Urinary miRNAs Enable Non-Invasive Prognostic Evaluation of IgA Nephropathy

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Urinary miR-92a-3p, miR-425-5p, and miR-185-5p were significantly increased in patients with IgAN and were all associated with tubular atrophy/interstitial fibrosis.

Zhi-Yu Duan | Credit: Loop

Zhi-Yu Duan

Credit: Loop

Findings from a recent study suggest urinary miR-92a-3p, miR-425-5p, and miR-185-5p may serve as specific biomarkers for tubular atrophy and interstitial fibrosis in patients with IgA nephropathy.1

Results further detail an association between high expression levels of urinary miR-185-5p with a poor renal prognosis, facilitating the transformation of renal tubular epithelial cells to fibrotic phenotype through its target gene tight junction protein 1 (TJP1).1

Disease progression in IgA nephropathy varies from patient to patient, underscoring the importance of having viable tools for predicting prognosis. Treatment often includes angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, immunosuppressants, and lifestyle changes, although medical tests are often necessary to track disease progression.2

“The identification of non-invasive biomarkers for tubular atrophy and/or interstitial fibrosis can help nephrologists to monitor renal tubulointerstitial disease progression in their patients at any time,” Zhi-Yu Duan, of the department of nephrology at First Medical Center of Chinese PLA General Hospital, and colleagues wrote.1

The single-center observational study included patients > 16 years of age with biopsy-confirmed primary IgAN and estimated glomerular filtration rate (eGFR)>15 mL/min/1.73 m2 before renal biopsy at the First Medical Center of the People’s Liberation Army General Hospital between January 2013 and October 2014. Patients were excluded if they had secondary IgAN, urinary tract infection, or pregnancy before renal biopsy.1

A total of 188 patients who met the inclusion and exclusion criteria were enrolled in the study. Additionally, investigators included 33 age- and sex-matched healthy individuals to serve as the control group.1

Upon analysis with miRNA sequencing and cohort validation, the expression levels of urinary miR-92a-3p, miR-425-5p, and miR-185-5p were significantly increased among patients with IgAN versus those in the control group. To confirm these results, investigators established a confirmation cohort consisting of 40 patients with IgAN and 33 healthy controls. Again, results showed the levels of urinary miR-92a-3p, miR-425-5p, and miR-185-5p were significantly higher in the IgAN group (P <.001).1

Further analysis revealed the expression levels of urinary miR-92a-3p, miR-425-5p, and miR-185-5p were significantly greater among IgAN patients who had renal tubulointerstitial lesions (T1-T2) compared to patients who lacked renal tubulointerstitial lesions (T0) in a confirmation cohort. Similar to the previous assay, findings from a validation cohort revealed increased miR-92a-3p, miR-425-5p, and miR-185-5p among patients with T1-T2.1

Although the AUCs of urinary miR-92a-3p, miR-425-5p, and miR-185-5p for predicting renal tubulointerstitial lesions (T1-T2) in patients with IgAN were 0.684, 0.679, and 0.739, respectively, when the 3 indicators were combined, the AUC was 0.742, sensitivity was 63.8%, and specificity was 76.5%.1

Investigators examined the expression level of urinary miR-185-5p alone and found it was significantly increased among patients who progressed to end-stage renal disease versus those who did not (0.0292 vs 0.0123; P <.0001). When patients were divided into a high expression group and a low expression group based on the median expression level of urinary miR-185-5p, investigators found the renal prognosis was significantly worse in the high-expression group (P = .003).1

Further analysis with renal tissue in situ hybridization, bioinformatics analysis, and dual luciferase experiments confirmed miR-185-5p affects prognosis in patients with IgAN by influencing the expression of the TJP1 in renal tubular epithelial cells. Indeed, using mass spectrometry to compare TJP1 expression levels in renal tissue between the IgAN group and the control group, investigators determined the TJP1 expression level was significantly lower in the IgAN group (0.919 ± 0.156) than in the control group (1.053 ± 0.193; P = .003).1

Additionally, in vitro results revealed an miR-185-5p mimic could reduce TJP1 expression in HK-2 cells, while increasing the levels of α-smooth muscle actin, fibronectin, collagen I, and collagen III, thus promoting the transformation of renal tubular epithelial cells to a fibrotic phenotype. Inhibition of miR-185-5p expression alleviated tubular atrophy/interstitial fibrosis in a unilateral ureteral obstruction model.1

“Our findings suggest that a model can be established using multiple non-invasive biomarkers, along with various clinical indicators, to improve the sensitivity and specificity of tubular atrophy/interstitial fibrosis prediction,” investigators concluded.1

References:

  1. Duan ZY, Bu R, Liang S, et al. Urinary miR-185-5p is a biomarker of renal tubulointerstitial fibrosis in IgA nephropathy. Front. Immunol. https://doi.org/10.3389/fimmu.2024.1326026
  2. Mayo Clinic. IgA Nephropathy (Berger Disease). June 9, 2023. Accessed March 15, 2024. https://www.mayoclinic.org/diseases-conditions/iga-nephropathy/diagnosis-treatment/drc-20352274
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