Acute cholestatic liver disease protects against glycerol-induced acute renal failure in the rat

Background. It is widely held that liver disease predisposes toward acute t ubular necrosis. The present study examines the effect of acute cholestatic liver disease on the susceptibility to glycerol-induced acute tubular necr osis in the rat. Methods. Acute cholestatic liver disease was induced by ligation of the com mon bile duct, while the intramuscular injection of hypertonic glycerol was used to induce acute tubular necrosis. Renal injury was assessed by plasma creatinine concentration and renal histology. An in vitro model of heme pr otein-induced renal injury (hemoglobin in conjunction with glutathione depl etion) was employed to assess the cytoprotective effects of bilirubin. Results. Ligation of the common bile duct markedly reduced acute renal inju ry that occurs in the glycerol model (7.5 mL/kg body weight), as evidenced by a lower plasma creatinine concentration and less severe renal histologic injury. At a higher dose of glycerol (10 mL/kg body weight), ligation of t he common bile duct again reduced renal injury and cumulative mortality tha t occurs five days after the induction of this model of acute renal failure . These protective effects of ligation of the common bile duct could not be ascribed to less severe muscle injury or red cell damage. Ligation of the common bile duct induced heme oxygenase-1 in the kidney and markedly so in the liver. Inhibition of heme oxygenase significantly attenuated, but did n ot prevent, the protective effects conferred by ligation of the common bile duct. Bilirubin, in low micromolar concentrations, was cytoprotective agai nst heme protein-induced cell injury in vitro. Conclusions. Ligation of the common bile duct confers resistance to glycero l-induced acute tubular necrosis in the rat, actions that arise, in part, f rom the induction of heme oxygenase-1 in the kidney and liver. Bilirubin, i n micromolar concentrations, protects against heme protein-induced renal in jury. Our studies uncover a novel form of acquired resistance to renal inju ry, occurring, unexpectedly, in the setting of acute cholestatic liver dise ase. We speculate that such potentially cytoprotective alterations may safe guard the kidney against irreversible functional and structural injury in t he hepatorenal syndrome.