Anticoagulant related nephropathy

抗凝相关性肾病

基本信息

批准号：
10531237
负责人：
SERGEY BRODSKY
金额：
$ 34.97万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531237
关键词：
Acceleration Acute Acute Renal Failure with Renal Papillary Necrosis Agonist Animal Model Anticoagulant therapy Anticoagulants Anticoagulation Antigen-Antibody Complex Antioxidants Atrial Fibrillation Biological Assay Blood Coagulation Disorders Bowman&apos s space Case Study Characteristics Chronic Kidney Failure Clinical Clinical Trials Design Complication Data Deposition Dialysis procedure Disease Disease model Electron Microscopy Embryo Endothelial Cells Endothelium Epithelial Cells Erythrocytes Generations Glomerular Filtration Rate Hemorrhage Impaired Renal Function Injury Intervention Iron Iron Chelation Kidney Kidney Diseases Knockout Mice Mediating Modeling Molecular Mus Names Nephrectomy Obstruction Oral Outcome Oxidative Stress PAR-1 Receptor Pathogenesis Patients Pharmacology Study Phenotype Physiological Play Predisposition Prevention Public Health Publications Publishing Rattus Renal function Renal tubule structure Reporting Research Personnel Risk Role Safety Secondary to Seminal Severities Signal Transduction Specificity Testing Thrombin Thrombin Receptor Tubular formation Warfarin Work antagonist cell injury clinical practice experience glomerular endothelium glomerular filtration in vivo insight kidney biopsy knock-down mortality novel patient health information patient population pharmacologic pressure prevent protective effect protective pathway

项目摘要

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.

项目概要抗凝相关肾病（ARN）是我们发现的一种新的临床实体。描述与过度抗凝相关的一种急性肾损伤 (AKI) 的总称我们已经描述了接受华法林和其他抗凝药物的患者的 ARN 临床特征。在使用华法林的患者中进行研究，并表明患有慢性肾病 (CKD) 的患者此外，我们和其他人已经证明，直接口服也会发生 ARN。抗凝剂，例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。患有CKD且肾功能受损的患者很难控制抗凝，因此大量患者面临 ARN 风险根据肾活检推测的 AKI 机制。来自患者并在患有 CKD 的大鼠中建立疾病模型，发现凝血障碍是由以下因素引起的：超治疗抗凝，导致肾小球滤过屏障（GFB）损伤、肾小球出血以及随后的肾小管上皮细胞损伤和 AKI，我们认为 ARN 的发病机制是依赖性的。肾小球出血的起源是多因素的，包括对 GFB 的多次“打击”。（例如肾小球过度滤过/过度灌注、轻度免疫复合物沉积等）使GFB更易受超治疗性抗凝治疗（“第二次打击”）的影响。抗凝剂引起的 GBF 损伤与凝血酶活性降低有关，并通过凝血酶的丧失介导（病理）生理所需的凝血酶介导的蛋白酶激活受体 1 (PAR-1) 信号转导事实上，目前临床实践中使用的所有类别的口服抗凝剂。我们已经证明 5/6 肾切除术是合适的动物模型。为了研究 ARN，我们将确定凝血酶活性减弱和 PAR-1 信号传导的作用。由于凝血酶完全缺乏是胚胎致死的，因此我们将进行测试。接下来，我们将通过使用 5/6 肾切除术来降低凝血酶活性。我们将使用检查肾小球过度滤过/过度灌注在 ARN 发病机制中的作用。 5/6肾切除凝血酶敲低小鼠肾小球滤过的药理学操作和测试肾小球滤过的变化是否会加速或减轻 ARN 最后，氧化应激在 ARN 中的作用。将通过 5/6 肾切除大鼠的药物干预来研究 ARN 肾小管损伤的发病机制。在完成这些具体目标后，我们希望了解 ARN 的分子机制和是否可以预防 ARN 或减轻 AKI 的严重程度总之，该项目将提供。对于适当设计缓解 ARN 的临床试验至关重要的信息，ARN 是一项重要的公共卫生问题高度脆弱的患者群体中的问题。