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-

819 Recently we reported that an excessive anticoagulation with warfarin (INR>3.0) can result in acute kidney injury (AKI). Morphologic findings included glomerular hemorrhage and renal tubular obstruction by red blood cell (RBC) casts. The clinical outcome in these patients was unfavorable; more than half of them did not recover from acute kidney injury even after normalization of INR. Later we analyzed serum creatinine (SC) and INR in patients with chronic kidney disease (CKD) on warfarin therapy. We found that 46% of patients had increase in SC levels >0.3 mg/dl associated with INR>3.0. SC remained elevated above baseline after the first episode of abnormal INR. The slope of the following SC increase was higher after this abnormal INR episode. We called this condition warfarin related nephropathy (WRN). The current study is based on medical records of 4059 consecutive patients who were on warfarin therapy at the Ohio State Medical Center for a 5-year period. Of these, 838 (21%) experienced an increase in SC>0.3 mg/dl within 1 week after INR>3.0 (WRN group). The remaining 3221 patients (79%) were designated no-WRN. The WRN group had a 5-year mortality rate of 42%, as compared to 27% for the no-WRN group (p<.001). The highest risk of death in the WRN cohort occurred within the 1st month after INR>3.0 (hazard ratio =2.15). For both WRN and no-WRN groups, the 5-year mortality rate was consistently higher in those with CKD compared to those with no-CKD (50.8% vs. 37.0% for the WRN cohort; 39.7% vs. 24.5% for the no-WRN cohort; p<.0001). Compared to no-WRN patients, WRN patients tended to be older (63.7±14.7 years vs. 61.7±15.6 years, p=.025), diabetic (47% vs 37%, p<.0001), hypertensive (82% vs 72%, p<.001) and had a history of heart failure (62% vs 42%, p<.001). Preliminary models indicate that WRN still is a significant predictor of death even after adjusting for these factors. We conclude that WRN is associated with increased mortality rate in the elderly, the diabetic, and those with CKD and cardiovascular diseases. The possible pathophysiologic mechanisms may be glomerular hematuria and formation of occlusive RBC casts. Physicians, involved in the clinical care of patients on systemic anticoagulation therapy, should be aware of this serious renal complication of warfarin overdose and carefully monitor the kidney function and coagulation parameters in these patients Disclosures: No relevant conflicts of interest to declare.