Lise Giroux

Mitomycin-C Nephrotoxicity: A Clinico-Pathologic Study of 17 Cases

The potential nephrotoxicity of Mitomycin-C (MMC) was studied in 17 autopsies from patients treated with this drug, usually in association with other anti-neoplastic agents. Renal functional deterioration was present in seven cases while urinalysis showed an overt proteinuria and hematuria in six and four instances, respectively. Four of these patients also developed a severe microangiopathic hemolytic anemia (MAHA) and thrombopenia. Histological examination did not reveal residual tumor in three of them. However renal lesions similar to those observed in the hemolytic-uremic syndrome (HUS) were associated with glomerular mesangiolytic changes and nuclear atypias in glomerular and tubular cells. Immunofluorescence and ultrastructural studies confirmed these findings. In other patients, variable degrees of cellular atypias and of mesangiolysis were observed. The severity of the glomerular, vascular, and tubular lesions correlated with the total dosage of MMC received. The nephrotoxic potential of MMC seems to be delayed in onset and dose related.

Ritanserin Decreases Portal Pressure in Conscious and Unrestrained Cirrhotic Rats

We have recently demonstrated that ritanserin, a serotonin 5-hydroxytryptamine receptor antagonist void of systemic effects, caused a significant reduction of portal pressure in conscious cirrhotic dogs. The mechanism by which ritanserin lowers portal pressure is poorly defined. We investigated the splanchnic and systemic hemodynamic effects of ritanserin (0.63 mg/kg body wt i.v., a dose known to completely inhibit binding of 5-hydroxytryptamine to its receptors), in conscious and unrestrained cirrhotic rats (n = 13). Heparinized catheters were placed into the portal vein, inferior vena cava, aorta, and left ventricle with exit from the neck. Hemodynamic studies were performed 4 h after consciousness was regained. Cardiac output and regional blood flows were measured using radiolabeled microspheres and the reference sample method. Sixty minutes after administration, ritanserin caused a significant reduction of portal pressure (-17%) with minimal changes in portal venous inflow (+3%). Portal vascular resistance decreased significantly (-23%), whereas splanchnic arteriolar resistance was similar before and after ritanserin. A significant increase in mean arterial pressure (+5%) and cardiac output (+22%) was observed. Our results suggest that ritanserin lowers portal pressure through a mechanism separate from portal venous inflow. This effect could be due to changes in intrahepatic or on portocollateral resistances, or both. These findings support the potential use of this new agent in the treatment of portal hypertension.

Liver function improvement following increased portal blood flow in cirrhotic rats.

BACKGROUND/AIMS Liver microcirculation in cirrhosis is characterized by development of intrahepatic shunts and capillarization of sinusoids secondary to cell necrosis and deposition of new collagen, resulting in both decreased drug elimination and increased vascular resistance with portal hypertension. The aim of this study was to examine the effects of increased portal blood flow on hepatic microcirculation and drug elimination in 13 perfused livers from cirrhotic rats. METHODS Intrahepatic resistance was assessed under basal conditions (21.2 +/- 0.3 mL/min) and 1 hour after doubling the flow (41.6 +/- 1.0 mL/min). A multiple indicator dilution technique was used at both flow rates to measure sinusoidal volume, albumin and sucrose extravascular volumes, and cellular water volume. Hepatic elimination of labeled taurocholate and propranolol was also measured, and the recovery of 15-microns microspheres was used to evaluate large intrahepatic shunts. RESULTS After doubling the flow, intrahepatic resistance decreased by 31%. Sinusoidal and extravascular volume increased significantly without a change in microsphere recovery. However, there was a marked increase in taurocholate and propranolol elimination by cirrhotic livers. Moreover, during high flow, significant correlations were found between changes in albumin extravascular volume and taurocholate and propranolol elimination. CONCLUSIONS Increased portal blood flow in cirrhotic rats induces a decrease in intrahepatic resistance without changes in intrahepatic shunting and improves drug elimination by the liver without deleterious effects on hepatocyte viability.

