Abstract
Following creation, an arteriovenous fistula (AVF) must mature (i.e., enlarge lumen to allow high blood flow) before being used for hemodialysis. AVF maturation failure rates are high, and currently, there are no effective therapy to treat this problem. The maturation process is likely affected by the integrity of the vascular extracellular matrix (ECM). Natural Vascular Scaffolding (NVS) Therapy is a new technology that interlinks collagen and elastin via photoactivation of a locally delivered small molecule (4-amino-1,8-naphtalamide). We hypothesized that NVS Therapy may improve AVF remodeling by preserving ECM integrity. AVFs were created in Wistar male rats by connecting the femoral vein (end) to femoral artery (side) in the same limb. Immediately after blood flow was restored to dilate the femoral vein by arterial pressure, a 10 μl-drop of the NVS compound (2 mg/ml) was placed on the anastomosis perivascularly. Following 5-min incubation, the NVS treated area was exposed to 1-min illumination by 450-nm light. The control group received 10 μl-drop of phosphate buffered saline (PBS) and the same light activation. The skin was closed, and rats were euthanized 4 weeks (n = 6–9 per group) post-AVF creation for histology, morphometry, immunohistochemistry (IHC), and multiphoton microscopy for second-harmonic-generation evaluation of collagen fibers. The vascular thickness was similar in both groups. The AVF vein’s open lumen area and % open lumen area in NVS-treated rats were significantly larger than in PBS-treated rats (4.2-fold p = 0.014 and 2-fold p = 0.009, respectively). The inflammatory markers IL-6 and MMP-9 in the AVF walls were significantly decreased in the NVS group than the PBS group. Collagen fibers in the vascular wall trended toward perpendicular alignment to the lumen circumference in the NVS-treated AVFs, with more defined shape but less area than in the PBS-treated AVFs. These results indicate that the NVS Therapy exerted changes in collagen, which may influence AVF maturation. Rats tolerated the NVS treatment well, and the lack of cell death by the treatment was confirmed in cell culture experiments. These results suggest that NVS treatment is safe and may have therapeutic potential by facilitating lumen expansion to enhanced AVF maturation in patients.
Highlights
Functional vascular access is a hemodialysis patient’s lifeline
Our study showed that rats tolerated Natural Vascular Scaffolding (NVS) treatment well and the NVS treatment significantly increased the arteriovenous fistula (AVF) open lumen area, without significantly affecting the neointimal hyperplasia area, suggesting that NVS treatment is safe and may have therapeutic potential by facilitating outward remodeling to enhance AVF maturation in patients
In the present study we have evaluated the effect of NVS Therapy in a well-studied rat model of AVF (Langer et al, 2010) to test the hypothesis that, relinking the extracellular matrix (ECM) proteins at the time of AVF creation may lead to improved AVF development
Summary
Clinical practice guidelines elected an arteriovenous fistula (AVF), which is a direct connection of an artery to a vein in the upper extremity, as the preferred vascular access to provide adequate and efficient hemodialysis treatment to endstage kidney disease (ESKD) patients (Lok et al, 2020). A newly created AVF needs to mature (i.e., grow to have a sufficiently large lumen to carry sufficiently high blood flow) in order to be used for dialysis. The high incidence of AVF maturation failure has recently prompted a re-evaluation of previous guidelines (Lok et al, 2020). Failure of AVF maturation, together with the rapid growth of the ESKD population, translates into increasing healthcare costs (Lee, 2017). There are no treatments available to enhance AVF maturation, and reliable AVF maturation represents an unmet medical need
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