A NOVEL APPROACH TO PREVENT ARTERIOVENOUS ACCESS FAILURE IN HEMODIALYSIS PATIENTS

预防血液透析患者动静脉通路失败的新方法

• 批准号: 7588362
• 负责人: ERIC T. CHOI
• 金额: $ 19万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588362
• 关键词: Accounting; Address; Adverse effects; Adverse event; Advocate; Anastomosis - action; Anatomic Sites; Applications Grants; Arteries; Biodistribution; Biological Availability; Blood Platelets; Blood Vessels; Chronic Kidney Failure; Classification; Clinical; Coagulation Process; Data; Diagnosis; Dialysis procedure; Dose; Double-Blind Method; Drug Delivery Systems; Drug Kinetics; End stage renal failure; Failure; Family suidae; Fistula; Frequencies; Funding; Gel; Hemodialysis; Hemorrhage; Heparin; Hospitalization; Information Systems; Intervention; Kidney; Life; Methodology; Modeling; Multicenter Trials; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Operative Surgical Procedures; Oral; Paclitaxel; Patients; Pattern; Peptides; Persons; Pharmaceutical Preparations; Physiologic arteriovenous anastomosis; Placebos; Polymers; Polytetrafluoroethylene; Population; Prevention; Procedures; Prosthesis; RGD (sequence); Randomized; Recurrence; Safety; Secondary to; Sirolimus; Site; Stenosis; Stents; System; Technology; Therapeutic; Thrombosis; Time; United States; United States Department of Veterans Affairs; United States National Institutes of Health; Upper arm; Veins; Venous; absorption; base; biomaterial compatibility; cost; effective therapy; functional restoration; graft failure; hazard; in vivo; inhibitor/antagonist; innovation; interest; local drug delivery; novel; novel strategies; patient population; prevent; public health relevance

DESCRIPTION (provided by applicant): Patients with end-stage kidney disease require a durable arteriovenous access in order to receive life-sustaining hemodialysis. However, every year nearly 50% of this patient population suffers from access stenosis and thrombosis resulting in hospitalizations and surgical interventions while its costs approach one billion dollars per year in the United States alone. Without an effective therapy available, some clinicians have advocated using anti-platelet agents to prolong access patency despite the concerns for bleeding complications. Of note, access stenosis and thrombosis usually occur at or near the venous anastomosis, and therefore, we focused on delivering of an inhibitor to the site of interest to achieve its therapeutic concentration while minimizing its adverse systemic effects. Indeed, we found a combination of anti-stenotic peptide and anti-thrombotic peptide that prolonged access patency in murine and porcine models, and in doing so, we minimized the adverse effects of each inhibitor. In the first year of this grant proposal, we will deliver a mixture of peptide inhibitors or inactive controls in polymeric gel (for sustained release) to the venous anastomosis of arteriovenous accesses in pigs. We will address the pharmacokinetics of this methodology and the bioavailability of the inhibitors in the setting of chronic kidney disease. In the second year, we will randomize the pigs with AV access to a single-dose of peptide inhibitors or inactive control delivered directly to the venous anastomosis. In the setting of chronic kidney disease, these pigs will be followed for 6 months to determine if these inhibitors are effective in preventing AV access failure. Indeed, if this proposal is successful, we believe its impact would be significant and immediate, as we could address this urgent problem of arteriovenous access failure in our hemodialysis population without disrupting the current surgical practice pattern of access creation. PUBLIC HEALTH RELEVANCE: Patients with end-stage kidney disease require arteriovenous accesses for life-saving hemodialysis. However, these patients are confronted with the recurrent problem of access failure secondary to narrowing and clotting in the access blood vessels. We devised a novel approach to deliver small peptide molecules locally to the access blood vessels to inhibit narrowing and clotting while avoiding systematic adverse effects. We propose two specific aims: 1) to understand the pharmacokinetics of the peptide inhibitors in a porcine model in the setting of chronic kidney disease; and 2) to determine the efficacy of a single-dose of peptide inhibitor treatment in the prevention of arteriovenous access failure in a porcine model in the setting of chronic kidney disease.

描述（由申请人提供）：终末期肾病患者需要持久的动静脉通路才能接受维持生命的血液透析。然而，每年有近 50% 的患者群体患有通路狭窄和血栓形成，导致住院和手术干预，而仅在美国每年的费用就接近 10 亿美元。由于缺乏有效的治疗方法，一些临床医生主张使用抗血小板药物来延长通路通畅，尽管担心出血并发症。值得注意的是，通路狭窄和血栓形成通常发生在静脉吻合处或附近，因此，我们专注于将抑制剂输送到感兴趣的部位以达到其治疗浓度，同时最大限度地减少其不利的全身影响。事实上，我们发现抗狭窄肽和抗血栓肽的组合可以延长小鼠和猪模型中的通路通畅，并且通过这样做，我们最大限度地减少了每种抑制剂的不利影响。在这项拨款提案的第一年，我们将向猪的动静脉通路的静脉吻合术提供聚合凝胶中的肽抑​​制剂或无活性对照的混合物（用于持续释放）。我们将讨论该方法的药代动力学以及慢性肾病情况下抑制剂的生物利用度。第二年，我们将随机分配 AV 猪，使其接受单剂量肽抑制剂或直接递送至静脉吻合口的非活性对照。在慢性肾病的情况下，这些猪将被跟踪 6 个月，以确定这些抑制剂是否能有效预防 AV 通路失败。事实上，如果该提案成功，我们相信其影响将是重大且直接的，因为我们可以在不破坏当前建立通路的外科实践模式的情况下解决血液透析人群动静脉通路失败的紧迫问题。公众健康相关性：终末期肾病患者需要动静脉通路进行挽救生命的血液透析。然而，这些患者面临着继发于通路血管狭窄和凝血的通路失败的反复问题。我们设计了一种新方法，将小肽分子局部递送至血管通路，以抑制狭窄和凝血，同时避免系统性不良反应。我们提出了两个具体目标：1）了解慢性肾病猪模型中肽抑制剂的药代动力学； 2) 确定单剂量肽抑制剂治疗在慢性肾病猪模型中预防动静脉通路衰竭的功效。