Study patients
A total of 346 patients were enrolled in the study. The mean age of the patients was 61.3 years, and 69.7% of the patients were men. The mean duration of diabetes was 11.1 years. One-third of the subjects had albuminuria, and the prevalence of retinopathy and neuropathy was 9.2%. Sixty-four (18.5%) patients had stage 3 chronic kidney disease. The mean HbA1C was 7.1%, mean blood pressure was 114.6 mmHg, and mean body mass index (BMI) was 26.3 kg/m2. The baseline characteristics of the study population are summarized in Table 1.
Association of sTNFR2 with the renal outcomes
Over a median follow-up time of 4 years, 69 participants had a renal composite event, which is composed of 44 events of progression of albuminuria stages and 25 events of a >30% reduction in the eGFR. Among the 44 events of progressive albuminuria, 21 participants had a transition from normoalbuminuria to microalbuminuria, and 22 participants progressed from microalbuminuria to macroalbuminuria. One patient had a rapid progression from normoalbuminuria to macroalbuminuria. Patients with renal composite events had longer durations of diabetes, higher percentages of retinopathy or neuropathy, higher UACRs, and lower eGFRs at baseline. The coverage of the renin-angiotensin system (RAS) blockade was more extensive in patients with renal outcomes (Table 1). Correlations between sTNFR2 concentrations and BMIs or waist-to-hip ratios were weak (Pearson’s correlation coefficient -0.057 for sTNFR2 and BMI, p = 0.292; -0.015 for sTNFR2 and waist-hip-ratio, p = 0.778). The sTNFR2 concentration was associated with the renal outcomes in the univariate Cox proportional analysis (hazard ratio [HR] 1.27, 95% confidence interval [CI] 1.05-1.53, p = 0.013). Other clinical covariates, such as the duration of diabetes, presence of retinopathy or neuropathy, eGFR and UACR at baseline, and the use of RAS inhibitors were also associated with renal outcomes. The association of sTNFR2 concentration with renal events was attenuated after adjustment in sequential models (Table 2).
The ideal cut-off point for sTNFR2 concentration is the point where true-positive findings and few false-positive results are detected in most patients. The optimal cut-off value of sTNFR2 levels obtained using the receiver operating characteristic curve analysis was 1.608 ng/mL, allowing for a sensitivity of 73.9% and a specificity of 48.7%. The area under the receiver operating characteristic curve of sTNFR2 was 0.61 (95% CI 0.54-0.68, p = 0.005; Figure 1). The highest tertile of sTNFR2 concentration had an increased risk of renal composite events (p = 0.035 from the log-rank test; Figure 2a).
Association of sTNFR2 levels ≥1.608 ng/mL with the renal outcomes
The clinical characteristics of the study population stratified based on sTNFR2 concentrations (≥1.608 ng/mL or <1.608 ng/mL) are shown in Supplementary Table 1. The patients with sTNFR2 concentrations ≥1.608 ng/mL were older and had longer durations of diabetes, higher UACRs, and lower eGFRs at baseline. The coverage of the RAS blockade was more extensive in patients with sTNFR2 concentrations ≥1.608 ng/mL than in patients with sTNFR2 concentrations <1.608 ng/mL (55.4% vs. 39.9%, p = 0.004). The patients with sTNFR2 concentrations ≥1.608 ng/mL had more renal composite events at the end of the study than those with sTNFR2 concentrations <1.608 ng/mL did (26.4% vs. 11.8%; p = 0.005 from the log-rank test; Figure 2b). Regarding the separate components of the renal composite events, the frequency of worsening albuminuria was also higher in the study group with sTNFR2 concentrations ≥1.608 ng/mL (17.1% vs. 7.8% for worsening albuminuria, p = 0.011; Supplementary Table 1).
In the univariate Cox proportional analysis, sTNFR2 concentrations ≥1.608 ng/mL were associated with higher renal event rates (HR 2.07, 95% CI 1.21-3.54, p = 0.008). A sTNFR2 concentration ≥1.608 ng/mL predicted renal events in all of the multivariate models (HR 2.05, 95% CI 1.17-3.61, p = 0.013 for model 1; HR 2.01, 95% CI 1.14-3.53, p = 0.016 for model 2; HR 1.95, 95% CI 1.01-3.74, p = 0.046 for model 3).
We performed a subgroup analysis based on age (younger or older than 60 years), sex, systolic blood pressure (≥ or <140 mmHg), eGFR (≥ or <60 mL/min/1.73m2), UACR (≥ or <30 mg/g creatinine), and the use of RAS inhibitors. The association of a sTNFR2 concentration ≥1.608 ng/mL with renal outcomes remained significant across all subgroups, including patients with an eGFR ≥60 mL/min/1.73m2 or normoalbuminuria (Table 3).