard ratio, 3.0; 95% confidence interval, 1.7-5.5). The risk associated with high TNFR1 values was slightly less than that associated with high TNFR2 values. TNFR levels were unrelated to baseline free TNFα level and remained stable over long periods within an individual. In conclusion, early GFR loss in patients with type 1 diabetes without proteinuria is strongly associated with circulating TNF receptor levels but not TNFα levels (free or total).
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Gohda
authors.forename: Monika A
authors.initials: MA
authors.lastname: Niewczas
authors.forename: Linda H
authors.initials: LH
authors.lastname: Ficociello
authors.forename: William H
authors.initials: WH
authors.lastname: Walker
authors.forename: Jan
authors.initials: J
authors.lastname: Skupien
authors.forename: Florencia
authors.initials: F
authors.lastname: Rosetti
authors.forename: Xavier
authors.initials: X
authors.lastname: Cullere
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Johnson
authors.forename: Gordon
authors.initials: G
authors.lastname: Crabtree
authors.forename: Adam M
authors.initials: AM
authors.lastname: Smiles
authors.forename: Tanya N
authors.initials: TN
authors.lastname: Mayadas
authors.forename: James H
authors.initials: JH
authors.lastname: Warram
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Krolewski
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D002908:Chronic Disease; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D007674:Kidney Diseases / Q000453:epidemiology* / Q000209:etiology* / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000453:epidemiology* / Q000209:etiology* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood*; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology
chemical_list: D015415:Biomarkers; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II