Abstract Body: Introduction: Chronic kidney disease (CKD) is characterized by blood pressure dysregulation. While mean blood pressure is a known risk factor, visit-to-visit blood pressure variability (BPV) is emerging as a driver of cardiovascular outcomes. Knowledge gaps exist regarding the mechanobiological pathways linking BPV to vascular injury. We propose that BPV-induced hemodynamic stress activates neutrophils via CD95 (Fas ligand) and CD182 (CXCR2) signaling, promoting the formation of endothelial-neutrophil aggregates (ENAs). These aggregates serve as mobile niduses of thrombo-inflammation, bridging the gap between hemodynamic instability and adverse cardiovascular outcomes.
Hypothesis: Increased diastolic BPV (DBPV) drives the formation of ENAs and is independently associated with an increased risk of cardiovascular disease in CKD.
Methods: We analyzed 420 CKD patients (stages II–V) across two parallel cohorts: an epidemiological discovery cohort (n=408; 2,063 patient-years; 22,014 BP readings) and a mechanistic validation cohort (n=14; 1479 readings). BPV was quantified using coefficient of variation, average real variability, and a novel weighted metric normalized for visit frequency. In the mechanistic cohort, flow cytometry identified activated neutrophils (CD95+CD182+) and endothelial-neutrophil doublets. ENA formation was quantified by fold change in median fluorescence intensity (MFI) of endothelial markers (CD309/VEGFR2 and CD34) on doublet-to-singlet neutrophil populations. Correlations were assessed using Spearman’s rank test.
Results: In the epidemiological cohort, DBPV (but not systolic BPV) was strongly associated with a spectrum of CV pathologies: peripheral arterial disease (+31.2%, p=0.032), arrhythmia (+28.6%, p=0.0007), and stroke (+21.6%, p=0.0146). Mechanistically, DBPV significantly correlated with the presence of activated CD95+CD182+ neutrophils and the formation of ENAs, as evidenced by increased CD309 fold change on neutrophils (rho=0.644, p=0.0129). Systolic variability showed no such correlation, suggesting diastolic fluctuations drive the recruitment of endothelial fragments by activated neutrophils.
Conclusion: DBPV is a potent driver of vascular inflammation in CKD, promoting the formation of endothelial-neutrophil aggregates that may facilitate systemic thrombo-embolic events. These findings suggest DBPV as a novel therapeutic target and a precision biomarker for cardiovascular risk stratification in the CKD population.