5/6 Nephrectomy as a Validated Rat Model Mimicking Human Warfarin-Related Nephropathy
5/6 Nephrectomy as a Validated Rat Model Mimicking Human Warfarin-Related Nephropathy
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DOI：
10.1159/000337918
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发表时间：
2012-01-01
影响因子：
4.2
通讯作者：
Brodsky, S. V.
中科院分区：
文献类型：
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作者：
Ozcan, A.;Ware, K.;Brodsky, S. V.
背景/目的：我们之前报道了接受华法林治疗的慢性肾脏疾病（CKD）患者，其国际标准化比率增加到bbb3.0可能由于肾小球出血和阻塞性红细胞（RBC）铸型的形成而发生急性肾损伤（AKI）。我们将这种情况命名为华法林相关性肾病（WRN）。我们之前也报道了5/6肾切除（5/6NE）大鼠急性过度抗凝使用brodifacoum（超华法林）诱导AKI。brodifacoum模型的局限性妨碍了对剂量-反应关系的仔细评估。方法：5/6NE采用华法林治疗。结果：我们在此报告，华法林治疗5/6NE大鼠导致血清肌酐（SC）的剂量依赖性增加。与消融术后8周相比，消融术后3周和19周华法林治疗后SC的增加更大。SC升高与凝血酶原时间升高相关。形态学上，5/6NE大鼠出现急性肾小管损伤，小管中有红细胞和红细胞铸型，而对照组大鼠没有。用维生素K治疗可以防止与华法林治疗相关的SC增加和肾脏形态学改变。在5/6NE中，单次发作的WRN不影响CKD的进展。结论：(1)CKD的5/6NE模型是研究WRN发病机制的合适动物模型。(2)华法林的药代动力学比溴代法更适合于WRN的研究。(3) 5/6NE晚期比早期更容易发生WRN。(4)维生素K治疗可预防WRN。巴塞尔S. Karger股份有限公司版权所有
Background/Aims: We previously reported that patients with chronic kidney disease (CKD) receiving warfarin therapy and whose international normalized ratio increases to >3.0 may develop acute kidney injury (AKI) as a result of glomerular hemorrhage and formation of obstructive red blood cell (RBC) casts. We named this condition warfarin-related nephropathy (WRN). We also previously reported that acute excessive anticoagulation with brodifacoum (superwarfarin) induces AKI in 5/6 nephrectomy (5/6NE) rats. Limitations of the brodifacoum model precluded a careful assessment of dose-response relationships. Methods: Warfarin treatment was used in 5/6NE. Results: Herein we report that warfarin treatment of 5/6NE rats resulted in a dose-dependent increase in serum creatinine (SC). The increase in SC following warfarin treatment was greater at 3 and 19 weeks after the ablative surgery, than that observed 8 weeks after the ablative surgery. The SC increase was correlated with the prothrombin time increase. Morphologically, 5/6NE, but not control rats, had acute tubular injury with RBC and RBC casts in the tubules. Treatment with vitamin K prevented SC increase and morphologic changes in the kidney associated with warfarin treatment. A single episode of WRN did not affect the progression of CKD in 5/6NE. Conclusion: (1) The 5/6NE model of CKD is an appropriate animal model to study the pathogenesis of WRN. (2) The pharmacokinetics of warfarin is better suited to the study of WRN than that of brodifacoum. (3) The more advanced stages of 5/6NE are more susceptible to WRN than the earlier stages. (4) Vitamin K treatment prevents WRN. Copyright (C) 2012 S. Karger AG, Basel