Levels of proinflammatory cytokines associate with risk for developing type 2 diabetes but whether chronic inflammation contributes to the development of diabetic complications, such as ESRD, is unknown. In the 1990s, we recruited 410 patients with type 2 diabetes for studies of diabetic nephropathy and recorded their characteristics at enrollment. During 12 years of follow-up, 59 patients developed ESRD (17 per 1000 patient-years) and 84 patients died without ESRD (24 per 1000 patient-years). Plasma markers of systemic inflammation, endothelial dysfunction, and the TNF pathway were measured in the study entry samples. Of the examined markers, only TNF receptors 1 and 2 (TNFR1 and TNFR2) associated with risk for ESRD. These two markers were highly correlated, but ESRD associated more strongly with TNFR1. The cumulative incidence of ESRD for patients in the highest TNFR1 quartile was 54% after 12 years but only 3% for the other quartiles (P,0.001). In Cox proportional hazard analyses, TNFR1 predicted risk for ESRD even after adjustment for clinical covariates such as urinary albumin excretion. Plasma concentration of TNFR1 outperformed all tested clinical variables with regard to predicting ESRD. Concentrations of TNFRs moderately associated with death unrelated to ESRD. In conclusion, elevated concentrations of circulating TNFRs in patients with type 2 diabetes at baseline are very strong predictors of the subsequent progression to ESRD in subjects with and without proteinuria.

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 ...

The risk of end-stage renal disease (ESRD) remains high in patients with type 1diabetes and proteinuria; however, little is known about the rate of decline in their renal function. To help determine this we enrolled patients with 1 diabetes and proteinuria whose estimated glomerular filtration rate (eGFR) was normal (equal to or above 60 ml/min/1.73m2). Using a minimum of 5 serial measurements of serum creatinine for 161 patients, we determined individual trajectories of eGFR change and the occurrence of ESRD during 5–18 years of follow-up. The rates were linear for 110 patients, for 24 the non-linear rate was mild enough to satisfy a linear model, and the rates were clearly non-linear for only 27 patients. Overall, in more than one third of patients, the eGFR decline was less than 3.5 ml/min/1.73m2 per year and the lifetime risk of ESRD could be considered negligible. In the remainder of patients, eGFR declined with widely different slopes and ESRD developed within 2 to 18 years. Based on up to five years observation when renal function was within the normal range, the estimates of early eGFR slope predicted the risk of ESRD during subsequent follow-up better than the baseline clinical characteristics of glycated hemoglobin, blood pressure, or the albumin to creatinine ratio. Thus, the early slope of eGFR decline in patients with type 1diabetes and proteinuria can be used to predict the risk of ESRD.