ADIPOSE BIOLOGY AND AV FISTULA FAILURE

描述（由申请人提供）：美国有超过2000万人患有慢性肾脏疾病，每年用于终末期肾脏疾病管理的公共和私人资金超过400亿美元。对于接受血液透析的肾衰竭患者，广泛的共识是自体动静脉内瘘（AVF）是首选的通路类型，与其他选择相比，具有更好的生存率、更少的并发症、更长的通畅性和更低的成本。然而，由于高达60%的尝试AVF从未成熟到可用于透析的程度，因此早期AVF失败是这些患者最大化健康结局的关键障碍。高AVF失败率导致在很大比例的患者中开始基于导管的透析， 患者感染和过早死亡的风险增加。成熟失败被认为与内膜增生、炎症和负性壁重塑导致的吻合口周围狭窄有关。这些因素发生在代谢活跃的血管周围脂肪组织的存在下，我们的理论影响整体重塑。慢性全身性炎症与晚期肾病患者的尿毒症环境有关，新出现的证据将促炎介质的升高与脂肪组织直接联系起来。此外，我们对AVF患者的初步研究表明，基底脂肪表型和最终瘘成熟之间存在明确的联系。此外，动脉粥样硬化形成过程中的遗传因素也可能导致AVF失败率高。与22号染色体上的ApoL 1基因相关的多态性已被证明会导致非裔美国人的肾衰竭。该基因编码一种蛋白质，其功能尚不完全清楚，但它是循环中HDL的一种成分，在已知动脉粥样硬化并发症预测因子的患者中表达水平较高。这表明该蛋白本身可能与动脉粥样硬化形成相关或成为动脉粥样硬化形成的标志物，因此也可能导致AVF失败率增加。因此，对于当前项目，我们假设吻合口周围AVF脂肪炎症和APOL 1 SNP状态/基因表达模式驱动早期AVF负性壁重塑，导致不能成熟。这些假设将通过以下特定目的进行检验：1）确定脂肪组织表达谱和AVF失败的临床决定因素。2)确定脂肪细胞相关介质的循环和组织水平之间的关系。3)了解ApoL 1基因状态和蛋白表达对AVF重塑和成熟的影响。这些目标的完成将提供对瘘管成熟机制的深入了解，这可能最终转化为这种重病患者人群的新型临床和治疗方法。此外，这项工作将在一个环境中执行，我将通过在一个高度结构化，积极指导的环境中将教学课程与临床和基础研究相结合来获得大量的个人培训经验。

DESCRIPTION (provided by applicant): 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.