摘要:

Background.Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, inhibits coronary transplant vasculopathy in the clinical setting. To further delineate the immune modulatory effect of this agent, it was tested in a rat cardiac transplant model of chronic rejection.Methods.Rat heterotopic abdominal cardiac transplants were performed using a Lewis to Fischer 344 combination. Fischer 344 recipients received a brief course of cyclosporine to decrease the incidence of acute rejection. Experimental groups were treated with either high-dose (10 mg/kg) or low-dose(5 mg/kg) pravastatin for 120 days, while a control group did not receive pravastatin. The effect of pravastatin on chronic rejection of cardiac allografts was analyzed by histology, and the expression of laminin, fibronectin, macrophages, and T cells was assessed by immunohistochemistry.Results.Coronary transplant vasculopathy was inhibited in both groups of pravastatin-treated animals, as compared with controls. Immunohistochemistry revealed that control animals had degraded laminin and fibronectin which paralleled the degree of tissue necrosis. In contrast, pravastatin-treated animals had modest amounts of extracellular matrix proteins retained within intermyocytes and endothelium, a pattern seen in native cardiac tissue. The pravastatintreated groups also had fewer graft-infiltrating macrophages, specifically within the arterial intima and perivascular areas.Conclusions.Progressive chronic vascular rejection, a leading cause of allograft failure, can be inhibited by pravastatin in a well-defined rat cardiac transplant model. Pravastatin appears to inhibit the synthesis and subsequent degradation of extracellular matrix proteins and block the infiltration of macrophages to the graft, which emphasizes that this inflammatory cell plays a major role in the pathogenesis of transplant chronic rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Fas ligand (FasL) induces apoptosis of cells bearing its receptor Fas, and has been shown to be important in T-cell development and regulation and in immune privilege. We hypothesized that FasL expression by renal allografts might provide protection from rejection.Methods.The murine FasL cDNA was cloned into a replication-defective adenovirus (AdV-FasL). Protein expression was confirmed by immunostaining of AdV-FasL-transduced HeLa cells. Allogeneic kidney transplants were performed between WF (RT1u) donors and Lewis(RT1) recipients. Donor kidneys were perfused in situ with saline alone (control), or 9×109plaqueforming units of AdV-FasL. One native kidney was removed at the time of transplant and the other at 6 or 7 days. Uremic death was the endpoint, and deaths within 7 days of transplant were excluded. Transduced allografts were stained for FasL expression using a monoclonal antibody and tested for FasL mRNA production by reverse transcriptase-polymerase chain reaction and Northern blotting.Results.Immunostaining of AdV-FasL-transduced allografts demonstrated efficient gene transfer lasting approximately 2 weeks, and FasL mRNA production in the AdV-FasL-transduced allografts was confirmed by Northern blotting and reverse transcriptase-polymerase chain reaction. Mean survival of animals with AdV-FasL-transduced renal allografts was 27.8 days vs. 11.6 days in control animals (P<0.05).Conclusions.(1) Adenoviral vectors can successfully transduce rat kidneys with the FasL cDNA. (2) FasL gene transfer prolongs rat renal allograft survival.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.The aim of this study was to compare the effects of Euro-Collins and University of Wisconsin solutions on pulmonary mitochondrial function after cold ischemia and subsequent warm reperfusion.Methods.Seventeen pigs underwent lung harvesting after classical lung flush with either University of Wisconsin or Euro-Collins solutions. The mitochondria were isolated from fresh swine lungs, from swine lungs subjected to 24 hr of cold ischemia, and from swine lungs subjected to 24 hr of ischemia followed by 30 min of subsequentex vivoreperfusion at 37 °C with Krebs-Henseleit buffer solution and air ventilation. Mitochondrial oxidative phosphorylation parameters were determined in isolated mitochondria by in vitro measurement of oxygen consumption rates. During reperfusion, the lung function was assessed by the pulmonary aerodynamic parameters and the pulmonary vascular resistance.Results.Relative to controls, mitochondria submitted to cold ischemia showed an alteration in the oxidoreductase activities of the respiratory chain. However, the yield of oxidative phosphorylation was conserved. After reperfusion, pulmonary mitochondria underwent a significant worsening in the oxidoreductase activities of the respiratory chain, and a decrease in the respiratory control and the efficiency of oxidative phosphorylation. Meanwhile, the reperfused lungs showed evidence of early dysfunction, assessed by the aerodynamic parameters and pulmonary vascular resistance. In this model, there was no advantage of University of Wisconsin solution over Euro-Collins solution.Conclusions.The mild mitochondrial alterations after cold ischemia were not sufficient to explain the limited tolerance of lung to ischemia. After reperfusion, the mitochondrial damage was more severe and could be involved in the posttransplant lung dysfunction.