Background
Venous neointimal hyperplasia and venous stenosis (VS) formation can result in a decrease in arteriovenous fistula (AVF) patency in patients with end‐stage renal disease. There are limited therapies that prevent VNH/VS. Systemic delivery of simvastatin has been shown to reduce VNH/VS but local delivery may help decrease the side effects associated with statin use. We determined if microparticles (MP) composed of cyclodextrins loaded with simvastatin (MP‐SV) could reduce VS/VNH using a murine arteriovenous fistula model with chronic kidney disease.
Methods and Results
Male C57BL/6J mice underwent nephrectomy to induce chronic kidney disease. Four weeks later, an arteriovenous fistula was placed and animals were randomized to 3 groups: 20 μL of PBS or 20 μL of PBS with 16.6 mg/mL of either MP or MP‐SV. Animals were euthanized 3 days later and the outflow veins were harvested for quantitative reverse transcriptase–polymerase chain reaction analysis and 28 days later for immunohistochemistical staining with morphometric analysis. Doppler ultrasound was performed weekly. Gene expression of vascular endothelial growth factor‐A (
Vegf‐A
), matrix metalloproteinase‐9 (
Mmp‐9
), transforming growth factor beta 1 (
Tgf‐β1
), and monocyte chemoattractant protein‐1 (
Mcp‐1
) were significantly decreased in MP‐SV treated vessels compared with controls. There was a significant decrease in the neointimal area, cell proliferation, inflammation, and fibrosis, with an increase in apoptosis and peak velocity in MP‐SV treated outflow veins. MP‐SV treated fibroblasts when exposed to hypoxic injury had decreased gene expression of
Vegf‐A
and
Mmp‐9
.
Conclusions
In experimental arteriovenous fistulas, periadventitial delivery of MP‐SV decreased gene expression of
Vegf‐A
,
Mmp‐9
,
Tgf‐β1
and
Mcp‐1,
VNH/VS, inflammation, and fibrosis.
FP479FIBROBLAST GROWTH FACTOR 23 AS AN EARLY MARKER OF MINERAL AND BONE DISORDERS IN PREDIALYSIS CHRONIC KIDNEY DISEASE PATIENTS