Circulating TGF-β1-Regulated miRNAs and the Risk of Rapid Progression to ESRD in Type 1 Diabetes

We investigated whether circulating TGF-beta 1-regulated miRNAs detectable in plasma are associated with the risk of rapid progression to end-stage renal disease (ESRD) in a cohort of proteinuric patients with type 1 diabetes (T1D) and normal eGFR. Plasma specimens obtained at entry to the study were examined in two prospective subgroups that were followed for 7-20 years (rapid progressors and nonprogressors), as well as a reference panel of normoalbuminuric T1D patients. Of the five miRNAs examined in this study, let-7c-5p and miR-29a-3p were significantly associated with protection against rapid progression and let-7b-5p and miR-21-5p were significantly associated with the increased risk of ESRD. In logistic analysis, controlling for HbA(1c) and other covariates, let-7c-5p and miR-29a-3p were associated with more than a 50% reduction in the risk of rapid progression (P <= 0.001), while let-7b-5p and miR-21-5p were associated with a >2.5-fold increase in the risk of ESRD (P <= 0.005). This study is the first prospective study to demonstrate that circulating TGF-beta 1-regulated miRNAs are deregulated early in T1D patients who are at risk for rapid progression to ESRD.