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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

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Background & Aims Proinflammatory and profibrotic cytokines such as osteopontin (OPN) and tumor necrosis factor-alpha receptor 1 (TNFR1) may be critically involved in the pathogenesis of cholangiopathies and biliary fibrosis. We therefore aimed to determine the role of genetic loss of either OPN or TNFR1 in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice as a model of xenobiotic-induced sclerosing cholangitis with biliary-type liver fibrosis using respective knock-out mice. Methods OPN and TNFR1 knock-out mice were fed a 0.1% DDC-supplemented diet for 4 weeks and compared to corresponding wild type (WT) controls. Liver morphology (H&E staining), serum markers of liver injury and cholestasis (ALT, AP, bilirubin), markers of inflammation in liver (CD11b and F4/80 immunostaining, mRNA expression of iNOS, MCP-1, IL-1β, INF-γ, TNF-α, and OPN), degree of ductular reaction (immunohistochemistry with morphometric analysis and Western blotting for cholangiocyte specific marker keratin 19) and degree of liver fibrosis (Sirius red-staining, hepatic hydroxyproline content for quantification) were compared between groups. Results DDC feeding in OPN and TNFR1 knock-out mice and respective WT controls resulted in comparable extent of liver injury, inflammatory response, ductular reaction, and liver fibrosis. Summary & Conclusions Our data indicate that genetic loss of neither OPN nor TNFR1 significantly impacts on the pathogenesis of DDC-induced sclerosing cholangitis, ductular reaction and resulting biliary fibrosis.

Keratin 8 (K8) and keratin 18 (K18) form the major hepatocyte cytoskeleton. We investigated the impact of genetic loss of either K8 or K18 on liver homeostasis under toxic stress with the hypothesis that K8 and K18 exert different functions. krt8À/À and krt18 À/À mice crossed into the same 129-ola genetic background were treated by acute and chronic administration of 3,5-diethoxy-carbonyl-1,4-dihydrocollidine (DDC). In acutely DDC-intoxicated mice, macrovesicular steatosis was more pronounced in krt8 À/À and krt18 À/À compared with wild-type (wt) animals. Mallory-Denk bodies (MDBs) appeared in krt18 À/À mice already at an early stage of intoxication in contrast to krt8 À/À mice that did not display MDB formation when fed with DDC. Keratin-deficient mice displayed significantly lower numbers of apoptotic hepatocytes than wt animals. krt8 À/À , krt18 À/À and control mice displayed comparable cell proliferation rates. Chronically DDC-intoxicated krt18 À/À and wt mice showed a similarly increased degree of steatohepatitis with hepatocyte ballooning and MDB formation. In krt8 À/À mice, steatosis was less, ballooning, and MDBs were absent. krt18 À/À mice developed MDBs whereas krt8 À/À mice on the same genetic background did not, highlighting the significance of different structural properties of keratins. They are independent of the genetic background as an intrinsic factor. By contrast, toxicity effects may depend on the genetic background. krt8À/À and krt18 À/À mice on the same genetic background show similar sensitivity to DDC intoxication and almost resemble wt animals regarding survival, degree of porphyria, liver-to-body weight ratio, serum bilirubin and liver enzyme levels. This stands in contrast to previous work where krt8 À/À and krt18 À/À mice on different genetic backgrounds were investigated.