Renal hemodynamics underlie hepatorenal physiology in bile duct-ligated rats.

Abstract

Hepatorenal syndrome (HRS), a distinctive form of acute kidney injury, is a life-threatening but potentially reversible complication of cirrhosis. The median survival time for affected patients is only 2-4 weeks. Treatment options for HRS are very limited. The absence of an established animal model that accurately reflects human disease has hindered efforts to find treatment targets. We aimed to describe the renal hemodynamic changes that occur over time in the rat common bile duct ligation (BDL) model of cirrhosis. Male Sprague-Dawley rats underwent BDL or sham surgery and were studied at 2-5 weeks post-surgery. BDL caused persistent liver failure, which was linked to the development of liver fibrosis as early as 2 weeks. Renal function declined over time. Arterial blood pressure was significantly lower at 3 weeks after BDL and worsened further by 5 weeks. Additionally, renal blood flow, essential for kidney function, was dramatically reduced in BDL rats by 3 weeks. Decreased renal blood flow correlated with increased thromboxane synthase mRNA expression and higher thromboxane levels from 2 to 5 weeks in BDL rats. Similarly, enhanced constriction of the afferent arteriole in response to the thromboxane mimic, U46619, was seen at 2 weeks but not at 4 weeks in BDL rats. Levels of endothelin-1 increased between 2 and 5 weeks and were associated with heightened afferent arteriolar constriction in BDL rats. The rat BDL model replicates key systemic and renal hemodynamic features of decompensated cirrhosis in humans and provides a practical animal model for studying and developing therapies for HRS-AKI.