Anticoagulant related nephropathy

项目摘要 抗凝剂相关性肾病（ARN）是一种新的临床实体，我们已经确定。ARN是一个 描述与过度抗凝相关的一种急性肾损伤（AKI）的总称 在接受华法林和其他抗凝剂的患者中。我们描述了ARN的临床特征 在使用华法林的患者中，已经表明既存慢性肾病（CKD）患者 尤其容易受到ARN的影响。此外，我们和其他人已经表明，ARN也发生在直接口服 抗凝剂，如达比加群和阿哌沙班。因为抗凝剂的使用在患者中很常见 CKD患者，并且在肾功能受损的患者中难以控制抗凝，因此， 许多患者面临ARN风险。基于肾脏活检，该AKI的假定机制 从患者和模型的疾病，在大鼠与CKD，是凝血病，诱导的 超治疗抗凝，导致肾小球滤过屏障（GFB）损伤，肾小球出血 随后伴有肾小管上皮细胞损伤和AKI。我们认为ARN的发病机制依赖于 肾小球出血，这是多因素的起源，包括多次"击中" GFB。"第一击" (e.g.肾小球过度滤过/过度灌注、轻度免疫复合物沉积等）使GFB更 易受超治疗抗凝（"二次打击"）。我们假设， 抗凝剂诱导的GBF损伤与凝血酶活性降低有关，并通过凝血酶活性的丧失介导。 凝血酶介导的蛋白酶激活受体-1（PAR-1）信号转导在 肾小球内皮细胞事实上，目前临床实践中使用的所有类型的口服抗凝剂 降低生理凝血酶活性。我们已经证明5/6肾切除是一个合适的动物模型 学习ARN。使用这个模型，我们将确定凝血酶活性和PAR-1信号转导减少的作用。 GFB损伤的发病机制。由于凝血酶完全缺乏是胚胎致死的，我们将测试 凝血酶基因敲除小鼠中使用5/6肾切除术降低凝血酶活性的作用。接下来我们就 研究肾小球高滤过/高灌注在ARN发病机制中的作用。我们将使用 在5/6肾切除术凝血酶敲低小鼠中肾小球滤过的药理学操作和试验 肾小球滤过的改变是否加速或减轻ARN。最后，氧化应激在 在5/6肾切除大鼠中通过药物干预研究ARN中肾小管损伤的发病机制。 在这些具体目标的结论，我们希望了解ARN的分子机制， 是否可以预防ARN或减轻AKI的严重程度。总之，该项目将提供 对临床试验的适当设计至关重要的信息，以减轻ARN，这是一个重要的公共卫生问题。 这是一个非常脆弱的患者群体的问题。

Project Summary Anticoagulant related nephropathy (ARN) is a novel clinical entity that we have identified. ARN is an umbrella term to describe a form of acute kidney injury (AKI) that is associated with excessive anticoagulation in patients receiving warfarin and other anticoagulants. We have described the clinical characteristics of ARN in patients using warfarin and have shown that patients with pre-existing chronic kidney disease (CKD) are especially vulnerable to ARN. Furthermore, we and others have shown that ARN also occurs with direct oral anticoagulants, such as dabigatran and apixaban. Because the use of anticoagulants is common in patients with CKD and it is difficult to control anticoagulation in patients with impaired renal function, thus a large number of patients are at risk for ARN. The postulated mechanism of this AKI, based on kidney biopsies from patients and modeling the disease in rats with CKD, is that the coagulopathy, induced by supratherapeutic anticoagulation, results in glomerular filtration barrier (GFB) injury, glomerular hemorrhage with subsequent tubular epithelial cell injury and AKI. We propose that the pathogenesis of ARN is dependent on glomerular hemorrhage, which is multifactorial in origin and includes multiple “hits” to the GFB. A “first hit” (e.g. glomerular hyperfiltration/hyperperfusion, mild immune complex deposition, etc.) makes the GFB more vulnerable to supratherapeutic anticoagulation (“second hit”). We hypothesize that the main mechanism of the anticoagulant-induced GBF injury is related to decreased thrombin activity and is mediated via the loss of (patho)physiologically-required thrombin-mediated protease-activated receptor-1 (PAR-1) signaling in the glomerular endothelial cells. Indeed, all classes of oral anticoagulants currently used in the clinical practice reduce physiologic thrombin activity. We have demonstrated that 5/6 nephrectomy is a suitable animal model to study ARN. Using this model, we will determine the role of diminished thrombin activity and PAR-1 signaling in the pathogenesis of GFB injury. Because complete thrombin deficiency is embryonically lethal, we will test the role of diminished thrombin activity by using 5/6 nephrectomy in thrombin knockdown mice. Next, we will examine the role of glomerular hyperfiltration/hyperperfusion in the pathogenesis of ARN. We will use pharmacologic manipulations of glomerular filtration in 5/6 nephrectomy thrombin knockdown mice and test whether changes in glomerular filtration accelerate or mitigate ARN. Finally, the role of oxidative stress in the pathogenesis of tubular injury in ARN will be studied by pharmacologic interventions in 5/6 nephrectomy rats. At the conclusion of these Specific Aims we expect to understand the molecular mechanisms of ARN and whether ARN can be prevented or the severity of AKI diminished. In summary, this project will provide information critical to the appropriate design of clinical trials to mitigate ARN, which is a significant public health problem in a highly vulnerable patient population.