THU0236 URINARY EXOSOMAL MIR-31, MIR-107 AND MIR-135B-5P FROM TUBULAR RENAL CELLS AS RESPONDER BIOMARKER IN LUPUS NEPHRITIS
Authors: Cristina Solé-Marcé, Eloi Garcia-Vives, Irene Agraz, Josep Ordi-Ros, Josefina Cortés-Hernández
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Lupus nephritis (LN), occurring in ∼40–75% of patients with systemic lupus erythematosus (SLE), continues to be one of the most severe forms of lupus with an unpredictable course. Conventional clinical parameters are not sensitive or specific enough for detecting ongoing disease activity, early relapse, disease progression or response to therapy [1]. Exosomal-derived urinary miRNAs can accurately reflect renal dysfunction and structural damage making them good biomarkers for diagnosis and prognosis [2]. In LN, urinary exosomal miR-29c expression levels have been identified as predictor of early fibrosis [3] and miR-146a upregulation as marker to discriminate active LN [4]. To the best of our knowledge, this is the first screening of miRNAs in urinary exosomes from LN patients to study their role as predictors of response to therapy. <h3>Objectives:</h3> Identify a non-invasive miRNA profile predictive of clinical response in LN following standard treatment. <h3>Methods:</h3> Urinary exosomes were isolated and characterized from lupus patients (N=14) during flare and post-treatment time. Patients were divided between responder and non-responder and urinary exosomal miRNA screening analysis was performed according their clinical response. To validate initial results, a new cohort of LN patients were used (N=44). <i>In situ hybridization</i> of miRNAs in kidney renal biopsies and <i>in vitro</i> experiments with human primary renal cells were performed in order to determinate cell origin of exosome production and their delivery cell target (Figure 1). <h3>Results:</h3> In the screening, 25 miRNAs were significantly differences in comparative group analysis. High levels of miR-31, miR-107 and miR-135b-5p were confirmed to be related with responder patients. We found that miR-135b has the best profile to distinguish the two groups (AUC= 0.783 (95% confidence interval [CI], 0.640 - 0.926), cut-off &lt;0.0884 with 77.8% sensitivity and 71.4% specificity). Renal tissue samples from responder patients showed miR-31, miR-107 and miR-135b-5p to be highly expressed compared with non-responders. All miRNAs were predominantly localized in the tubular cells. Stimulated tubular renal cells displayed the higher expression levels of exosome-derived miR-31, miR-107 and miR-135b-5p when compared with endothelial or mesangial cells (p&lt;0.0001). Nevertheless, urinary exosomes from non-responder patient's internalization was only of ∼ 50% by mesangial cells compared to ∼90% from responders. <h3>Conclusion:</h3> These results indicated that levels of urinary exosomal miRNAs produced by tubular cells might have a renal recovery role in mesangial cells and be used as new biomarkers of lupus nephritis outcome. <h3>References:</h3> [1] Adler M, et al. Rheumatology. 2006;45(9):1144–7. [2] Valadi H, et al. Nat Cell Biol. 2007;9(6):654-U672. [3] Solé C, et al. Neprol Dial Transplant. 2015. 30(9):1488-96. [4] Perez-Hernandez J, et al. PLoS One. 201510(9):e0138618. <h3>Acknowledgement:</h3> This work was supported by grants from the Spain Government (Instituto de Salud Carlos III, PI15/02117) and the Catalan Lupus Foundation. The funders of this study were not involved in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. <h3>Disclosure of Interests:</h3> Cristina Solé-Marcé: None declared, Eloi Garcia-Vives: None declared, Irene Agraz: None declared, Josep Ordi-Ros: None declared, Josefina Cortés-Hernández Grant/research support from: GSK, Speakers bureau: GSK