Table of Contents

1. Introduction………………………………………………………………………………………1
1.1. Poor Clinical Outcomes in Arteriovenous Fistulae Utilization……………………….1
1.2. Mechanisms of Fistula Maturation and Failure…………………………………………….1
1.3. Akt1 signaling in AVF maturation……………………………………………………4
2. Statement of Purpose and Aims…………………………………………………..6
2.1. Statement of Purpose
2.2. Aims
3. Methods……………………………………………………………………………………7
3.1. Study Approval……………………………………………………….7
3.2. Infrarenal aorto-caval fistula……………………………………..7
3.3. Confirmation of fistula patency and measurement of fistula dilation…………..7
3.4. Histology.………………………………………………….8
3.5. Immunohistochemistry and Immunofluorescence……………………….8
3.6. Western Blot.………………………………………………….……10
3.7. Rapamycin and clodronate treatment…………………………………..……11
3.8. Adenovirus treatment……………………………………………..12
3.9. Statistics.…………………………………………………..12
4. Results……………………………………………………………………………….13
4.1. Reduced AVF wall thickness, extracellular matrix deposition, SMC and
macrophages with rapamycin…………………………………………13
4.2. Reduced M1- and M2-type macrophages with rapamycin…………………………15
4.3. Reduced Akt1 and mTORC1 but not mTORC2 phosphorylation with
rapamycin…………………………….…………………17
4.4. Macrophage depletion is associated with reduced AVF wall thickness and
patency ……………………………….……………………24
4.5. Rapamycin treatment is associated with reduced AVF wall thickness but
increased AVF patency..…………………………………26
4.6. Rapamycin enhances early AVF remodeling to improve patency……………….27
5. Discussion……………………………………………….31
6. Conclusion……………………………………………………………….36
7. References…………………………………………………………37
8. Appendix………………………………………………………………42