Serum Levels of miR-148b and Let-7b at Diagnosis May Have Important Impact in the Response to Treatment and Long-Term Outcome in IgA Nephropathy

Abstract

Background/aims: Previous studies showed that two microRNAs, let-7b and miR-148, which regulate the O-glycosylation process of IgA1, may predict diagnosis of primary IgA nephropathy (IgAN). The combined analysis of their serum levels in calculated statistical models may act as serum biomarkers for the diagnosis of primary IgAN. In the present study, we aimed to assess their impact not only on clinical and histological findings at onset but also on renal function after a long-term follow-up.

Patients and methods: We enrolled 61 Caucasian patients with biopsy-proven IgAN. Serum levels of miR-148b, let-7b, and galactose-deficient IgA1 (Gd-IgA1) at the time of diagnosis were measured using real-time quantitative PCR and enzyme-linked immunosorbent assay using the monoclonal antibody KM55, respectively. Their values along with calculated Models 1 and 2 were correlated with histologic scoring system (Oxford classification system) and with renal function at diagnosis and after 11.9 ± 6.6 years. Fifty-five healthy volunteers were enrolled as controls.

Results: No significant correlation was found between miRNA and Gd-IgA1 levels and eGFR and proteinuria at diagnosis. A significant negative association was detected between the presence of crescents and serum levels of let-7b (p = 0.002), miR-148b (p = 0.01), and Models 1 and 2 (p = 0.02 and p = 0.007, respectively). At the end of follow-up, eGFR correlated with let-7b levels (p = 0.01), Model 1 (p = 0.002), and Model 2 (p = 0.004). Patients with fast progression of the renal damage had significantly increased levels of let-7b (p = 0.01), Model 1 (p = 0.003), and Model 2 (p = 0.005) compared to slow progressors, as did those who reached ESKD (p = 0.002, p = 0.001, and p = 0.001, respectively). Results were most prominent in those treated with corticosteroids. Finally, cut off levels in Models 1 and 2 could also predict the renal function outcome after long-term follow-up.

Conclusions: Serum levels of let-7b and miR-148b and their combination, may serve as predictors for long-term renal function outcomes, particularly in patients treated with corticosteroids.

Keywords: IgA nephropathy; biomarker; microRNA; serum.

Figure 1

Histology of IgAN patients showing glomeruli with mesangial hyperplasia (A), focal segmental sclerosis (B), endocapillary and extracapillary hypercellularity (C), and cellular crescent (D).

Figure 2

Serum levels of miR-148 (A), let-7b (B) at time of renal biopsy, Model 1 (C), and Model 2 (D) in IgAN patients with MEST-C0 and MEST-C1,2.

Figure 3

Differences in serum levels of let-7b (A), Model 1 (B), and Model 2 (C) between SP, MP and FP. * p < 0.001 (FP vs. SP), ** p < 0.01 (FP vs. MP). SP: Slow Progressors, MP: Moderate Progressors, FP: Fast Pogressors.

Figure 4

Impact of mRNA let-7b serum levels and calculated models in the outcome of renal function, as defined by fast progression (A), ESRD (B), and combined ≥50% reduction in eGFR and ESRD (C).