COLD ISCHEMIA-REPERFUSION INJURY OF THE LIVER: Role of the Liver Donor Nutritional Status in Rats

To verify the role of donor nutritional status on the quality of liver preservation after cold storage, we assessed hepatocyte and liver endothelial cell viabilities and functions in an isolated perfused rat liver model. Livers from fed and fasted Wistar rats were isolated and perfused either immediately after liver harvesting or after a 24-hr cold (4 degrees C) preservation in University of Wisconsin solution. Hyaluronic acid (150 ng/ml) and taurocholate (11.5 micrograms/ml) were infused into the reservoir, and their eliminations were assessed to evaluate liver endothelial cell function and hepatocyte function, respectively. Liver viability was estimated by intrahepatic resistance, oxygen consumption, bile secretion, and lactate dehydrogenase release. In addition, cell viabilities were evaluated by trypan blue staining. In fed-rat livers, glycogen content did not differ before or after the cold preservation, although a reduction was observed during the subsequent perfusion period. Liver glycogen content in fed rats was markedly higher than in the fasted rats at each time point studied. In fasted and fed rats, liver viability parameters and hepatocyte function were moderately altered, whereas liver endothelial cell function was markedly impaired after cold preservation. However, feeding had no influence on either hepatocyte or liver endothelial cell functions which were similarly altered in both nutritional conditions. The present data show that the nutritional status of liver donors does not play an important role in the preservation of liver endothelial cells after cold ischemia-reperfusion and, thus, should not affect the overall resistance of livers to hypothermic-ischemic injury.

The effect of alcohol-induced hepatomegaly on portal hypertension in cirrhotic rats

Male Sprague-Dawley rats with CCl4-induced cirrhosis (confirmed by increased collagen content and light microscopy) were fed either ethanol (Group A, n = 9) or isocaloric carbohydrate diet (Group B, n = 8) for 4 weeks. Histologic and hemodynamic measurements were obtained in the awake state before (time 1) and after the 4 weeks of diet (time 2). Portal-systemic shunts were evaluated using radiolabelled microspheres. Liver weight was increased in Group A (16.5 +/- 0.5 vs. 14.2 +/- 0.5 g, mean +/- SE, p less than 0.005) as was the ratio of liver weight over total body weight (3.41 +/- 0.05 vs. 2.86 +/- 0.09%, p less than 0.0001, +19.2%). Hepatocytes surface area was increased in the ethanol group (357 +/- 9 vs. 294 +/- 7 microns 2, p less than 0.0001). In Group B, only 9 +/- 2% of hepatocytes had steatosis as opposed to 69 +/- 3% of centronodular and 34 +/- 3% of perinodular hepatocytes in Group A (p less than 0.001). Portal pressure remained stable in both groups (time 1 (A) 16.9 +/- 0.8, (B) 15.8 +/- 1.1 mmHg, n.s.; time 2 (A) 15.9 +/- 0.7, (B) 15.8 +/- 0.6 mmHg, n.s.). Portal-systemic shunts did not change with time or diet (time 1 (A) 10.6 +/- 3.7%, (B) 4.1 +/- 2.1%, n.s.; time 2 (A) 13.4 +/- 5.9%, (B) 10.8 +/- 4.3%, n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cold ischemia–warm reperfusion on the cirrhotic rat liver

Cirrhosis is known to induce capillarization of the sinusoidal endothelial cells (SECs) and collagenization of the space of Disse, resulting in a reduced access of plasma and plasma‐dissolved substances to hepatocytes due to their limited diffusion in the extravascular space. The aim of the present study was to use a well known effect of cold ischemia–warm reperfusion (CI‐WR) on liver SECs, that is, their retraction and detachment, progressing to a denudation of the SEC lining. The disappearance of the capillarized SEC lining would improve the access of plasma and plasma‐dissolved substances to the hepatocytes and consequently might improve the metabolic function of cirrhotic livers. This study was performed using the isolated perfused rat liver model subjected to 24‐hour CI followed by a 60‐minute WR in thioacetamide‐induced cirrhosis. Liver microcirculation was evaluated using the multiple indicator dilution curve (MIDC) technique. Hepatocyte, SEC, and Kupffer cell functions were evaluated using specific elimination processes. As occurs in normal livers, CI‐WR induced extensive SEC necrosis with a marked reduction of the hyaluronic acid elimination. By contrast, the hepatic microcirculation was not modified: vascular, extravascular, and the cellular spaces were similar before and following CI‐WR. In addition, the hepatic metabolic functions, as evaluated by propranolol and taurocholate hepatic uptake, were neither improved nor decreased, as were Kupffer cell functions. The present data strongly suggest that capillarization of SECs plays a lesser role than collagenization of the space of Disse in the reduced exchange between sinusoids and hepatocytes in thioacetamide‐induced cirrhotic rat livers, which appear to be quite resistant to CI‐WR. Liver Transpl 14:486–493, 2008.