TNF-a/TNF-a Receptor System as Clinical Biomarker

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Recently, epidemiological and intervention studies in humans have shown that TNF-a and its receptors are also valuable biomarkers in DN. Both TNF-α and TNFRs are present in the circulation as soluble forms [63]. In patients with type 2 diabetes, serum TNF-α levels correlate with albuminuria [64] and urinary TNF-α levels with clinical markers of DN and disease progression [65]. In the Eurodiab study, TNF-α levels were associated with diabetic complications, including DN, and the association between NT-proBNP and diabetic complications was TNF-α-dependent [66]. Circulating TNFR2 levels were inversely and significantly correlated with eGFR in a cross-sectional study in type 2 diabetic patients [67]. A study examining serum inflammatory markers for association with GFR in type 1 diabetic patients without proteinuria has shown that both TNFRs were cross-sectionally associated with renal function decline even after adjustment for urinary albumin excretion [68].

Recently, longitudinal studies have confirmed that TNFR1 or TNFR2 are excellent predictors of progressive kidney disease in patients with a wide variety of stages and both types of diabetes [69-73] (Table 1). Type 1 diabetic patients with normo/microalbuminuria and TNFR2 levels in the highest quartile had a 55% cumulative incidence of reaching stage 3 CKD compared with less than a 15% incidence for patients with TNFR2 levels in the lower 3 quartiles after 12 years of follow-up [69]. In the Diabetes Control and Complications Trial (DCCT), both TNFR1 and TNFR2 were associated with an increased risk for the development of overt nephropathy [71]. Type 2 diabetic patients with proteinuria and TNFR1 levels in the highest quartile had a nearly 80% cumulative incidence of progressing to ESKD after 12 years of follow-up, the rate was less than 20% in those with TNFR1 levels in the lowest 3 quartiles [70]. Collectively these data indicate that TNFRs hold great promise as biomarkers for renal function decline in diabetic patients. Consistent with this, a recent prospective study performed on the FinnDiane cohort has shown that TNRF1 is independently associated with the cumulative incidence of ESRD and has an added value as a biomarker of ESRD risk in patients with type 1 diabetes with macroalbuminuria [72]. However, prolonged longitudinal studies are needed to validate these biomarkers in a broad range of populations prior to implementation in routine diabetes management.