Urinary exosomal miRNA-451a can be used as a potential noninvasive biomarker for diagnosis, reflecting tubulointerstitial damage and therapeutic response in IgA nephropathy

Abstract

To investigate the potential clinical value of urinary exosomal (uE) miR-451a as a biomarker for IgAN, urinary exosomes were isolated from 40 patients with IgAN, 30 patients with primary renal diseases without IgA as disease controls (non-IgAN group) and 21 healthy controls (HCs). The expression of miR-451a within exosomes was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). uE miR-451a was significantly upregulated in patients with IgAN compared to non-IgAN and HCs. The uE miR-451a level was positively correlated with the change in eGFR and negatively correlated with serum creatinine, urinary macrophage migration inhibitory factor (MIF), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α). A dual-luciferase reporter assay confirmed that MIF was a direct target of miR-451a. Receiver operating characteristic (ROC) curve analysis revealed that the expression of uE miR-451a showed potential diagnostic value for IgAN. Additionally, the uE miR-451a level could distinguish patients with IgAN with mild tubular atrophy/interstitial fibrosis from those with severe tubular atrophy/interstitial fibrosis. After a mean follow-up of 14.2 months, the levels of eGFR loss (ml/min/1.73 m²/year) were negatively correlated with baseline miR-451a. The levels of baseline miR-451a in the complete remission group were significantly higher than those in the non-complete remission group. uE miR-451a expression was significantly elevated in patients with IgA nephropathy and may serve as a potential biomarker for the diagnosis of IgAN and evaluation of tubulointerstitial damage, while the baseline levels of uE miR-451a may be predictors of therapeutic efficacy and disease progression.

Keywords: IgA nephropathy; MicroRNA; noninvasive biomarkers; therapeutic response; tubulointerstitial damage.

Figure 1.

Comparison of uE miR-451a levels among the IgAN, non-IgAN, and HC groups. *Significant difference between patients with IgAN and HCs (p = 0.011); #significant difference between patients with non-IgAN and HCs (p = 0.0013).

Figure 2.

Comparison of uE miR-451 levels between the two subgroups according to the eGFR < 50 mL/min/1.73 m2 and ≥ 50 mL/min/1.73 m2 in patients with IgAN (9 vs 31 cases). *Significant difference between patients with the two subgroups according to the eGFR < 50 mL/min/1.73 m² and ≥ 50 mL/min/1.73 m² in patients with IgAN (p = 0.007).

Figure 3.

Hsa-miR-451a mimic transfection can inhibit wild-type MIF 3′UTR (p = 0.03).

Figure 4.

Relationship between uEsmir-451a levels and different scores of tubular atrophy/interstitial fibrosis in IgA nephropathy according to the Oxford classification. #Significant difference between patients with T1 and T0 (p = 0.011). *Significant difference between patients with T2 and T0 (p = 0.026).

Figure 5.

ROC analysis of uE miR-451a for the diagnosis of IgAN. AUC: Area under the curve; 95% CI: 95% confidence interval.

Figure 6.

ROC curve of discriminating patients with IgAN with tubular atrophy/interstitial fibrosis T0 from patients with T1 + T2. AUC: Area under the curve; 95% CI: 95% confidence interval.