Warfarin Treatment Results in Impaired Renal Function and Morphologic Changes in the 5/6 Nephrectomy Model of Ablative Nephropathy (AN) in Rats, Resembling Warfarin Related Nephropathy (WRN) in Humans
Sergey V Brodsky, Kyle M Ware, Ayhan Ozcan, Edward P Calomeni, Gyongyi Nadasdy, Anjali Satoskar, Tibor Nadasdy. The Ohio State University, Columbus, OH; Gulhane Military Medical Academy, Ankara, Turkey
Background: We had previously reported that patients with chronic renal disease on warfarin therapy with INR>3.0 may develop acute kidney injury as the result of glomerular hemorrhage and formation of occlusive tubular red blood cell (RBC) casts. We termed this condition WRN. No animal model is available to study the pathogenesis of WRN.
Design: Herein we report changes in serum creatinine (SC) and morphologic findings in the AN rats treated with increasing warfarin doses at different stages of AN development. Serum creatinine levels, prothrombin time (PT) and hematuria were measured and renal pathology was evaluated.
Results: Warfarin treatment resulted in an increase of PT (surrogate INR) up to 5 folds. The PT increase was accompanied by an increase in SC in AN rats, but not in control rats. The SC increase was more prominent in AN rats treated with warfarin at 19 and 3 weeks (AN 19w, AN 3w) as compared to AN rats treated at 8 weeks (AN 8w) after the ablative surgery.
The SC increase was correlated well with PT changes in AN rats, but not in control (R2=0.567 in AN 19w; R2=0.310 in AN 8w; R2=0.570 in AN 3w; R2=0.054 in control). Warfarin treatment was not associated with blood pressure changes in any of the experimental groups.
Warfarin treated AN, but not control rats had acute tubular injury with RBC and RBC casts in the tubules. Hematuria was increased with PT elevation, more prominently in AN rats. The morphologic changes were more prominent in AN 19w rats as compared to AN 8w and AN 3w rats and worsened with PT elevation. Interestingly, even a small increase in PT (2-3 folds) resulted in tubular RBC and RBC casts formation in AN rats.
Treatment with vitamin K prevented SC increase and RBC casts formation associated with warfarin treatment.
Conclusions: 1. Warfarin treatment results in increased SC and morphologic changes resembling human WRN in AN rats; therefore, the 5/6 nephrectomy model of AN is an appropriate animal model to study WRN. 2. Warfarin effects are more prominent with the progression of chronic kidney disease. 3. Vitamin K treatment prevents functional and morphologic changes of WRN.
Category: Kidney (does not include tumors)
Wednesday, March 21, 2012 1:00 PM
Poster Session VI # 266, Wednesday Afternoon