Circulating TNF Receptors 1 and 2 Predict Stage 3 CKD in... : Journal of the American Society of Nephrology (original) (raw)

Clinical Research

Gohda, Tomohito*,†,‡; Niewczas, Monika A.*,†,§; Ficociello, Linda H.*,†; Walker, William H.*; Skupien, Jan*,†; Rosetti, Florencia‖; Cullere, Xavier‖; Johnson, Amanda C.*; Crabtree, Gordon*; Smiles, Adam M.*; Mayadas, Tanya N.‖; Warram, James H.*; Krolewski, Andrzej S.*,†

*Research Division, Joslin Diabetes Center and

†Department of Medicine, Harvard Medical School, Boston, Massachusetts;

‡Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan;

§Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland; and

‖Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

T.G. and M.A.N. contributed equally to this work.

Correspondence: Dr. Andrzej S. Krolewski, Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Email: [email protected]

Received June 28, 2011

Accepted October 24, 2011

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 m2 (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 TNF_α_ concentration and appeared unrelated to free TNF_α_. The cumulative incidence of estimated GFR less than 60 mL/min per 1.73 m2 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 TNF_α_ 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 TNF_α_ levels (free or total).