Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice

Abstract

Tubular epithelial injury represents an underestimated but important cause of renal dysfunction in patients with cholestasis and advanced liver disease, but the underlying mechanisms are unclear. To address the hypothesis that accumulation and excessive alternative urinary elimination of potentially toxic bile acids (BAs) may contribute to kidney injury in cholestasis, we established a mouse model for detailed in vivo time course as well as treatment studies. Three-day common bile duct ligation (CBDL) induced renal tubular epithelial injury predominantly at the level of aquaporin 2-positive collecting ducts with tubular epithelial and basement membrane defects. This was followed by progressive interstitial nephritis and tubulointerstitial renal fibrosis in 3-, 6-, and 8-week CBDL mice. Farnesoid X receptor knockout mice (with a hydrophilic BA pool) were completely protected from CBDL-induced renal fibrosis. Prefeeding of hydrophilic norursodeoxycholic acid inhibited renal tubular epithelial injury in CBDL mice. In addition, we provide evidence for renal tubular injury in cholestatic patients with cholemic nephropathy. Conclusion: We characterized a novel in vivo model for cholemic nephropathy, which offers new perspectives to study the complex pathophysiology of this condition. Our findings suggest that urinary-excreted toxic BAs represent a pivotal trigger for renal tubular epithelial injury leading to cholemic nephropathy in CBDL mice. (HEPATOLOGY 2013;58:2056-2069 A cute kidney injury (AKI) is a common complication in patients with end-stage liver disease and represents a high-risk situation.1 Because of the fact that hepatorenal syndrome (HRS), an important and principally reversible cause of renal failure in patients with liver cirrhosis, may be difficult to differentiate from other causes of AKI in clinical practice, a revised clinical classification has been proposed. 2 Interestingly, recent studies revealed a high proportion of structural abnormalities, including vascular and

Bile Acid-Induced Cholemic Nephropathy

“…basolateral hepatocellular export), facilitating their alternative renal elimination [68,69,70,71,72]. Despite the beneficial hepatic and systemic effects of alternative excretion of cholephiles, this may also flood the kidney ultimately causing renal injury, which was recently shown in CBDL mice, a mouse model for the most extreme form of cholestasis exhibiting all phenotypical features of CN [65]. …”

“…Due to higher concentrations of bilirubin in distal nephron segments, the green color is especially accentuated in the medulla (renal pyramids) [33]. To date, all histological kidney alterations in jaundice, including tubular epithelial changes and formation of bile casts, were reported to be predominantly present at the level of tubules and especially distal nephron segments [33,65]. Intraluminal bile casts consist of exfoliated epithelial cells and could be easily identified and confirmed by histochemical Hall (or Fouchet) staining or periodic-acid Schiff (PAS) stains of kidney sections [33].…”

“…Bilirubin, however, has even been found to be renoprotective in experimental settings [64]. The most recent concepts revealed bile acids as key pathogenetic factors in CN [32,65]. Cholestasis is characterized by the retention of potentially toxic cholephilic molecules such as bile acids or bilirubin, which accumulate within the liver and serum [66,67].…”

“…Farnesoid X receptor knockout (FXR -/- ) mice eliminate more hydrophilic, thus less toxic bile acids via urine during biliary obstruction [79]. In contrast to wild-type mice, FXR -/- mice were therefore protected from CN [65]. In line with our concept that toxic bile acids might be the culprit for CN and a less toxic bile acid composition may prevent/reduce kidney injury, also prefeeding of the hydrophilic side-chain shortened bile acid ‘ nor ursodeoxycholic acid' prevents the development of collecting duct tubular epithelial lesions in CBDL mice.…”

Morphological changes in the liver and kidneys of rats subjected to terminal ileum exclusion during obstructive cholestasis

“…Hemodynamic alterations such as peripheral renal vasodilatation, bile acid and bilirubin nephrotoxidity and increased oxidative stress are involved in the physiopathology of this type of kidney failure [16][17][18] .…”