Author(s): River Tobias, Yuxia He, Brayden Fairbourn, Amani Oumar, Marina Knysheva
Mentor(s): Yan-Ting Shiu
Institution U of U
Introduction End-stage kidney disease (ESKD) patients require hemodialysis, which necessitates a vascular access site capable of handling high blood flow. The arteriovenous fistula (AVF), a surgical connection between a vein and an artery, is the preferred access type. A common cause of AVF failure is neointimal hyperplasia, where tissue growth narrows the lumen. Advanced glycation end products (AGEs) and the receptor for advanced glycation end products (RAGE) increase oxidative stress, a factor involved in vascular inflammation. RAGE has been linked to reduced cardiovascular health and may contribute to AVF failure [1, 2]. Understanding this connection could offer a novel treatment approach for ESKD patients. Methods C57BL/6 male mice (3-4 months old) were used. RAGE activity was inhibited in two ways: (1) FPS-ZM1 drug treatment (n = 5), administered daily for 5 days before AVF creation at a concentration of 25 mg/kg, with 12 total injections; (2) homozygous whole-body RAGE knockout (n = 8). AVFs were surgically created, and tissue samples were processed using histology protocols. Verhof-Van Geisen (VVG) and Masson Trichrome (MT) stains were performed and imaged. Neointimal hyperplasia and open lumen areas were quantified from VVG images, while fibrosis was assessed in MT images. Both groups were compared to untreated wild-type mice (n = 5) using a one-way unpaired t-test, with a significance threshold of p = 0.05. Results Only one statistically significant difference was found in the internal elastic lamina area between untreated and knockout groups. Other comparisons showed no significant differences, suggesting that RAGE inhibition does not significantly affect AVF maturation. Discussion Current data do not support RAGE inhibition as a treatment for improving AVF maturation. Limitations include small sample sizes, a single maturation time point, one drug concentration, and a lack of ESKD mouse models. Future work could involve larger sample sizes, longer maturation periods, and ESKD models to better reflect patient conditions. References 1. Leurs, Paul, and Bengt Lindholm. “The AGE–RAGE Pathway and Its Relation to Cardiovascular Disease in Patients with Chronic Kidney Disease.” Archives of Medical Research, Special Issue: Chronic Kidney Disease, 44, no. 8 (November 1, 2013): 601–10. https://doi.org/10.1016/j.arcmed.2013.11.002. 2. Senatus, Laura M., and Ann Marie Schmidt. “The AGE-RAGE Axis: Implications for Age-Associated Arterial Diseases.” Frontiers in Genetics 8 (2017). https://www.frontiersin.org/articles/10.3389/fgene.2017.00187.