Abstract Body: Background: Chronic kidney disease (CKD) carries a high thrombotic risk that traditional factors do not fully explain. CKD patients often exhibit a paradoxical immune state: innate monocytes are hyperactivated, yet adaptive T cells show signs of early exhaustion. We hypothesized that monocyte - T cell (CD3⁺CD14⁺ ) complexes act as a cellular bridge linking this immune dysregulation to endothelial thrombogenicity.
Methods: We used multi-ancestry GWAS and two-sample Mendelian randomization (MR) to identify genetically causal inflammatory pathways linking kidney dysfunction to venous thromboembolism (VTE). We recruited healthy controls and CKD patients (stages II-V) from our LSUHS-Nephrology clinic for mechanism discovery using PBMC bulk and single-cell RNA-seq. Findings were validated in independent GEO cohorts (n>200) and our prospective clinical cohort (n=30) using spectral flow cytometry. Functional relevance was tested in endothelial co-culture assays using targeted blockade of adhesion (LFA-1/ICAM-1) and inflammatory signaling (TNF/CD40).
Results: Genetic mapping identified significant CKD-associated loci in CD40, TNFRSF1A, and mTOR, with effects amplified in populations of African ancestry. MR established a causal relationship between eGFR and VTE, with inflammatory signaling mediating approximately 40% of the total risk. Transcriptomic profiling revealed monocyte TNF–NF-κB/mTOR hyperactivation alongside reduced CD40L-CD40 signaling, a signature consistent with adaptive immune exhaustion that was highly reproducible (r=0.99). Flow cytometry showed a 2.9-fold expansion of CD3⁺CD14⁺ complexes in CKD patients (P<0.001), correlating with increased monocyte activation (HLA-DR⁺) and T-cell exhaustion (PD-1⁺TIM-3^-). Crucially, the frequency of these complexes strongly predicted endothelial tissue factor induction and thrombogenicity, which were specifically reversed by LFA-1/ICAM-1 blockade.
Conclusions: We identified monocyte - T cell complexes as a key driver of thrombosis in CKD. These complexes bridge the gap between immune cell exhaustion and high thrombosis risk. Targeting the adhesion between these cells offers a precision medicine approach for the treatment of CKD-related vascular disease, particularly in populations with genetic predispositions.