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

acute renal failure in the rat. Background. It is widely held that liver disease predisposes toward acute tubular necrosis. The present study examines the effect of acute cholestatic liver disease on the susceptibility to The view is entrenched in clinical practice and teaching glycerol-induced acute tubular necrosis in the rat. that liver disease predisposes to the occurrence of acute Methods. Acute cholestatic liver disease was induced by ligatubular necrosis [1–4]. Acute tubular necrosis occurs in tion of the common bile duct, while the intramuscular injection of hypertonic glycerol was used to induce acute tubular necrosis. settings in which the kidney is exposed to ischemic or Renal injury was assessed by plasma creatinine concentration nephrotoxic insults, and such insults are considered more and renal histology. An in vitro model of heme protein-induced likely to instigate acute tubular necrosis when liver funcrenal injury (hemoglobin in conjunction with glutathione deple- tion is concomitantly and significantly impaired by hetion) was employed to assess the cytoprotective effects of bilipatocellular or cholestatic lesions [1–4]. Patients with rubin. Results. Ligation of the common bile duct markedly reduced significant liver disease are thus regarded as having an acute renal injury that occurs in the glycerol model (7.5 mL/kg increased risk for acute tubular necrosis when they exbody weight), as evidenced by a lower plasma creatinine con- perience systemic hypotension, as may occur in the pericentration and less severe renal histologic injury. At a higher operative period, when they are exposed to potentially dose of glycerol (10 mL/kg body weight), ligation of the com- nephrotoxic agents or endogenous toxicants such as heme mon bile duct again reduced renal injury and cumulative morproteins, or when systemic sepsis supervenes during the tality that occurs five days after the induction of this model of acute renal failure. These protective effects of ligation of the clinical course of these patients [1–4]. These clinical obcommon bile duct could not be ascribed to less severe muscle servations are supported by findings derived from disease injury or red cell damage. Ligation of the common bile duct models wherein obstructive jaundice in the rat sensitizes induced heme oxygenase-1 in the kidney and markedly so in the kidney to injury induced by ischemic insults [5, 6], the liver. Inhibition of heme oxygenase significantly attenuated, gentamicin [7], and endotoxin [8]. but did not prevent, the protective effects conferred by ligation The present study examines the effect of acute choleof the common bile duct. Bilirubin, in low micromolar concentrations, was cytoprotective against heme protein-induced cell static liver disease in the rat on the susceptibility to injury in vitro. glycerol-induced acute tubular necrosis. This study conConclusions. Ligation of the common bile duct confers resis- tinues a line of investigation that seeks to determine the tance to glycerol-induced acute tubular necrosis in the rat, ac- nature of responses instigated in the kidney sequentially tions that arise, in part, from the induction of heme oxygenase-1 exposed to similar or dissimilar insults [9–12]. Such rein the kidney and liver. Bilirubin, in micromolar concentrations, protects against heme protein-induced renal injury. Our studies sponses are germane to the overarching issue of the deteruncover a novel form of acquired resistance to renal injury, minants of susceptibility to renal injury in general and occurring, unexpectedly, in the setting of acute cholestatic liver to the phenomenon of acquired resistance of the kidney disease. We speculate that such potentially cytoprotective alter- to injury, in particular, wherein the kidney, subjected to a given insult, acquires resistance to the same or different insult [13–18]. As utilized in prior studies [9–12], the