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Background: Donor's age and immunosuppression influence the severity of hepatitis C virus (HCV) recurrence. We analyzed the 18-month mortality in 302 consecutive HCV recipients, divided into three groups, with homogeneous immunosuppression and preemptive antiviral therapy in the last group., Patients: Group 1: one hundred thirty-three patients (1996-2000) mainly received a triple therapy (steroids- cyclosporine A [CyA]-azathioprine); first line treatment of biopsy-proven acute rejection (BPAR) was with steroid boluses; second-line with OKT3. Group 2: ninety-one patients (2001-2003) mainly received a double therapy (steroids-CyA) and induction with anti-CD25 antibody; first-line BPAR treatment was increased dose/switch of the calcineurin inhibitor; second-line steroid boluses; third-line extracorporeal photopheresis (ECP). Group 3: seventy-eight patients (2004-June 2006) mainly received a monotherapy (CyA) associated with ECP and induction with anti-CD25 antibody; first-line BPAR treatment was increased dose/switch of calcineurin inhibitor with increased ECP frequency, second-line steroid boluses, and third-line retransplantation., Results: Median donor's age increased from 54 (13-84) years in group 1 to 60 (10-93) years in group 2 and 66 (17-84) years in group 3 (P<0.001). Overall mortality in groups 1, 2, and 3 decreased from 28.6% to 22% and 10.2% respectively (P = 0.003); HCV-related mortality from 7.5% and 12.1% to 1.3%, respectively (P = 0.029). BPAR were 33.8% in group 1 and 9.0% in group 3. Applicability of the preemptive antiviral therapy in group 3 was 69.2%. Sustained viral clearance occurred in 38.9% of 36 patients who completed the protocol. At multivariate analysis, a single-drug immunosuppressive regimen was the only variable independently associated with survival (P=0.05)., Conclusion: Low and steady immunosuppression combined with preemptive antiviral therapy significantly improved the short-term mortality of HCV recipients transplanted with aged organs. Prolonged follow-up will assess whether this benefit is maintained in the long run.

Background: Hepatitis C virus (HCV) recurrence in HCV+ liver transplant recipients is almost inevitable and may be promoted by immunosuppression. We compared the amount of liver damage with regard to usage of steroids and basiliximab., Methods: A total of 140 HCV+ adult liver transplant recipients were randomly allocated to basiliximab + steroids or basiliximab + placebo (plus cyclosporine and azathioprine). Primary endpoint: hepatitis C histological recurrence (liver damage as for Ishak grading score >or=8 by biopsy at 12 months); secondary endpoints: treatment failure (death, graft loss, patient withdrawal), biopsy proven acute rejection (BPAR), treated acute rejection (tAR), allograft and patient survival rates at 12 months., Results: Any significant difference has been observed in the 12-month hepatitis C histological recurrence rate (41.2% basiliximab + steroids, 37.5% basiliximab + placebo, P = 0.354). The treatment failure rate was significantly higher in basiliximab + steroids (28.8%) than in basiliximab + placebo (15.6%), P = 0.03; the combination test for the evaluation of the joint hypothesis resulted in a borderline nonsignificant overall result (P = 0.059). BPAR rate was significantly lower in the group treated with steroids (24.3% basiliximab + steroids, 39.4% basiliximab + placebo, P = 0.04), while the tAR rate was similar (29.7% basiliximab + steroids and 37.9% basiliximab + placebo). Any significant differences in 1-year graft and patient survival rates have been observed (72.9% and 84.8% basiliximab+steroids; 81.5% and 89.0% basiliximab + placebo)., Conclusions: Results suggest that steroid-free therapy is associated with a significantly lower treatment failure rate, although histological recurrence rate of hepatitis C is similar in the two groups. This benefit is not offset by an evident increase in graft rejection rate requiring treatment.

