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 TNFa concentration and appeared unrelated to free TNFa. 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 TNFa 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 TNFa levels (free or total). 23: 516-524, 201223: 516-524, . doi: 10.1681 In a companion manuscript about nephropathy in type 2 diabetes (T2D), we report that elevated plasma concentrations of TNF receptor 1 (TNFR1) and receptor 2 (TNFR2) predict the development of ESRD. 1 Particularly interesting was the ability of these values to predict ESRD not only in proteinuric patients but also in nonproteinuric patients whose ESRD onset was 6-12 years after measurement of those receptors. On the basis of this ability to anticipate far-distant events, we speculate that the concentrations of these receptors are not merely markers of the injury leading to ESRD but also are involved in the inception of renal function decline. J Am Soc NephrolThe 55-kD TNFR1 and 75-kD TNFR2 are cell membrane-bound receptors involved in apoptosis, survival, and key aspects of inflammation and immune response. the cell surface, they are released into the extracellular space. For example, circulating TNFR1 is released by two mechanisms: the inducible cleavage of the 34-kD TNFR1 ectodomain by a disintegrin and metalloproteinase 17 (ADAM17) and constitutive release of full-length 55-kD TNFR1 within exosome-like vesicles. [4][5][6] Whether the same mechanisms apply to TNFR2 release, how this process is regulated and subsequent effects of the circulating forms of TNF receptors are not well known. Some authors consider the receptors as proxies for exposure to TNFa, but empirical support for ...

Metastatic tumors to the iris generally originate from primary malignancies in the breast, lung, or skin (melanoma). Despite successful ocular treatment, life prognosis is poor.