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.

项目摘要抗凝剂相关肾病（ARN）是我们已经确定的新型临床实体。 Arn是一个雨伞术语描述与过量抗凝作用有关的急性肾脏损伤（AKI）在接受华法林和其他抗凝剂的患者中。我们已经描述了ARN的临床特征在使用华法林的患者中，已经表明患有慢性肾脏疾病（CKD）的患者是特别容易受到ARN的影响。此外，我们和其他人表明，ARN也是直接口头的抗凝剂，例如dabigatran和apixaban。因为使用抗凝剂在患者中很常见使用CKD，很难控制肾功能受损的患者的抗凝治疗，因此很大患者人数有ARN的风险。基于肾脏活检的AKI的假定机制来自患者并用CKD大鼠对疾病进行建模的是，由上抗抗凝性，导致肾小球滤过屏障（GFB）损伤，肾小球出血随后的管状上皮细胞损伤和AKI。我们建议ARN的发病机理取决于在肾小球出血上，该出血是多因素的，包括GFB的多个“命中”。 “第一击” （例如，肾小球过滤/过度灌注，轻度免疫复合物沉积等）使GFB更多容易受到抗凝性抗凝（“第二击”）的影响。我们假设抗凝剂诱导的GBF损伤与凝血酶活性降低有关，并通过丧失（PATHO）在生理上是由生理学的凝血酶介导的蛋白酶激活的受体-1（PAR-1）信号传导肾小球内皮细胞。实际上，目前在临床实践中使用的所有类别的口服抗凝剂减少生理凝血酶活性。我们已经证明5/6肾切除术是合适的动物模型研究Arn。使用此模型，我们将确定凝血酶活性减少和PAR-1信号的作用在GFB损伤的发病机理中。因为完全凝血酶缺乏症是胚胎致死的，所以我们将测试通过在凝血酶敲低小鼠中使用5/6肾切除术，凝血酶活性减少的作用。接下来，我们会的检查肾小球过滤/高灌注在ARN发病机理中的作用。我们将使用 5/6肾切除术凝血酶敲低小鼠的肾小球滤过的药理操作和测试肾小球过滤的变化是否加速还是减轻ARN。最后，氧化应激在在5/6肾切除术大鼠的药物干预措施中，ARN管状损伤的发病机理将进行研究。在这些特定目的的结论下，我们期望了解ARN的分子机制和是否可以预防ARN或AKI的严重程度减弱。总而言之，该项目将提供对于适当设计临床试验以减轻ARN至关重要的信息，这是重要的公共卫生在高度脆弱的患者人群中的问题。