Background: Liver transplantation has become established therapy for end-stage liver disease. Survival rates are satisfactory and the current challenge is the implementation of cost-optimization policies., Methods: This study was a cost-outcome and cost-determinant analyses in an Italian National Health Services liver transplantation unit. Collection of data related to survival and costs in 235 adult transplant recipients from 1997 to 2000. Costs included consumption-related costs (e.g., diagnostics, medication) and structure-related costs (e.g., staff, general costs, and overhead) allocated individually according to hospital patient days. The main variables were average cost per patient alive at the end of each year, average cost per month of patient alive, and average cost per transplantation., Results: Two hundred fifty-two transplantations were performed in 235 adults (mean follow-up, 16.5 months). Average cost per patient alive was constant (e107,014-e117,782), whereas average cost per month of patient alive progressively diminished to e7,098. Costs differed according to reason for transplantation, being lower in nonviral (mainly alcoholic) hepatitis and higher in fulminant hepatic failure and in rare liver diseases. Higher costs were also observed in patients with portal thrombosis and high pretransplant serum creatinine. The average cost per transplantation was fairly constant (e75,747-e83,846) and plateaued after 120 to 140 transplantations., Conclusions: The optimization of the cost-to-outcome ratio is linked to a reasonably high number of transplants per year, which allows early achievement of a cost-per-transplant plateau associated with a better survival rate, in addition to careful consideration of risk factors and diagnoses.

This article discusses a new simple, fast, and easily performed technique that allows reduction of morbidity and hospital stay after T-tube removal. A retrospective analysis was conducted of 145 recipients who underwent T-tube removal 3 months after orthotopic liver transplantation. Patients were divided in two groups: group 1 (n=93) underwent T-tube removal and contemporary placement under fluoroscopic guidance of a counter-drain. Group 2 (n=52) T-tubes were removed from the bile duct under fluoroscopy but were left in place as a counter-drain. Overall, there were 33 (22.7%) complications related to T-tube removal. Treatment was always conservative and no deaths were related to T-tube. In group 1, 29 (31.2%) complications occurred; and the mean hospital stay was 9.4+/-9.3 days. In group 2, four complications (7.7%) occurred (P=0.002); and the mean hospital stay was 5.8+/-5.5 days (P=0.012). The adoption of this new technique-under fluoroscopic guidance, using the T-tube itself as a counter-drain-for T-tube removal allowed us to significantly reduce biliary complications and hospital stay.

Background: Although exceedingly rare, kinking of suprahepatic vena cava after liver transplantation can lead to both graft failure and patient demise. The features of a case of suprahepatic vena caval kinking are herein reported along with the description of an original solution adopted to rescue the graft., Methods: In order to correct vascular kinking, two surgical gloves filled with sterile saline solution were placed in appropriate positions in the subdiaphragmatic space., Results: Caval obstruction was immediately relieved. Over a period of 7 days, gloves were progressively deflated and eventually removed without need for laparotomy. Vena caval kinking did not recur., Conclusions: The "water-glove balloon system" described in this report seems to be an efficient and inexpensive method to rescue liver grafts in the presence of kinking or torsion of the suprahepatic vena cava. Surgeons dedicated to the transplantation of the liver should therefore retain this option in their cultural background.

Background: Cyclosporine (CsA)-induced acute nephrotoxicity could be reduced by prevention of parenchymal accumulation of the drug itself. The objective of this prospective study was to evaluate whether cilastatin, an inhibitor of active tubular resorption of CsA, reduces CsA-induced acute nephrotoxicity in kidney graft recipients., Methods: Sixty-nine kidney recipients with immediate graft functional recovery were randomly assigned to either the treatment group (imipenem/cilastatin, n=33) or the control group (ceftazidime, n=36). All patients followed a standard immunosuppressive regimen based on CsA and low-dose prednisone. Graft function and CsA levels were evaluated 3, 5, 10, 15, and 30 days after transplantation., Results: Compared with the control group, imipenem/cilastatin administration reduced the serum creatinine level in the first 2 weeks after transplantation, reaching a significant effect on postoperative day 10 (P<0.05). No significant differences were demonstrated between the two groups for CsA levels, patient and graft survival, and all the other examined parameters., Conclusions: Our findings support the hypothesis that cilastatin administration can reduce CsA-induced acute nephrotoxicity after kidney transplantation.