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Fatty livers are more prone to primary nonfunction after transplantation. We hypothesized that sinusoidal lining cells (SLCs) in fatty livers of obese Zucker rats are more susceptible to ischemia/reperfusion injury than in normal livers.Methods.Cold University of Wisconsin solution-preserved (30 min or 24 hr) livers from obese and lean Zucker rats were perfused ex vivo for 90 min with oxygenated warm acellular buffer containing hyaluronate. Bile output, alanine transferase, and hyaluronate clearance were measured during reperfusion. Trypan blue was infused at completion of reperfusion to assess cell membrane integrity. Another group of 24-hr preserved livers were reperfused with cold hypoxic buffer to differentiate the effects of preservation from reoxygenation.Results.After 30 min of preservation, fatty livers had significantly decreased flow (1.9 vs. 2.6 ml/g/min), increased resistance, decreased hyaluronate clearance (17 vs. 35 μg/g liver) and lower bile output (13 vs. 42 μl/g) in comparison with normal livers. Hepatocyte and SLC trypan blue uptake were minimal and similar in both groups. After 24 hr of preservation, flow (2.0 vs. 2.0), resistance, hyaluronate clearance, and bile output were similar in both fatty and normal livers. The SLC trypan blue uptake was increased but similar in both groups (22 vs. 20%). In contrast, a significantly greater number of hepatocytes were trypan bluestained in fatty livers (32 vs. 0.6%), accompanied by a marked increase in lactate dehydrogenase and alanine transferase release. Hypoxic reperfusion caused a significant decrease in hepatocyte and SLC trypan blue uptake.Conclusions.Fatty livers demonstrate impaired hepatocyte and SLC function, after even a very brief preservation. With increasing preservation, hepatocytes appear to be more susceptible to injury than SLCs. Reoxygenation appears to be important in triggering this event.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Natural antibodies (NAbs) against a terminal α1-3 galactosyl(αGal) epitope have been identified as the major human anti-pig NAbs.Methods and Results.We used two synthetic αGal trisaccharides-type 6 (αGal6) and type 2(αGal2)-linked to an inert matrix to remove NAbs from human plasma in vitro. Flow cytometry indicated that an average of 85% of the NAb binding activity was depleted by adsorption with αGal6. By measuring the binding of NAbs to pig peripheral blood mononuclear cells and bone marrow cells, we demonstrated that αGal6 was more effective than αGal2 in removing NAbs, and the combination of αGal6 + αGal2 did not further increase removal of NAbs. The specificity of the removal of NAbs (IgM and IgG) reactive with the αGal epitope by αGal6 matrix was shown by enzyme-linked immunosorbent assay. In vivo studies in nonhuman primates compared plasma perfusion through a αGal6 immunoaffinity column with hemoperfusion through a pig liver for changes in blood pressure, hematocrit, platelets, and NAb adsorption.Conclusions.Both methods reduced the level of anti-pig IgM and IgG xenoreactive antibodies to nearly background, but column perfusion caused less hypotension and reduction in platelets than liver perfusion. Four pig kidneys transplanted into monkeys after column perfusion did not undergo hyperacute rejection, remaining functional for 2-10 days, with a mean functional period of 7 days, demonstrating that a pig kidney can support renal function in a primate.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Mycophenolate mofetil (MMF) prolongs allograft survival in experimental animals, prevents acute rejection in humans, and has recently been approved for use in renal transplantation in combination with cyclosporine. Tacrolimus (Prograf) has been shown to be effective for the prevention and treatment of allograft rejection in liver transplantation. However, there has been limited experience with the combination of tacrolimus and MMF in liver transplantation.Methods.This retrospective pilot study examined the results in 130 primary, consecutive, adult liver transplants under two separate immunosuppressive protocols. Patients in the study group received MMF (1 g p.o. b.i.d.), tacrolimus (0.1 mg/kg p.o. b.i.d.), and a standard steroid taper. MMF was also tapered and then discontinued within 3 months of transplantation. A historical control received tacrolimus (0.15 mg/kg p.o. b.i.d.) and the same steroid taper.Results.Pretransplant demographics, including creatinine, were not significantly different between the groups. The 6-month patient and graft survivals of 96.3% (control) versus 92.0% (study) were not significantly different. The incidence of acute rejection was 45.0% in the control group versus 26.0% in the study group (P=0.03). The study group had a lower incidence of rejection (mean episodes/patient ± SEM): 0.28±0.07 vs. 0.61±0.10 (P=0.007). All of the study group members responded to high-dose steroids. In the control group, three patients required monoclonal antibody therapy and two patients required the addition of MMF. The incidence of cytomegalovirus was similar in the study group and the control group (13.8% vs. 10.0%,P=NS). Early renal function was better preserved in the tacrolimus/MMF group (mean creatinine ± SEM): 1.09 mg/dl ± 0.05 vs. 1.51 mg/dl ± 0.08 at 30 days,P=0.0001. The study design required dosing with less tacrolimus (mean mg/day ± SEM), which was achieved at 1 week (23.2±0.7 vs. 13.5±0.5); 1 month (18.7±0.8 vs. 11.4±0.5); 3 months (14.5±0.6 vs. 9±0.5); and 6 months(11.6±0.6 vs. 8.2±0.6);P=0.0001, for all time points.Conclusion.Combination therapy with tacrolimus and MMF may significantly reduce the incidence of acute liver allograft rejection, allow a significant reduction in tacrolimus dosage, and decrease the incidence of nephrotoxicity. Long-term analysis will be necessary to assess any increased risk of opportunistic infections.