Anticoagulant related nephropathy

项目总结

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.