Kupffer cells (KC) constitute 80-90% of the tissue macrophages present in the body. They reside within the lumen of the liver sinusoids, and are therefore constantly exposed to gut-derived bacteria, microbial debris and bacterial endotoxins, known to activate macrophages. Upon activation KC release various products, including cytokines, prostanoides, nitric oxide and reactive oxygen species. These factors regulate the phenotype of KC themselves, and the phenotypes of neighboring cells, such as hepatocytes, stellate cells, endothelial cells and other immune cells that traffic through the liver. Therefore, KC are intimately involved in the liver's response to infection, toxins, ischemia, resection and other stresses. This review summarizes established basic concepts of KC function as well as their role in the pathogenesis of various liver diseases.

Ursodeoxycholic acid (UDCA) exerts anticholestatic effects by undefined mechanisms. Previous work suggested that UDCA stimulates biliary exocytosis via Ca ؉؉ -and protein kinase C (PKC)-dependent mechanisms. Therefore, the effect of taurine-conjugated UDCA (TUDCA) was studied in the experimental model of taurolithocholic acid (TLCA)-induced cholestasis on bile flow, hepatobiliary exocytosis, distribution of PKC isoforms, and density of the apical conjugate export pump, Mrp2, in canalicular membranes. Isolated perfused rat livers were preloaded with horseradish peroxidase (HRP), a marker of vesicular exocytosis, and were perfused with bile acids or dimethylsulfoxide (control) only. PKC isoform distribution and membrane density of

Background and aims: Diagnosis of moderately impaired renal function is of particular importance in patients with cirrhosis of the liver. Whereas patients with a markedly impaired glomerular filtration rate can be diagnosed easily by elevated serum creatinine concentrations, moderately reduced renal function may be missed by this conventional parameter. Recently, cystatin C has been suggested as a sensitive marker of renal function, independent of sex or muscle mass. Therefore, the aim of this study was to investigate the value of serum cystatin C concentration for the detection of moderately impaired renal function. Methods: Ninety seven inhospital patients with cirrhosis and a 24 hour creatinine clearance of at least 40 ml/min were investigated and divided into group 1 (creatinine clearance >70 ml/min; n=55) and group 2 (creatinine clearance 40-69 ml/min; n=42). Results: Serum cystatin C concentrations (mean (SD): 1.31 (0.51) v 1.04 (0.34) mg/l (p=0.008)) and creatinine concentrations (1.03 (0.52) v 0.86 (0.22) mg/100 ml (p=0.03)) were higher in group 2 than in group 1; there was no significant difference in urea concentrations. Receiver-operator characteristics (ROC) revealed a differential diagnostic advantage of cystatin C over creatinine and urea. At cut off concentrations of 1.0 mg/l, 0.9 mg/100 ml, and 28 mg/100 ml, respectively, cystatin C, creatinine, and urea exhibited 69%, 45%, and 44% sensitivity (p<0.05). As patients with a small muscle mass or reduced physical activity could be particularly prone to overestimation of their renal function, separate analyses were performed for the subgroups of female and Child-Pugh class C patients, respectively. In both groups, discrimination between patients with moderately impaired and normal renal function was best with cystatin C. In female patients, sensitivity of cystatin C (77.8%) was superior (p<0.05) to that of creatinine (38.9%) and urea (41.2%). In Child-Pugh C patients, the ROC curve was significantly better for cystatin C than for creatinine. Conclusions: Serum cystatin C determination could be a valuable tool in patients with cirrhosis, particularly with Child-Pugh class C or in female patients, for early diagnosis of moderately impaired renal function.

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Peripheral vasodilation is considered an important factor in the pathophysiology of the hepatorenal syndrome (HRS). Therefore, the aim of this study was to evaluate the therapeutic potential of the vasoconstrictor ornipressin plus dopamine in the treatment of the most severe form of HRS, namely HRS type 1. Seven cirrhotic patients (creatinine clearance 15 ؎ 1 mL/min, UNaV 7 ؎ 2 mmol/24 h) with HRS type 1 were included in the study after normalization of central venous pressure with intravenous albumin and low-dose dopamine had failed to prevent further deterioration of renal function. Ornipressin was given continuously (intravenous 6 IU/h) in combination with dopamine (2-3 g/kg/min) until creatinine clearance had increased to above 40 mL/min or adverse events prevented further treatment. HRS was reverted in 4 of 7 patients after 5 to 27 days (creatinine clearance 51 ؎ 4 mL/min, UNaV 47 ؎ 11 mmol/24 h) of treatment. Withdrawal was necessary in 1 patient after 15 days because of intestinal ischemia. Treatment failure was observed in 2 of 7 patients (creatinine clearance 19 ؎ 10 mL/min, UNaV 8 ؎ 3 mmol/24 h). Two of 4 responders had recidivant HRS 2 and 8 months after initial therapy, respectively. HRS in 1 of these patients was reverted with 18 days of ornipressin retreatment. The other patient had to be withdrawn from ornipressin after 2 hours because of ventricular tachyarrhythmia. Altogether, 3 of 7 patients survived HRS type 1, 1 after successful ornipressin therapy and liver transplantation, 1 with 2 successful courses of ornipressin, and 1 with liver transplantation after ornipressin treatment had failed. Thus, ornipressin plus dopamine can be a useful therapeutic option in patients with HRS type 1, especially as bridge to liver transplantation. (HEPATOLOGY 1999;30:870-875.)The hepatorenal syndrome (HRS) is a serious complication in patients with cirrhosis and ascites and associated with a poor prognosis. 1 It is characterized by a marked reduction of renal blood flow and glomerular filtration rate and a progressive increase in blood urea nitrogen and serum creatinine concentration in patients with markedly reduced liver function and ascites refractory to medical therapy. 2,3 Peripheral arterial vasodilation is thought to play an important role in the pathogenesis of HRS: By reducing the central blood volume peripheral vasodilation activates volume-and sodiumretaining neurohumoral systems, such as the renin-aldosterone system and the sympathetic nervous system. These mediators are responsible for renal vasoconstriction and avid sodium retention in advanced cirrhosis. 4,5 So far, liver transplantation is considered the only causal therapy for HRS. The outcome after transplantation, however, seems to be significantly impaired in patients with HRS compared with patients with normal renal function before liver transplantation. 6 Therefore, pharmacological interventions such as low-dose dopamine infusions have been recommended as a bridge to transplantation. 7 Despite improved renal perfusion in patients with HRS...