Liver regeneration following experimental major hepatectomy with choledochojejunostomy.

BACKGROUND: Surgical treatment for perihilar cholangiocarcinoma frequently involves hepatectomy and extrahepatic bile duct resection with a choledochojejunostomy (CJ). Cholangitis owing to bilioenteric anastomosis is a common complication. The impact of CJ or regurgitating cholangitis on the liver regeneration process after major hepatectomy is unknown. METHODS: Rats underwent 70 per cent hepatectomy (Hx group) or hepatectomy with CJ (Hx + CJ group). The intrahepatic inflammatory response, hepatic regeneration rate, and expression of regeneration-associated genes in the liver and blood were compared between these two groups. RESULTS: Levels of hepatobiliary markers in the blood were significantly higher 4 and 7 days after operation in the Hx + CJ group than the Hx group. Intrahepatic expression of inflammation-associated genes, such as interleukin 6 and tumour necrosis factor α, was also significantly higher in the Hx + CJ group on days 4 and 7. A progressive periportal inflammatory response was identified in the Hx + CJ group by histological examination. The hepatic regeneration rate was significantly lower in the Hx + CJ group than in the Hx group on day 2 (mean(s.d.) 14·2(6·3) versus 21·4(2·6) per cent; P = 0·013) and day 4 (32·4(5·3) versus 41·3(4·4) per cent; P = 0·004). Gene expression levels of hepatic regeneration-promoting factors such as hepatocyte growth factor were significantly lower in the Hx + CJ group than the Hx group on day 1. CONCLUSION: CJ perturbs early liver regeneration after hepatectomy. An excessive inflammatory response in the liver and suppression of liver regeneration-associated factors may play a role. Surgical relevance Patients with perihilar cholangiocarcinoma may need major hepatectomy with extrahepatic bile duct resection and choledochojejunostomy. This carries a substantial risk of postoperative complications including liver failure. A rat model of partial hepatectomy with choledochojejunostomy was established. The molecular mechanisms underlying liver regeneration, and perturbation of this process by duodenobiliary reflux via the choledochojejunostomy, are described. The results give insight into the pathophysiological events following major hepatectomy with extrahepatic bile duct resection and choledochojejunostomy. This may help to develop a treatment strategy to reduce postoperative liver failure.

Real-time monitoring of liver damage during experimental ischaemia-reperfusion using a nitric oxide sensor.

BACKGROUND: Hepatic ischaemia-reperfusion (IR) injury may lead to liver damage during liver surgery, and intrahepatic nitric oxide (NO) levels may play a role in this context. The aim of this study was to demonstrate real-time changes in intrahepatic NO concentration during IR and to correlate potential hepatic NO production with liver damage using a selective NO sensor. METHODS: Wistar rats were exposed to 15 min of hepatic ischaemia followed by reperfusion, after which changes in intrahepatic NO levels were measured using an NO sensor. Additionally, rats were exposed to five successive periods of IR, each consisting of 15 min ischaemia followed by 5 or 15 min reperfusion, and hepatic damage was evaluated by blood tests and histological examination. Hepatic expression of Akt, phosphorylated Akt, endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS was examined at different time points during and after IR by western blot and immunohistochemical analysis. RESULTS: During ischaemia, intrahepatic NO levels increased and reached a plateau at approximately 10 min. Repeated 15 min ischaemia-5 min reperfusion cycles reduced the maximum amount of NO produced during ischaemia gradually, and almost no NO production was observed during the fifth period of ischaemia. NO production following repeated ischaemia was proportional to the degree of hepatic viability. Phosphorylated eNOS was upregulated and correlated with the level of NO production during hepatic ischaemia. CONCLUSION: Intrahepatic NO levels decrease during repeated IR in rats. Real-time monitoring of intrahepatic NO levels is useful for the prediction of IR-related liver injury during experimental liver surgery.

Effects of fosfomycin and imipenem-cilastatin on the nephrotoxicity of vancomycin and cisplatin in rats.

The nephrotoxicity of vancomycin and cisplatin and the protective effects of fosfomycin and imipenem-cilastatin on renal function have been studied in rats. The renal clearance of vancomycin after the induction of renal dysfunction was also evaluated by calculating the glomerular filtration rate (GFR) and its secretory clearance. Plasma concentrations of creatinine and urea nitrogen increased dose-dependently after vancomycin injection. No such increases were observed after co-treatment with fosfomycin or imipenem-cilastatin. Changes of N-acetyl-beta-D-glucosaminidase activity in the urine of vancomycin-treated rats were not remarkable compared with those in cisplatin-treated animals. The reduced renal clearance of vancomycin in rats with acute renal failure induced by vancomycin was because of a decrease in both GFR and secretory clearance. However, the changes in GFR and secretory clearance were not proportional-the change in GFR was more pronounced than that of secretory clearance in the experimental groups. In addition, the renal clearance of vancomycin was maintained at the control level after co-administration of fosfomycin or imipenem-cilastatin with vancomycin. These results suggest that vancomycin impairs glomerular filtration more markedly than renal tubular function as compared with cisplatin. Co-administration with fosfomycin or imipenem-cilastatin confers significant protection against the nephrotoxic effects of vancomycin.

Effects of fosfomycin and imipenem/cilastatin on nephrotoxicity and renal excretion of vancomycin in rats.

PURPOSE: The effects of fosfomycin and imipenem/cilastatin on the nephrotoxicity of vancomycin were studied in rats, and those on the renal handling of vancomycin were also investigated in perfused kidneys. METHODS: The protective effects of fosfomycin and imipenem/cilastatin on vancomycin nephrotoxicity were evaluated by increases in plasma concentration of creatinine and urea nitrogen in rats. The urinary excretion of vancomycin was measured and analyzed kinetically in the perfused rat kidney. RESULTS: The nephrotoxicity induced by vancomycin (500 mg/kg, i.v.) was inhibited almost completely by co-administration of fosfomycin or imipenem/cilastatin. In the perfused rat kidney, the excretion ratio of vancomycin was less than those of p-aminohippurate and cimetidine, and greater than that of arbekacin, suggesting the secretion and reabsorption of vancomycin in renal tubules. The tissue/perfusate ratios of unbound vancomycin were not significantly changed by co-treatment with fosfomycin or imipenem/cilastatin. Imipenem/cilastatin significantly decreased the excretion ratio of vancomycin. Fosfomycin also decreased vancomycin excretion ratio, although this effect was not significant. CONCLUSIONS: The renal handling of vancomycin was different from those of organic anions and cations and an aminoglycoside antibiotic. The protective effects of fosfomycin and imipenem/cilastatin against the nephrotoxicity of vancomycin might be partly due to the change in renal handling of vancomycin, probably in its tubular secretion/ reabsorption, in rats.

Renal excretion of vancomycin in rats with acute renal failure.

We have investigated the renal excretion of vancomycin in rats with acute renal failure (ARF) induced by uranyl nitrate or cisplatin. The renal clearance of the antibiotic after uranyl nitrate or cisplatin injection was separately evaluated by calculating the glomerular filtration rate (GFR) and secretory clearance. The reduced renal clearance of vancomycin in these ARF rats was a result of a decrease in both GFR and secretory clearance. The extents of the decreases in GFR and in secretory clearance were not, however, proportional, the extent of the decrease in secretory clearance being more pronounced. These results suggest that the renal tubular secretion of vancomycin was reduced more predominantly than glomerular filtration in these ARF models.