The autogenous arteriovenous (A-V) fistula represents the most important lifeline of >600,000 Americans currently on hemodialysis. However, ~40 percent of newly created fistulas cannot be used for dialysis without a salvage procedure because stenosis (narrowing) prevents them from reaching the necessary blood flow. This problem represents significant comorbidity for the end-stage renal disease (ESRD) population and a substantial economic burden that currently surpasses $2 billion annually. Most troubling about this glaring statistic is that it has plateaued over the past five decades, highlighting a pressing need for revamped efforts to improve vascular access outcomes using novel and innovative therapeutic approaches. This translational proposal establishes a new modality to treat post-operative A-V fistula failure using an emerging anti-inflammatory concept. We have built this proposal upon the premise that a newly discovered agonist of Mac-1 integrin prevents stenosis in A-V fistulas by controlling post-operative inflammatory activity. Macrophages and other myeloid inflammatory cells control the underlying causes of stenosis, such as the development of post-operative intimal hyperplasia (IH) and fibrosis. Herein we hypothesize that pharmacological and genetic activation of the Mac-1 integrin is sufficient to control myeloid- derived inflammatory cell infiltration in the fistula without compromising access maturation. We also hypothesize that activation of the Mac-1 integrin attenuates the RAGE signaling in macrophages that leads to inward remodeling in newly created A-V fistulas. Our scientific premise is supported by published and preliminary data that demonstrate our experience with animal models to study fistula maturation biology. We will test our hypothesis in three specific aims and five experimental layouts to: 1) demonstrate that increased monocyte adhesion following Mac-1 activation protects experimental A-V fistulas from failure; 2) demonstrate the anti- inflammatory mechanism following Mac-1 activation in the fistula wall; and 3) demonstrate that Mac-1 activation attenuates post-operative inflammation, IH, and stenosis in preclinical A-V fistulas. We will combine fine microsurgical techniques and transgenic mice to achieve our goals successfully. In conclusion, successful completion of this proposal will pave the way to the design of new drugs using a novel mode of action to effectively target A-V fistula fibrosis and IH and reduce vascular access complications.