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Urinary MicroRNA Biomarkers of Drug-induced Kidney Injury (DIKI) Demonstrate Differences in Sensitivity within Exosomal Fraction Compared to Whole Urine
Citation:
Dasgupta, S., T. Sharapova, P. Mahalingaiah, B. Chorley, A. Abokifa, T. Tsuji, A. dos Santos, R. Chari, A. Ebrahimi, D. Dalmas, S. Pettit, B. Bawa, E. Vaughan, T. van Vleet, C. Mitchell, AND P. Yuen. Urinary MicroRNA Biomarkers of Drug-induced Kidney Injury (DIKI) Demonstrate Differences in Sensitivity within Exosomal Fraction Compared to Whole Urine. SOT Annual meeting, Salt Lake City, UT, March 10 - 14, 2024. https://doi.org/10.23645/epacomptox.25565628
Impact/Purpose:
This is is being submitted for an SOT poster abstract. This collaborative study served as a follow-up for the HESI eSTAR miRNA Workgroup (highlighted as a subproduct CSS.4.6.6.3) which established a panel of miRNAs specific for nephron subregions that were released into the urine with nephrotoxicant exposures in a rat model. Here, we tested these miRNAs in an archived primate study to see if they correlated with histopath lesions and protein biomarkers after exposure to a mild nephrotoxicant. Both whole urine and exosomal fractions were measured. The results of this study, while limited, demonstrated the utility of this panel to correlate with mild kidney damage, which will be important in biomarker development for cross-sector safety testing (drug development and toxicity studies in a regulatory environment). This study furthers the data to support the utility of miRNA measures as non-invasive biomarkers of tissue toxicity.
Description:
Background and Purpose: Drug-induced kidney injury (DIKI) is a significant concern because it can lead to acute or chronic kidney damage and may potentially result in kidney failure. Therefore, early diagnosis of DIKI is crucial to apply therapeutic strategies. Traditional biomarkers of DIKI, such as creatinine, do not allow for early detection prior to injury. Therefore, identifying biomarkers of early detection is crucial. Since microRNAs are stable in urine, the aim of this project was to identify reliable urinary microRNA (miR) biomarkers that can be used as potential predictors of DIKI before disease diagnosis. Methods: Using qPCR, this study quantified a panel of six miRs (miRs-210-3p, 423-5p, 143-3p, 130b-3p, 486-5p, 193a-3p) within urinary samples of a previous investigation evaluating effects of a proprietary nephrotoxicant in cynomolgus monkeys across multiple weeks of exposure and recovery. In addition to miRs, a battery of urinary protein biomarkers was also quantified, and histopathological analyses of kidneys were conducted. Results: While minimal significance in differential miR expression was seen in both exosome and whole urinary samples during the duration of the experiment, correlative trends emerged when Spearman correlations were calculated between miR expression and histopathological scores. During treatment and recovery phases of the experiment, histopathology-miR expression correlation coefficients were stronger (>0.7) for several exosomal miRs (eg: miRs-143-3p, -486-3p) compared to whole urine miRs. Additionally, stronger correlations were found (>0.7) between miRNAs measured within the exosomal fraction as compared to correlations between miRNAs measured in unfractionated urine (0.24-0.68). Conclusion: Taken together, these results suggest that exosomal miRs are more sensitive to DIKI compared to whole urine and several exosomal miRs can be potentially used as a cluster for DIKI diagnosis. Although further research and mechanistic studies are required to elucidate how these miRNAs regulate signaling in disease pathways, we present, for the first time, data that several miRNAs displayed strong correlations with histopathology scores, thus indicating their potential use as biomarkers to predict the development of DIKI in preclinical studies and clinical trials.
URLs/Downloads:
DOI: Urinary MicroRNA Biomarkers of Drug-induced Kidney Injury (DIKI) Demonstrate Differences in Sensitivity within Exosomal Fraction Compared to Whole Urine
DASGUPTA-ET-AL-MIR-POSTER-HESI-SOT2024.PDF (PDF, NA pp, 1766.957 KB, about PDF)