Transfer RNAs, not microRNAs, are linked to ischemic stroke and major bleeding in patients with end-stage kidney disease – a nested case-control study from the VIVALDI cohort

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Introduction Patients with end-stage kidney disease (ESKD) are at particularly high risk for thromboembolism and bleeding. This study aimed to identify small non-coding RNAs (sncRNAs), specifically microRNAs and transfer RNA (tRNA)-derived fragments (tRFs), as potential novel biomarkers for thromboembolism and bleeding in this high-risk population. Method In this sncRNA discovery research, we leveraged the VIVALDI cohort, consisting of 625 ESKD patients on hemodialysis, to conduct two nested case-control studies, each comprising 18 participants. The primary outcomes were ischemic stroke in the first investigation and major bleeding in the second. Plasma samples were processed using the mIND pipeline for RNA-seq analysis to investigate differential expression of microRNAs and tRNA/tRFs between cases and their respective matched controls, with results stringently adjusted for false discovery rate (FDR). Results No significant differential expression of microRNAs for either ischemic stroke or major bleeding outcomes was observed in either of the two nested case-control studies. However, we identified four tRNAs significantly differentially expressed in ischemic stroke cases and seven in major bleeding cases, compared to controls (FDR<0.1, see [ Fig. 1 ]). Coverage plots indicated that specific tRNA fragments (tRFs), rather than full-length tRNAs, were detected (example provided in [ Fig. 2 ]). Alternative mapping approaches revealed challenges and technical limitations that precluded in-depth differential expression analyses on these specific tRFs. Yet, they also underscored the potential of tRNAs and tRFs as markers for thromboembolism and bleeding. Fig. 1 Volcano plot representing differential expression and statistical significance of tRNAs in Fig. 2 Coverage plots of the differential tRNA-derived fragments pattern coding for tRNA-Val-AAC-1 ; Highlighted in red is a pattern of fragments present in patients with a major bleeding event compared to their controls. Conclusion While microRNAs did not show significant differential expression, our study identified specific tRNAs/tRFs as potential novel biomarkers for ischemic stroke and major bleeding in ESKD patients, which need to be further validated externally. Publication History Article published online: 26 February 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

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