Added Value of Soluble Tumor Necrosis Factor-α Receptor 1 as a Biomarker of ESRD Risk in Patients With Type 1 Diabetes

OBJECTIVE Recent studies have suggested that circulating levels of the tumor necrosis factor-alpha receptor 1 (sTNF alpha R-1) may be a useful predictor for the risk of end-stage renal disease (ESRD) in patients with diabetes. However, its potential utility as a biomarker has not been formally quantified. RESEARCH DESIGN AND METHODS Circulating levels of sTNF alpha R-1 were assessed in 429 patients with type 1 diabetes and overt nephropathy from the Finnish Diabetic Nephropathy (FinnDiane) cohort study. Predictors of incident ESRD over a median of 9.4 years of follow-up were determined by Cox regression and Fine-Gray competing risk analyses. The added value of sTNF alpha R-1 was estimated via time-dependent receiver operating characteristic curves, net reclassification index (NRI), and integrated discrimination improvement (IDI) for survival data. RESULTS A total of 130 individuals developed ESRD (28%; ESRD incidence rate of 3.4% per year). In cause-specific modeling, after adjusting for baseline renal status, predictors of increased incidence of ESRD in patients with overt nephropathy were an elevated HbA(1c), shorter duration of diabetes, and circulating levels of sTNF alpha R-1. Notably, sTNF alpha R-1 outperformed estimated glomerular filtration rate in terms of R-2. Circulating levels of the sTNF alpha R-1 also remained associated with ESRD after adjusting for the competing risk of death. A prediction model including sTNF alpha R-1 (as a -0.5 fractional polynomial) was superior to a model without it, as demonstrated by better global fit, an increment of R2, the C index, and area under the curve. Estimates of IDI and NRI(>0) were 0.22 (95% CI 0.16-0.28; P < 0.0001) and 0.98 (0.78-1.23; P < 0.0001), respectively. The median increment in the risk score after including sTNF alpha R-1 in the prediction model was 0.18 (0.12-0.30; P < 0.0001). CONCLUSIONS Circulating levels of sTNF alpha R-1 are independently associated with the cumulative incidence of ESRD. This association is both significant and biologically plausible and appears to provide added value as a biomarker, based on the absolute values of NRI and IDI.