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).

Figure 1.

Scatter plot of circulating concentrations of TNFR1 and TNFR2 in baseline samples from study participants with T1D and normal renal function (Spearman correlation between TNFR1 and TNFR2: r=0.78; P<0.0001). Gray circles represent patients whose renal function remained normal at the end of follow-up. Red squares represent patients whose renal function declined to CKD≥3. Vertical and horizontal lines are the 25th, 50th, and 75th percentiles of the respective markers.

Figure 2.

Cumulative risk for CKD≥3 in patients with T1D during 12 years of follow-up according to quartile (Q1–Q4) of circulating TNFR2 at baseline.

Figure 3.

Effect of each TNF pathway marker at baseline on the risk for CKD≥3 in T1D patients followed up to 12 years. Hazard ratios are estimates from a Cox proportional hazards model for a fourth-quartile effect versus first through third quartiles and adjusted for HbA1c, AER, and eGFRcystatin. Diamonds and solid lines represent the point estimates and 95% CIs for individual markers adjusted by clinical covariates. Diamonds and broken lines marked with an asterisk represent point estimates and 95% CIs adjusted by clinical covariates and with both TNFα total and TNFR2 in the model.