Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes

Abstract

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.

Figure 1.

Cumulative risk of ESRD in patients with T2D during 12 years of follow-up according to quartiles of plasma TNFR1 at baseline examination and proteinuria status.

Figure 2.

Effect of each TNF pathway marker on the risk of ESRD in T2D patients during 8–12 years of follow-up. Data are estimates of HRs for an increase by one quartile in the distribution of the marker concentration. The estimates are from a Cox proportional hazard model that adjusted for AER, eGFR, and HbA1c. Other clinical covariates were not significant and did not confound the effects of the receptors. Diamonds and solid lines represent point estimates and 95% CIs for individual markers. The third and fifth lines in the figure are broken and marked by an asterisk to indicate that they represent point estimates and 95% CIs when both total TNFα and TNFR1 were included in the model. For additional details of these analyses, see Supplemental Table 5.