title: N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy.
abstract: 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⁻¹·day⁻¹) 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 + vehicle. However, in animals receiving warfarin + NAC, the increase in Scr was lessened, starting at 40 mg·kg⁻¹·day⁻¹ NAC, and completely prevented at 80 mg·kg⁻¹·day⁻¹ 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.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Ware
authors.forename: Zahida
authors.initials: Z
authors.lastname: Qamri
authors.forename: Ayhan
authors.initials: A
authors.lastname: Ozcan
authors.forename: Anjali A
authors.initials: AA
authors.lastname: Satoskar
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Nadasdy
authors.forename: Brad H
authors.initials: BH
authors.lastname: Rovin
authors.forename: Lee A
authors.initials: LA
authors.lastname: Hebert
authors.forename: Tibor
authors.initials: T
authors.lastname: Nadasdy
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Brodsky
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use*; D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000517:prevention & control* / Q000652:urine; D000818:Animals; D003404:Creatinine / Q000097:blood; D003676:Deferoxamine / Q000627:therapeutic use; D004912:Erythrocytes; D008297:Male; D009392:Nephrectomy; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy; D014556:Urine / Q000166:cytology; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D014859:Warfarin; D003404:Creatinine; D003676:Deferoxamine; D000111:Acetylcysteine
keywords: 5/6 nephrectomy; oxidative stress; warfarin-related nephropathy