More than 20 million people in the US have chronic kidney disease, and the cost of end stage renal disease management is over $40 billion annually in public and private funding. For renal failure patients on hemodialysis, broad consensus is that native arteriovenous fistulas (AVF) are the preferred access type, with better survival, fewer complications, longer patency, and reduced costs relative to other options. However, because up to 60% of attempted AVF never mature to the point of usability for dialysis, early AVF failure is a key barrier to maximizing health outcomes in these patients. The high AVF failure rate contributes to initiation of catheter-based dialysis in a large percentage of patients, with increased risks of infection and premature death. Maturation failure is thought to be related to peri-anastomotic stenoses resulting from intimal hyperplasia, inflammation, and negative wall remodeling. These factors occur in the presence of metabolically active perivascular adipose tissue which we theorize impacts overall remodeling. Chronic systemic inflammation is linked to the uremic milieu of patients with advanced kidney disease, and emerging evidence directly links elevation of pro-inflammatory mediators to adipose tissue. Furthermore, our pilot studies on AVF patients suggest clear links between base adipose phenotype and eventual fistula maturation. In addition, a genetic contributor to the process of atherogenesis may also lead to high rates of AVF failure. Polymorphisms associated with the ApoL1 gene on chromosome 22 have been shown to cause kidney failure in African Americans. The gene codes for a protein whose function incompletely understood, but is a component of HDL in circulation and is expressed in higher levels in patients with known comorbid predictors of atherogenesis. This indicates that the protein itself may be either associated with or a marker for development of atherogenesis and therefore may also contribute to increased rates of AVF failure. Thus for the current project we hypothesize that peri-anastomotic AVF adipose inflammation and APOL1 SNP status/gene expression patterns drive early AVF negative wall remodeling, contributing to failure to mature. These hypotheses will be tested via the following Specific Aims: 1) Identify adipose tissue expression profiles and clinical determinants of AVF failure. 2) Determine relationships between circulating and tissue levels of adipocyte-related mediators. 3) Understand the impact of ApoL1 gene status and protein expression on AVF remodeling and maturation. Completion of these aims will provide insights into the mechanisms of fistula maturation which may ultimately translate into novel clinical and therapeutic approaches in this extremely ill patient population. Furthermore, this work will be executed in a setting where I will gain enormous personal training experience by combining didactic coursework with clinical and basic research in a highly structured, actively mentored environment.
Approximately half of all surgically created arteriovenous fistulas (AVF) fail to become usable, creating a substantial cost burden, delaying the initiation o hemodialysis, and resulting in further operations for patients. Although inflammation and genetics likely play a role in the remodeling process that leads to AVF failure, the mechanisms by which this occurs are not well understood. This study will employ genotyping and phenotyping to characterize human adipose tissue and determine which factors associate with AVF failure in an effort to improve overall rates of AVF usability.