Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Physiol Rep. 2021 Jan;9(1):e14697. doi: 10.14814/phy2.14697.
Anticoagulant-related nephropathy (ARN), that was described in humans first as warfarin-related nephropathy, is characterized by acute kidney injury and red blood cell (RBC) tubular casts in the kidney. 5/6 nephrectomy (5/7NE) rats treated with warfarin or dabigatran show changes in kidney function and morphology that are similar to human disease. The role of glomerular filtration rate (GFR) in the pathogenesis of ARN is not clear. The aim of these studies was to elucidate the role of GFR in the pathogenesis of dabigatran-induced ARN in 5/6NE rats.
5/6NE rats were treated per os with 150 mg/kg/day dabigatran alone or with drugs that lower (enalapril, 1.5 mg/kg/day) or increase (albuterol, 4.0 mg/kg/day) GFR for 7 days. Changes in coagulation and kidney function were recorded daily. Kidney morphology was evaluated on day 7 after the treatment.
Dabigatran resulted in activated partial thromboplastin time increase that was not affected by GFR-modifying drugs. Blood pressure was significantly lower in 5/6NE rats treated with enalapril and dabigatran as compared to dabigatran alone. The GFR was decreased by 35% in enalapril/dabigatran- and increased by 26% in albuterol/dabigatran-treated animals. There were no changes in serum creatinine, hematuria or urinary kidney injury molecule (KIM-1) levels when GFR-modifying drugs were added to dabigatran. All dabigatran-treated animals had RBC casts in the kidney regardless of the GFR modification.
GFR does not play a significant role in the dabigatran-induced acute kidney injury in 5/6 nephrectomy model in rats. Based in these data, modification of GFR in patients with ARN is not warranted.
抗凝相关肾病（ARN）最初在人类中被描述为华法林相关肾病，其特征为急性肾损伤和红细胞（RBC）管状铸型在肾脏中。用华法林或达比加群治疗的 5/6 肾切除（5/7NE）大鼠表现出与人类疾病相似的肾功能和形态变化。肾小球滤过率（GFR）在 ARN 发病机制中的作用尚不清楚。这些研究的目的是阐明 GFR 在 5/6NE 大鼠达比加群诱导的 ARN 发病机制中的作用。
5/6NE 大鼠经口给予 150mg/kg/天的达比加群单独或与降低（依那普利，1.5mg/kg/天）或增加（沙丁胺醇，4.0mg/kg/天）GFR 的药物联合治疗 7 天。每天记录凝血和肾功能变化。治疗后第 7 天评估肾脏形态。
达比加群导致部分凝血活酶时间延长，而 GFR 调节药物对其无影响。与单独用达比加群相比，用依那普利和达比加群治疗的 5/6NE 大鼠血压明显降低。依那普利/达比加群和沙丁胺醇/达比加群治疗组的 GFR 分别降低 35%和增加 26%。当 GFR 调节药物与达比加群联合使用时，血清肌酐、血尿或尿肾损伤分子（KIM-1）水平没有变化。所有用达比加群治疗的动物的肾脏中都有 RBC 铸型，无论 GFR 是否改变。
GFR 在大鼠 5/6 肾切除模型中达比加群诱导的急性肾损伤中没有发挥重要作用。基于这些数据，在 ARN 患者中调节 GFR 是没有必要的。
