#6120 MIRNA PROFILING OF URINARY EXTRACELLULAR VESICLES (EVS) IN TBMN AND CFHR5 NEPHROPATHY FOR THE IDENTIFICATION OF NOVEL DISEASE BIOMARKERS

Abstract

Abstract Background and Aims Thin basement membrane nephropathy (TBMN) and complement factor-H related protein 5 (CFHR5) nephropathy are two of the most common renal monogenic diseases with high phenotypic heterogeneity that is only partly accounted for by locus and allelic factors. Intra-familial variability in the age of ESKD onset for some patients particularly exemplifies such highly variable phenotypes, suggesting a potential modifying role of additional factors such as non-coding regulatory RNAs. Given that miRNAs are key regulators of gene expression, miRNAs from urine-derived extracellular vesicles (EVs) were investigated for their potential use as biomarkers in TBMN and CFHR5 diagnosis and prognosis. Method MiRNA profiling of human urinary EVs was carried out by small RNA-sequencing in an initial discovery cohort of 54 patients with TBMN and 44 patients with CFHR5 nephropathy, each classified further into three subgroups based on disease severity (Grey-zone: eGFR >60 ml/min/1.73m2 and age <50 y/o; Mild: eGFR >60 ml/min/1.73m2 and age <50 y/o; Severe: eGFR <60 ml/min/1.73m2 independently of age). Differential expression of miRNAs from urine-derived EVs was compared with 30 age and sex matched healthy controls, whilst bioinformatic analysis was performed to delineate their associated mechanisms. Results Kidney-enriched candidate miRNA families were identified in urine-derived EVs for both TBMN and CFHR5 patients and further verified by RT-qPCR in the respective validation cohorts. Distinct miRNAs with significantly differentiated expression levels, compared to that of healthy control cohort, showed significant correlations with some of the evaluated clinical characteristics for both TBMN and CFHR5 patients suggesting a possible diagnostic and prognostic value on long follow-up. Finally, inverse correlations of miRNA expression with their predicted targeted genes identified dysregulated pathways and transcriptional networks for further investigation. Conclusion Collectively, distinct profiles of miRNAs from urine-derived EVs were identified in TBMN and CFHR5 nephropathy suggesting that a subset of differentially expressed miRNAs could serve as novel non-invasive biomarkers of disease progression and/or targets for the development of novel therapeutic approaches.