Single-Cell Transcriptomics and Urine Extracellular Vesicle (uEV) Biomarkers After Left Ventricular Assist Device (LVAD) Implantation

Background: Kidney dysfunction following LVAD implantation is common. The effects of implantation and mechanical circulatory support are uncertain. We investigated whether biomarkers identified using uEV proteomics (encompassing surgery and early recovery) in LVAD recipients corresponded to kidney cell transcriptome changes in human and mouse AKI and fibrotic transition. Methods: We have previously identified 21 kidney-expressed proteins with differential abundance in uEVs at post-op day 7 vs pre-op (FDR<0.05, FC>2) in 33 adult LVAD recipients using untargeted mass spec. We used kidney scRNA-seq data from human kidney biopsies (healthy, AKI, and CKD, n=79) (KPMP) and mouse ischemia-reperfusion injury (IRI) and fibrotic transformation (GSE190887) to evaluate expression patterns of the markers in kidney cells and evaluate differential expression with AKI and fibrotic transition. Results: The 33 LVAD recipients were median age 60 and 12% female. Expression of the 21 uEV markers encompassed all major nephron cell types in humans, with highest expression of GPX3, FTL, and FTH1 in the proximal tubule cells (FigA). Expression patterns in mouse models showed overlap with several proteins in both AKI and fibrotic transformation stages. For example, the mouse analogs Gpx3, Ftl1, and Fth1 showed increased expression 6 hours following IRI (B). Conclusion: Single cell transcriptomics from human AKI and mouse models have corroborated uEV biomarkers of kidney stress identified in LVAD recipients. This may support the utility of uEV biomarkers in this setting and the importance of iron-related stress to post-LVAD kidney dysfunction and protection via GPX3. Funding: NIDDK SupportExpression of 21 uEV-derived biomarkers in human kidney cells B. Differential expression of 3 of the biomarkers in mouse AKI (IRI-6 hours vs. healthy)