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Am J Physiol Renal Physiol. 2013 Jun 15;304(12):F1421-7. doi: 10.1152/ajprenal.00689.2012. Epub 2013 Apr 10.

N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy.

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1
Department of Pathology, The Ohio State University, Columbus, OH 43210, USA.

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.

KEYWORDS:

5/6 nephrectomy; oxidative stress; warfarin-related nephropathy

PMID:
23576637
DOI:
10.1152/ajprenal.00689.2012
[Indexed for MEDLINE]
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