The impact of chronic kidney disease on arteriovenous fistula remodeling: studies in a murine model of autosomal dominant polycystic kidney disease

The arteriovenous fistula (AVF) is the gold standard for hemodialysis vascular access, although inadequate vascular remodeling and intimal hyperplasia pose a major limitation. It is essential to study this in a clinically relevant model. We used 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. Jugular-carotid AVFs were created in adult <i>B6OlaPkd1</i>^nl/nl (ADPKD) mice and <i>B6OlaPkd1</i>^+/+ littermates. AVFs were harvested 7 days postsurgery for bulk mRNA sequencing or 3 wk postsurgery 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 6 days after AVF surgery. Longitudinal flow data was analyzed using mixed-effects model, histological data using the Mann-Whitney <i>U</i> test. <i>Pkd1</i>^nl/nl mice developed cystic kidneys and elevated blood urea levels (8.7 ± 2.8 mmol/L vs. 24.0 ± 3.8 mmol/L) and higher mean arterial blood pressure (92 vs. 113). AVF flow in <i>Pkd1</i>^nl/nl mice was consistently higher post-AVF creation (1.9-fold difference, <i>P</i> < 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. The arterial AVF wall had disruption of the elastic laminae. <i>Pkd1</i>^nl/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 with normotensive mice with normal kidney function.<b>NEW & NOTEWORTHY</b> This work explores the impact of chronic kidney disease (CKD) on arteriovenous fistula (AVF) remodeling using an autosomal dominant polycystic kidney disease (ADPKD) mouse model. Our findings reveal that ADPKD enhances AVF flow and luminal volume while reducing intimal hyperplasia, due to altered extracellular matrix deposition, offering new insights into the vascular AVF changes in a CKD setting. This study highlights the suitability of the ADPKD model for investigating AVF remodeling in a CKD context.