Novel Biological Markers in Impaired Arteriovenous Fistula Maturation

描述(由申请人提供)： 原发动静脉瘘(AVF)衰竭，即4至5个月不适合透析的AVF，仍然是美国AVF使用总体流行率上升的最大障碍。目前还没有临床或生物学标记物来预测哪些患者会经历原发性动静脉瘘衰竭。该项目的长期目标是开发一组来自血液和静脉组织的生物标记物，以更好地了解原发动静脉瘘失败的机制，并作为临床工具预测具有高成熟失败风险的动静脉动静脉瘘。这项建议的近期目标集中在氧化应激和既往静脉新生内膜增生上，并将：(1)检验术前氧化应激水平、既往新生内膜增生和原发动静脉动静脉瘘衰竭之间的关系，以及(2)研究这些新的危险因素在原发动静脉动静脉瘘衰竭的病理生理学中的作用。这项研究将采用前瞻性队列研究设计，招募需要新的动静脉瘘安置的慢性肾脏病和终末期肾病患者。手术前将采集血液样本，手术时将采集静脉组织样本。完成这些目标将提供关于血液和组织氧化应激水平以及先前存在的新生内膜增生在原发性动静脉动静脉瘘衰竭中所起的作用的新信息，以及组织氧化应激是否与先前存在的新生内膜增生相关。从这项建议中获得的知识将导致未来的研究，目的是使用全身和局部递送系统来改善氧化应激和新生内膜增生，以改善动静脉瘘的成熟度。这项研究提案将构成蒂米·李博士在国际公认的血液透析血管通路狭窄专家普拉比尔·罗伊-乔杜里博士的指导下的五年职业发展计划的核心。Lee博士提出了一项职业发展计划，将翻译研究方法方面的教学培训、高级生物统计学课程以及与了解血管通道狭窄相关的实验室培训相结合，如血液和静脉组织中氧化应激的测量以及人体静脉组织中新的内膜增生的测量。与精心挑选的合作者一起，这一职业发展计划将促进Lee博士发展成为一名成熟的临床和翻译研究员，拥有复杂研究方法方面的专业知识，以及血管通道狭窄机制方面的实验室专业知识。 公共卫生相关性：动静脉瘘发展不良仍然是血液透析患者的一个重要问题。这项提案的工作将提高对为什么一些动静脉瘘没有充分成熟以成功用于透析以及哪些人面临成熟失败风险的理解。希望净影响将是患者生活质量的改善和患者存活率的总体增加。

DESCRIPTION (provided by applicant): Primary arteriovenous fistula (AVF) failure, AVFs that are not suitable for dialysis at four to five months, remains the most significant obstacle in increasing overall prevalence of AVF use in the United States. There are currently no clinical or biological markers to predict which patients will experience primary AVF failure. The long-term goal of this project is to develop a panel of biomarkers from blood and venous tissue to better understand the mechanisms of primary AVF failure and that will serve as clinical tools to predict AVFs at high risk for maturation failures. The immediate objectives of this proposal focus on oxidative stress and pre-existing venous neointimal hyperplasia and will: (1) examine the relationship between pre-surgical levels of oxidative stress, pre-existing neointimal hyperplasia, and primary AVF failure, and (2) study the role of these novel risk factors in the pathophysiology of primary AVF failure. This study will utilize a prospective cohort study design recruiting chronic kidney and end-stage renal disease patients requiring a new AVF placement. Blood samples will be collected prior to surgery, and venous tissue samples will be collected at the time of surgery. Accomplishing these objectives will provide new information about the role blood and tissue oxidative stress levels and pre-existing neointimal hyperplasia play in primary AVF failure, and whether tissue oxidative stress is associated with pre-existing neointimal hyperplasia. Knowledge from this proposal will lead to future studies with targeted interventions directed at modifying oxidative stress and neointimal hyperplasia using both systemic and local delivery systems in order to improve AVF maturation. This research proposal will form the core of a five-year career development plan for Dr. Timmy Lee under the mentorship of Dr. Prabir Roy-Chaudhury, an internationally-recognized expert in hemodialysis vascular access stenosis. Dr. Lee proposes a career development plan that combines didactic training in translational research methods, advanced biostatistical coursework, and laboratory training related to understanding vascular access stenosis such as measurement of oxidative stress in blood and venous tissue and neointimal hyperplasia in human venous tissue. In conjunction with carefully selected collaborators, this career development plan will foster Dr. Lee's development into an established clinical and translational investigator with expertise in complex research methodology and laboratory expertise in mechanisms of vascular access stenosis. PUBLIC HEALTH RELEVANCE: Poor arteriovenous fistula development remains a significant problem among hemodialysis patients. The work from this proposal will improve the understanding of why some arteriovenous fistulas do not mature adequately for successful use on dialysis and which individuals are at risk for maturation failures. The net impact will, hopefully, be an improvement in patient quality of life and an overall increase in patient survival.