5/6 nephrectomy as a validated rat model mimicking human warfarin-related nephropathy

Area of Science:

• Nephrology
• Pharmacology
• Toxicology

Background:

• Chronic kidney disease (CKD) patients on warfarin with elevated INR (>3.0) may develop acute kidney injury (AKI) due to glomerular hemorrhage and red blood cell (RBC) casts, termed warfarin-related nephropathy (WRN).
• Previous studies indicated brodifacoum induces AKI in 5/6 nephrectomy (5/6NE) rats, but limitations hindered dose-response assessments.

Purpose of the Study:

• To investigate the dose-response relationship of warfarin in a 5/6NE rat model of CKD.
• To evaluate the protective effect of vitamin K against warfarin-induced nephropathy.
• To assess the suitability of the 5/6NE model for studying WRN pathogenesis.

Main Methods:

• Warfarin was administered to 5/6NE rats at varying doses.
• Serum creatinine (SC) and prothrombin time (PT) were monitored.
• Kidney morphology was examined for acute tubular injury, RBCs, and RBC casts.
• Vitamin K was administered to assess its preventative effects.

Main Results:

• Warfarin treatment in 5/6NE rats caused a dose-dependent increase in SC, correlated with PT.
• The increase in SC was more pronounced at 3 and 19 weeks post-surgery compared to 8 weeks.
• Kidney histology revealed acute tubular injury with RBCs and casts in 5/6NE rats, absent in controls.
• Vitamin K administration prevented SC elevation and kidney damage.
• A single WRN episode did not impact CKD progression.

Conclusions:

• The 5/6NE rat model is suitable for studying WRN pathogenesis.
• Warfarin's pharmacokinetics are more appropriate than brodifacoum for WRN research.
• Advanced stages of CKD in the 5/6NE model are more susceptible to WRN.
• Vitamin K effectively prevents WRN.