Key Points: Surface expression of stage-specific embryonic antigen 4 on urinary extracellular vesicles and CD42a on plasma extracellular vesicles identified distinct recovery trajectories after AKI. A combined urinary–plasma extracellular vesicle index enhanced prognostic performance. These findings highlight extracellular vesicle surface profiling as a potential minimally invasive liquid biopsy strategy to monitor post-AKI repair. Background: Maladaptive repair processes after AKI can promote the progression of CKD, highlighting the need for biomarkers capable of monitoring post-AKI renal function trajectory. Extracellular vesicles (EVs), nanosized lipid vesicles secreted by cells into biofluids, are considered valuable biomarker sources, as their cargo may reflect the originating cells and their pathophysiologic condition. Methods: Urinary EV (uEV) and plasma EV surface markers were analyzed in patients with AKI compared with age- and sex-matched controls using multiplex flow cytometry. Patients were stratified according to renal function changes at 90-day follow-up, distinguishing between those with an improved or not-improved kidney disease. Results: In patients with AKI at hospital discharge, uEV analysis showed a downregulation of the tubular progenitor markers CD133 and CD24, with upregulation of mesenchymal/inflammatory markers CD29, stage-specific embryonic antigen 4 (SSEA-4), and HLA-DR, in comparison with controls. Plasma EV analysis showed concomitant modulation in patients with AKI of markers of endothelial dysfunction and platelet activation. Considering kidney function at 90 days of follow-up, uEVSSEA-4, a marker of cell dedifferentiation, was higher in patients with AKI with improved function and correlated with renal recovery. Conversely, plasma EV CD42a, a marker of platelet activation, was higher in patients with persistent renal impairment and negatively correlated with renal recovery. Furthermore, the combined urinary SSEA4/plasma EV-associated CD42a index provided higher correlation and regression performance compared with either marker alone. Conclusions: These findings suggest that EV surface profiling could represent a minimally invasive strategy to distinguish adaptive from maladaptive repair after AKI, supporting the potential use of integrated uEV and plasma EV biomarkers to predict kidney disease progression. Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/K360/2026_10_29_KID0000001331.mp3

Chronic kidney disease is associated with neurovascular complications including cognitive impairment, potentially involving blood–brain barrier (BBB) impairment. The protein-bound uremic toxin indoxyl sulfate (IS) promotes endothelial injury, but its effects on human brain microvascular endothelial cells remain incompletely understood. Human cerebral microvascular endothelial cells (hCMEC/D3) were exposed to IS 200 and 900 μM. BBB integrity was assessed by the FITC-dextran (4 kDa) transwell permeability assay and claudin-5 immunofluorescence. Transcriptional responses were quantified by qPCR for aryl hydrocarbon (AhR) target genes, oxidative stress-associated and inflammatory markers, senescence, and junction-associated genes. Senescence-associated phenotypic changes were evaluated by SA-β-galactosidase staining and cytokine array profiling. IS increased endothelial permeability at 24 and 48 h (~1.5-fold relative to control) without evidence of cytotoxicity and reduced claudin-5 staining intensity. IS strongly upregulated AhR target genes, including CYP1A1, CYP1B1, and CYP1A2. NFE2L2 and IDO1 increased, while NFKB1 remained unchanged. SA-β-gal positivity increased, accompanied by elevated GM-CSF and G-CSF secretion, while CDKN1A decreased at IS 900 µM and CDKN2A remained unchanged. CDH5 was downregulated, TJP1 increased at 900 µM, and CLDN5 remained unchanged. These findings indicate that IS exposure is associated with impaired BBB integrity, AhR-related transcriptional responses, oxidative stress-associated transcriptional changes, junctional remodeling, and senescence-like endothelial features. However, causal attribution to individual pathways requires inhibition or knockdown studies.