Prediction of arteriovenous fistula stenosis and failure via in vivo inflammation and fibrin molecular imaging

Dialysis Access is the “lifeline” for 1.5 million end-stage renal disease (ESRD) patients across the world. Effective hemodialysis treatment requires reliable large caliber vascular access. The preferred hemodialysis access is an arteriovenous fistula (AVF) because of its lower infection rate, lower hospitalization rate and relatively longer longevity compared to grafts.(1, 2) However, the primary failure rate of AVF approaches 50% with neointimal hyperplasia (NH) in the juxta-anastomotic region as a major cause of AVF failure.(3) Currently, no clinical diagnostic modality can reliably predict early AVF failure and no medical treatments can improve juxta-anastomotic stenosis in AVF. Intriguingly, studies have showed inflamed and pathologically altered endothelium plays a vital role in neointimal hyperplasia.(4) Yet the mechanisms by which pathological endothelium drives neointimal hyperplasia and thrombosis remain poorly understood, especially in vivo. The ability to quantitatively image pathological endothelium after arteriovenous fistula (AVF) creation could provide clinically relevant, vital new insights into AVF failure. We have recently shown in a murine end-to-side jugular vein to carotid artery AVF model with carotid artery mobilization that pathological endothelium can be imaged in vivo, and can predict arterial inflow neointimal hyperplasia, using a cell-targeted fluorescent nanoparticle (CLIO) and intravital microscopy (IVM).(5) However, the prior AVF model does not recapitulate venous side disease that more often drives human AVF failure. Therefore, in this study, we will investigate the ability to detect venous outflow inflammation by harnessing a recently described jugular vein mobilization murine AVF model by multi-target IVM.(6) We will then test whether the degree of venous side inflammation will predict subsequent venous neointimal hyperplasia. Lastly, as a translational step, we will perform noninvasive MRI of venous-side pathological endothelium labeled by CLIO. These studies will establish an in vivo translational imaging roadmap to predict venous-side AVF failure, and potentially identify subjects likely to benefit from early intervention.