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.
An acute increase in international normalized ratio (INR) to Ͼ3.0 in patients with chronic kidney disease (CKD) can associate with an unexplained acute increase in serum creatinine and accelerated progression of CKD. A subset of these patients have renal tubular obstruction by casts of red blood cells, presumably the dominant mechanism of the acute kidney injury described as warfarin-related nephropathy. Here, we developed an animal model of this acute kidney injury that is based on the 5/6-nephrectomy model to aid future investigation of the pathogenesis of this condition. We found that acute excessive anticoagulation with brodifacoum ("superwarfarin") increased serum creatinine levels and hematuria in 5/6-nephrectomized rats but not in controls. In addition, morphologic findings in 5/6-nephrectomized rats included glomerular hemorrhage, occlusive red blood cell casts, and acute tubular injury, similar to the biopsy findings among affected patients. Furthermore, in the rat model, we observed an increase in apoptosis of glomerular endothelial cells. In summary, the 5/6-nephrectomy model combined with excessive anticoagulation may be a useful tool to study the pathogenesis of warfarin-related nephropathy. The significance of this study derives from the fact that this is the first successful attempt to reproduce in an animal model the morphologic findings seen in patients with a newly recognized syndrome of warfarin-related nephropathy (WRN). WRN can have dire consequences, particularly in chronic kidney disease (CKD) patients. WRN is a not an uncommon complication of warfarin therapy, which is the most commonly used oral anticoagulant in North America.We recently reported that warfarin therapy can result in acute kidney injury (AKI) by causing glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts. 1 Subsequent analysis of 103 patients with CKD revealed that 37% experienced an unexplained increase in serum creatinine (SC) of Ն0.3 mg/dl within 1 week of an international normalized ratio (INR) Ͼ 3.0. 2 Also, patients with WRN had accelerated progression of CKD, as compared with patients without WRN.Moreover, our recent analysis of more than 15,000 warfarin-treated patients showed that WRN affects approximately 33% of CKD patients and 16% of non-CKD patients who experienced an INR Ͼ 3.0. 3 We also found that mortality rate in patients with WRN was significantly higher than in patients without WRN.Hitherto, there is no animal model available to study WRN. The need for an animal model to study WRN is substantial. An animal model could provide a clear understanding of the mech-
Our data indicate that WRN represents part of a broader syndrome, anticoagulant-related nephropathy (ARN). ARN, at least partially, is mediated via PAR-1. Our findings suggest that not only CKD patients, but other patients as well, are at high risk of developing AKI if the therapeutic range of anticoagulation with dabigatran is exceeded. Close monitoring of kidney function in patients on dabigatran therapy is warranted.
Superwarfarins were developed following the emergence of warfarin resistance in rodents. Superwarfarins have much longer half-lives and stronger affinity to vitamin K epoxide reductase versus warfarin, and therefore can cause death in warfarin-resistant rodents. By the mid-1970s, the superwarfarins brodifacoum (BDF) and difenacoum (DiF) were the most widely used rodenticides throughout the world. Unfortunately, increased use was accompanied by a rise in accidental poisonings, reaching >16,000 per year in the United States. Risk of exposure has become a concern since large quantities, up to hundreds of kilograms of rodent bait, are applied by aerial dispersion over regions with rodent infestations. Reports of intentional use of superwarfarins in civilian and military scenarios raises the specter of larger incidents or mass casualties. Unlike warfarin overdose, for which 1–2 days of treatment with vitamin K is effective, treatment of superwarfarin poisoning with vitamin K is limited by extremely high cost and can require daily treatment for a year or longer. Furthermore, superwarfarins have actions that are independent of their anticoagulant effects, including both vitamin K–dependent and –independent effects, which are not mitigated by vitamin K therapy. In this review, we will summarize superwarfarin development, biology and pathophysiology, their threat as weapons, and possible therapeutic approaches.
Ware K, Qamri Z, Ozcan A, Satoskar AA, Nadasdy G, Rovin BH, Hebert LA, Nadasdy T, Brodsky SV. N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy. Am J Physiol Renal Physiol 304: F1421-F1427, 2013. First published April 10, 2013 doi:10.1152/ajprenal.00689.2012.-Warfarin-related nephropathy (WRN) occurs under conditions of overanticoagulation with warfarin. WRN is characterized by glomerular hemorrhage with occlusive tubular red blood cell (RBC) casts and acute kidney injury (AKI). Herein we test the hypothesis that oxidative stress plays a role in the AKI of WRN. 5/6 Nephrectomy rats were treated with either warfarin (0.04 mg·kg Ϫ1 ·day Ϫ1 ) alone or with four different doses of the antioxidant N-acetylcysteine (NAC). Also tested was the ability of our NAC regimen to mitigate AKI in a standard ischemia-reperfusion model in the rat. Warfarin resulted in a threefold or greater increase in prothrombin time in each experimental group. Serum creatinine (Scr) increased progressively in animals receiving only warfarin ϩ vehicle. However, in animals receiving warfarin ϩ NAC, the increase in Scr was lessened, starting at 40 mg·kg Ϫ1 ·day Ϫ1 NAC, and completely prevented at 80 mg·kg Ϫ1 ·day Ϫ1 NAC. NAC did not decrease hematuria or obstructive RBC casts, but mitigated acute tubular injury. Oxidative stress in the kidney was increased in animals with WRN and it was decreased by NAC. The NAC regimen used in the WRN model preserved kidney function in the ischemia-reperfusion model. Treatment with deferoxamine (iron chelator) did not affect WRN. No iron was detected in tubular epithelial cells. In conclusion, this work taken together with our previous works in WRN shows that glomerular hematuria is a necessary but not sufficient explanation for the AKI in WRN. The dominant mechanism of the AKI of WRN is tubular obstruction by RBC casts with increased oxidative stress in the kidney. oxidative stress; warfarin-related nephropathy; 5/6 nephrectomy WE SHOWED THAT WARFARIN coagulopathy induces acute kidney injury (AKI) that is associated with severe glomerular hematuria causing widespread tubular obstruction by red blood cell (RBC) casts (5-7). We documented this association in both humans (5-7) and animal models (31, 41). We named this condition warfarin-related nephropathy (WRN). WRN can have dire consequences, particularly in chronic kidney disease (CKD) patients, whose CKD progression can be accelerated (5, 6). In humans, WRN is not an uncommon complication of excessive anticoagulation with warfarin. Our retrospective studies show that when the international normalized ratio (INR) acutely exceeds 3.0, 16% of non-CKD patients (6) and 33-37% of CKD patients (5, 6) may develop AKI within ϳ1 wk of the INR Ͼ 3.0. Those at greatest risk of WRN have CKD or cardiovascular disease (5, 6).The most conspicuous feature of WRN is the presence of numerous renal tubules obstructed by RBC casts. On this basis, it has been assumed that the tubular obstruction was t...
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