Anticoagulant related nephropathy

项目摘要 抗凝剂相关肾病(ARN)是我们发现的一种新的临床实体。ARN是一种 泛指与过度抗凝有关的一种急性肾损伤(AKI) 接受华法林和其他抗凝剂治疗的患者。我们描述了ARN的临床特征。 在使用华法林的患者中，并已表明既有慢性肾脏疾病(CKD)的患者 特别容易受到ARN的影响。此外，我们和其他人已经证明，ARN也发生在直接口服的情况下 抗凝剂，如达比加特兰和阿皮沙班。因为抗凝剂的使用在患者中很常见 患有慢性肾脏病，肾功能受损的患者很难控制抗凝，因此 许多患者有患ARN的风险。基于肾活检的AKI的假设机制 从患者和模型大鼠的疾病CKD，是凝血障碍，诱导 超治疗抗凝，导致肾小球滤过屏障(GFB)损伤，肾小球出血 继发肾小管上皮细胞损伤和AKI。我们认为ARN的发病机制是依赖的。 关于肾小球出血，这是多因素的起源，包括对GFB的多个“命中”。“第一支金曲” (例如，肾小球高滤/高灌、轻度免疫复合体沉积等)使GFB更多 易受超治疗抗凝(“二次打击”)。我们假设这一过程的主要机制是 抗凝剂诱导的GBF损伤与凝血酶活性降低有关，并通过失去 (病理)生理所需的凝血酶介导的蛋白酶激活受体-1(PAR-1)信号转导 肾小球内皮细胞。事实上，目前临床上使用的所有种类的口服抗凝剂 降低生理性凝血酶活性。我们已经证明5/6肾切除是一种合适的动物模型。 研究ARN。利用这个模型，我们将确定凝血酶活性降低和PAR-1信号转导的作用 在GFB损伤的发病机制中起重要作用。由于完全凝血酶缺乏症在胚胎上是致命的，我们将测试 凝血酶基因敲除小鼠5/6肾切除降低凝血酶活性的作用。接下来，我们将 探讨肾小球高滤过/高灌流在ARN发病机制中的作用。我们将使用 5/6肾切除凝血酶基因敲除小鼠肾小球滤过的药理干预及实验研究 肾小球滤过率的改变是加速还是缓解ARN。最后，氧化应激在 ARN肾小管损伤的发病机制将通过药物干预在5/6肾切除大鼠身上进行研究。 在总结了这些特定的目的后，我们希望了解ARN和ARN的分子机制。 是否可以预防ARN或减轻AKI的严重程度。总而言之，这个项目将提供 对适当设计临床试验以缓解ARN至关重要的信息，ARN是一个重要的公共卫生问题 在高度脆弱的患者群体中存在的问题。

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.