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.
