Reducing Tunneled Dialysis Catheter Dysfunction through Nitric Oxide Release

描述(申请人提供)：隧道式透析导管(TDC)是一种重要的透析血管通路。80%的透析患者开始使用TDC进行血液透析，而美国的总体患病率约为25%。不幸的是，TDCs在感染、血栓形成和中心静脉狭窄方面存在巨大的问题，导致非常显著的发病率、死亡率和经济成本。然而，尽管临床问题很严重，但还没有有效的治疗方法来治疗TDC功能障碍。一氧化氮(NO)是一种重要的生物介质，具有很强的抗细菌、抗血小板聚集和抗血管细胞增殖活性，有可能减少TDC的并发症。我们以前开发了一种新颖和创新的技术来电化学调节NO的释放(在导管管腔内)；其中嵌入在亚硝酸盐溶液中的铜电极能够在较长时间内产生NO(通过铜离子和亚硝酸盐之间的相互作用)。这一建议的中心假设是，电化学调节的NO从TDC内的管腔释放可以针对与TDC使用相关的所有三个主要并发症(感染、血栓形成和中心静脉狭窄)，从而显著降低与TDC使用相关的巨大发病率、死亡率和经济成本。我们计划通过一系列特定的目标来解决这一中心假设，这些目标集中在(A)开发和验证(在TDC管腔内)具有生物活性的电化学调节的NO释放系统(B)在活体猪模型中通过释放NO来减少感染、血栓形成和中心静脉狭窄。我们认为，对于减少TDC功能障碍的新疗法有着巨大的临床需求，并认为NO释放tDCs的概念可以显著降低与这一棘手问题相关的巨大临床发病率和经济成本。

DESCRIPTION (provided by applicant): Tunneled Dialysis Catheters (TDCs) are an important mode of dialysis vascular access. 80% of incident dialysis patients begin hemodialysis with a TDC and the overall prevalence in the US is approximately 25%. Unfortunately, TDCs have huge problems with infection, thrombosis and central venous stenosis, which results in a very significant morbidity, mortality and economic cost. Despite the magnitude of the clinical problem, however, there are no effective therapies for TDC dysfunction. Nitric oxide (NO) is an important biological mediator, which has potent anti-bacterial, anti-platelet aggregation and anti-smooth muscle cell proliferation activities, which could potentially reduce TDC complications. We have previously developed a novel and innovative technology to electrochemically modulate NO release (within a catheter lumen); in which a copper electrode embedded in a nitrite solution is able to generate NO (through the interaction between Cu ions and nitrite) over a prolonged period of time. The central hypothesis of this proposal, is that the electrochemically modulated release of NO from a lumen within a TDC could target all three major complications associated with TDC use (infection, thrombosis and central vein stenosis); thus significantly reducing the huge morbidity, mortality and economic cost associated with TDC use. We plan to address this central hypothesis through a series of specific aims that focus on (a) the development and validation (within a TDC lumen) of an electrochemically modulated NO release system with biological activity (b) reducing infection, thrombosis and central vein stenosis with NO releasing TDCs in-vivo, in a pig model. We believe that there is a huge unmet clinical need for novel therapies that reduce TDC dysfunction and feel that the concept of NO releasing TDCs could significantly reduce the huge clinical morbidity and economic cost associated with this intractable problem.