biostudies-literatureUnknown15(1)Inaba S<h4>Background</h4>Chronic kidney disease (CKD) leads to premature mortality from cardiovascular events before kidney replacement therapy. Despite recognition of syndromes like cardiorenal anemia and cardiovascular-kidney-metabolic, predictive models for kidney and cardiovascular outcomes remain inadequate. This study aimed to develop a minimally invasive, risk model using circulating small extracellular vesicle-derived miRNAs among patients with CKD.<h4>Methods</h4>A derivation cohort (n=36) underwent microarray-based miRNA profiling, and a least absolute shrinkage and selection operator-penalized Cox proportional hazards model was constructed. Validation was performed using TaqMan quantitative polymerase chain reaction in a cohort of 234 patients with CKD without kidney replacement therapy. The primary outcome was a ≥30% reduction in estimated glomerular filtration rate or progression to kidney replacement therapy. The secondary outcome included all-cause mortality, kidney replacement therapy initiation, and major adverse cardiovascular events.<h4>Results</h4>In the derivation cohort, 36% of patients had hypertensive glomerulosclerosis as the underlying CKD cause, increasing to 48% in the validation cohort. Twenty-three miRNAs were significantly downregulated in advanced CKD, associated with cellular senescence, FOXO (forkhead box, class O) signaling, and cell cycle pathways. From these, 3 miRNAs-<i>hsa-let-7d-5p</i>, <i>hsa-miR-24-3p</i>, and <i>hsa-miR-126-3p</i>-were selected and integrated into the final risk score with cystatin C and urinary protein levels, following optimization in the validation cohort. Lower miRNA levels were linked to cardiovascular comorbidities and cardiorenal anemia syndrome. Over a median follow-up of 39 and 59 months, 108 kidney events and 70 composite outcomes occurred. The model effectively predicted adverse outcomes across CKD causes, further stratifying risk within cardiovascular-kidney-metabolic stage classifications.<h4>Conclusions</h4>Circulating small extracellular vesicle-derived miRNA profiles enable a noninvasive, longitudinally predictive model for adverse kidney and cardiovascular outcomes in CKD. This approach may improve early risk identification and clinical decision-making.Journal of the American Heart Associatione045148https://www.ebi.ac.uk/biostudies/studies/S-EPMC12909002biostudies-literatureCirculating Extracellular Vesicle MicroRNAs as Predictive Biomarkers for Kidney and Cardiovascular Events.PMC12909002Mori YUchida SFujiki THasegawa TKoide TKikuchi HSuzukawa RSekiya HArai YInaba SNaito SSohara EMatsuki HSusa KAndo FIimori SNakano YMori TMandai SfalseCirculating Extracellular Vesicle MicroRNAs as Predictive Biomarkers for Kidney and Cardiovascular Events.<h4>Background</h4>Chronic kidney disease (CKD) leads to premature mortality from cardiovascular events before kidney replacement therapy. Despite recognition of syndromes like cardiorenal anemia and cardiovascular-kidney-metabolic, predictive models for kidney and cardiovascular outcomes remain inadequate. This study aimed to develop a minimally invasive, risk model using circulating small extracellular vesicle-derived miRNAs among patients with CKD.<h4>Methods</h4>A derivation cohort (n=36) underwent microarray-based miRNA profiling, and a least absolute shrinkage and selection operator-penalized Cox proportional hazards model was constructed. Validation was performed using TaqMan quantitative polymerase chain reaction in a cohort of 234 patients with CKD without kidney replacement therapy. The primary outcome was a ≥30% reduction in estimated glomerular filtration rate or progression to kidney replacement therapy. The secondary outcome included all-cause mortality, kidney replacement therapy initiation, and major adverse cardiovascular events.<h4>Results</h4>In the derivation cohort, 36% of patients had hypertensive glomerulosclerosis as the underlying CKD cause, increasing to 48% in the validation cohort. Twenty-three miRNAs were significantly downregulated in advanced CKD, associated with cellular senescence, FOXO (forkhead box, class O) signaling, and cell cycle pathways. From these, 3 miRNAs-<i>hsa-let-7d-5p</i>, <i>hsa-miR-24-3p</i>, and <i>hsa-miR-126-3p</i>-were selected and integrated into the final risk score with cystatin C and urinary protein levels, following optimization in the validation cohort. Lower miRNA levels were linked to cardiovascular comorbidities and cardiorenal anemia syndrome. Over a median follow-up of 39 and 59 months, 108 kidney events and 70 composite outcomes occurred. The model effectively predicted adverse outcomes across CKD causes, further stratifying risk within cardiovascular-kidney-metabolic stage classifications.<h4>Conclusions</h4>Circulating small extracellular vesicle-derived miRNA profiles enable a noninvasive, longitudinally predictive model for adverse kidney and cardiovascular outcomes in CKD. This approach may improve early risk identification and clinical decision-making.2026-01-01T00:00:00Z2026 Jan2026-07-07T03:08:56.619Z2026-07-07T03:08:04.059ZS-EPMC129090024136915610.1161/JAHA.125.045148