Cyclosporine (CsA), administered to rats at daily doses of 10 and 50 mg/kg body weight, for 21 days, influenced negatively the structures involved in the synthesis, storage and secretion of digestive enzymes in pancreatic acinar cells. A dose-related, significant reduction in basophilic cell regions, secretion granule content, and overall size of acinar cells was appreciable by light microscopy and morphometry. By electron microscopy, the acinar cells of the rats given 10 mg/kg/day CsA were similar to the controls, whereas with the higher dose most cells showed reduction in the size of nucleoli, increase in the number of lysosomes, and evidence of autophagy. In only a few cells was autophagy particularly severe and involved almost the entire cytoplasm. Nine weeks after withdrawal from CsA treatment, the structural recovery of acinal cells was complete, and features indicating enhanced protein synthesis and mitochondrial multiplication were observed by electron microscopy. In conclusion, prolonged administration of CsA to rats induces changes in the acinar cells indicating a depression of their activity, without substantial impairment in the viability of the most of them, even at high doses. This accounts for complete restoration of the acinar tissue upon withdrawal.

Daily cyclosporine doses of 10 mg/kg body weight for 21 days in Wistar rats cause impairment in glucose homeostasis and changes in the amount of immunostainable hormones and in the ultrastructure of the cells of the pancreatic islets. CsA induces hyperglycemia and reduced glucose tolerance, and causes a decrease in immunoreactive insulin and an increase of somatostatin and pancreatic polypeptide (PP) immunoreactivities, leaving glucagon immunoreactivity unaffected. Ultrastructurally, different degrees of dilation of rough endoplasmic reticulum cisternae and enlargement of Golgi apparatus can be observed in B cells, together with a pronounced reduction in the number of secretory granules. Nevertheless, there were no apparent morphological changes of the other cytoplasmic organelles, suggesting that the drug, besides a depression of protein synthesis, as previously stated, also induces a substantial defect in granulogenesis, probably due to impairment in the intracellular transport of the hormone from the sites of synthesis to the secretory granules. The B cell alterations are not accompanied by any sign of B cell degeneration or death. Non-B cells did not show any of the ultrastructural changes found in B cells and were similar to those of the control rats. The above findings indicate that CsA at immunotherapeutic doses causes impairment in the secretory processes of B cells specifically. An hypothesis on the mode of action of CsA on B cells is drawn.

Natural antidonor antibodies are known to play a prominent role in hyperacute xenograft rejection. The aim of this work was to devise an experimental protocol to prolong the survival time of guinea pig heart xenografts transplanted into rats. A technique of continuous plasma exchange adapted to small animals was used to remove the natural cytotoxic antibodies from the recipient prior to the transplantation. In some experiments, cyclosporine (CsA), cyclophosphamide (CY), or splenectomy were associated with the plasma exchange. In this highly discordant xenogenic donor-recipient combination, the mean graft survival time in nontreated rats was 16 min. When an exchange of 1.5 plasma volume was performed 24 hr before the transplantation, no prolongation of the graft survival time was observed. When CsA, CY, or splenectomy were associated with the plasma exchange, the graft survival time was significantly increased by more than 2500% (up to 418 min with CsA). When used isolately, none of these 3 immunosuppressive methods was able to prolong the graft survival time. Natural cytotoxic antibodies were monitored by a complement-mediated cytotoxicity assay. After a plasma exchange, the titers decreased from 1:16-1:32 to 1:1-1:2. When no immunosuppressive method was associated with the plasma exchange, the antibodies returned to their initial level within the 24 hr that preceded the transplantation, and the graft was rejected as in nontreated animals. When an immunosuppressive method was associated with the plasma exchange, and particularly in the case of CsA, the titers remained low, and the hyperacute rejection was delayed. Therefore, it can be concluded that plasma exchanges, associated with CsA, are an efficient experimental protocol in the rat to increase the survival time of guinea pig heart xenografts. The effect of the treatment is correlated with the decrease in natural cytotoxic antidonor antibodies.