Impact of CKD on Arteriovenous Fistula Remodeling: Studies in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

Background: The arteriovenous fistula (AVF) is the gold standard for hemodialysis vascular access, although inadequate vascular remodelling and intimal hyperplasia pose a major limitation. We utilised an autosomal dominant polycystic kidney disease (ADPKD) model, the most common hereditary cause of chronic kidney disease (CKD), to study the effect of CKD on AVFs. We hypothesized that CKD accelerates AVF failure. Methods: Jugular-carotid AVFs were created in adult B6OlaPkd1nl/nl (ADPKD) mice and B6OlaPkd1+/+ litter mates. AVFs were harvested seven days post-surgery for bulk mRNA sequencing or three weeks post-surgery for histological analysis. We performed weekly AVF flow measurements using doppler ultrasound and assessed kidney morphology and function by histology and blood urea analysis. Blood pressure was measured using a tail cuff, before and six days after AVF-surgery. Longitudinal flow data was analysed using Mixed-effects model, histological data using the Mann-Whitney U test. Results: Pkd1nl/nl mice developed cystic kidneys and elevated blood urea levels (8.7 ± 2.8 mmol/L versus 24.0 ± 3.8 mmol/L) and higher mean arterial blood pressure (92 versus 113). AVF flow in Pkd1nl/nl mice was consistently higher post-AVF creation (1.9-fold difference, p<0.001), with a 50% reduction in intimal hyperplasia and 30% increase in luminal AVF volume. RNA sequencing showed altered regulation of extracellular matrix in the venous ADPKD AVF, with reduced collagen deposition in the venous outflow tract. Conclusion: Pkd1nl/nl mice are a suitable model to study AVF remodeling in a CKD setting, resulting in enhanced luminal volume and higher AVF flow when compared to normotensive mice with healthy renal function.