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Liver allografts of PVG(RT1c)→DA(RT1a) are spontaneously accepted, whereas pancreas, heart, and kidney allografts are rejected. Our previous studies have shown that simultaneous liver and pancreas transplantation prevents pancreas allograft rejection. The aim of this study was to examine the effect of liver transplantation on subsequent pancreas allografts and on ongoing pancreas rejection.Methods.Heterotopic, duct-ligated segmental pancreas grafts were transplanted into streptozotocin-induced diabetic recipients (60 mg/kg body weight i.p.) with or without orthotopic liver grafting at different times. Experimental design was as follows. Group 1 received PVG→PVG pancreas syngrafts (n=6); group 2, PVG→DA pancreas allografts (n=7); groups 3-5, PVG→DA pancreas allografts followed by liver transplantation on day 2(n=6), on day 4 (n=5), and on day 6 (n=5), respectively, group 6, PVG→DA pancreas allograft's after liver transplantation at 4 weeks (n=6).Results.The results showed that pancreas allografts in group 2 were rejected from postoperative day 7 to 13. Liver transplantation prevented subsequent pancreas allograft rejection in group 6. Ongoing pancreas rejection was reversed by liver transplantation with subsequent graft acceptance in groups 3-5. Significant graft-infiltrating lymphocyte apoptosis was demonstrated at 2 weeks in pancreas transplants associated with liver grafting. Graft-versus-host disease was not detected in the pancreas recipients.Conclusions.We conclude that pancreas allografts in the PVG→DA combination are rejected rapidly with median survival time of 9 days. Liver transplantation can protect subsequent pancreas grafts from rejection and reverse ongoing pancreas graft rejection with subsequent pancreatic acceptance. Graft-infiltrating lymphocyte apoptosis may be associated with the process of graft acceptance.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Biliary anastomotic complications remain a major cause of morbidity in liver transplant recipients, ranging between 10% and 50% in large clinical series. An end-to-end choledochocholedochostomy with or without T tube (CDCD EE with T tube and CDCD EE w/o T tube) and a Roux-en Y choledochojejunostomy have been standard methods for biliary drainage.Methods.The objectives of this retrospective study were to: (1) evaluate the incidence of biliary tract complications using a new method of side-to-side choledochocholedochostomy without T tube (CDCD SS w/o T tube) and (2) compare the results of CDCD SS w/o T tube with those of CDCD EE with T tube and CDCD EE w/o T tube. From September 1991 through June 1996, 279 orthotopic liver transplants were performed in 268 patients and followed through December 1996(minimum of 6 months' follow-up). A total of 227 CDCD anastomoses in 220 patients were studied (7 retransplants >30 days): CDCD EE with T tube(n=124), CDCD EE w/o T tube (n=44), and CDCD SS w/o T tube (n=59).Results.Sixty-nine biliary complications were observed in 220 patients(30%). Anastomotic and/or T-tube leaks were seen in 43 patients (19%), and anastomotic strictures were found in 26 patients (12%). Forty patients (18%) required percutaneous or endoscopic stent placement (6%) or surgical interventions (12%). CDCD EE with T tube had the highest incidence of biliary leak requiring rehospitalization but the lowest anastomotic stricture and intervention rate and the lowest 6-month mortality rate.Conclusions.CDCD EE with T tube was superior to CDCD EE or CDCD SS w/o T tube despite the increased number of rehospitalizations. CDCD SS w/o T tube did not offer significant advantages over conventional biliary anastomotic techniques.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Leukocytosis without a recognizable etiology often poses a diagnostic and therapeutic dilemma in transplant recipients.Methods.Fifty consecutive episodes of leukocytosis in 47 liver transplant recipients were prospectively assessed.Results.Leukocytosis was documented in 70% (33/47) of the patients, whereas 30% (14/47) of the patients never developed leukocytosis. Three distinctive etiologies accounted for 82% of the episodes. Thirty-two percent (16/50) of the episodes occurred between 1 and 3 days after transplantation, were unaccompanied by fever, and resolved spontaneously within 2 days. Infections accounted for 28% (14/50) of the episodes of leukocytosis; median time to onset was 25 days after transplantation, and fever occurred in 57%. In 22%(11/50) of the episodes, a characteristic leukocytosis occurred 7-14 days after transplantation (in the absence of documented infections or rejection) that was unaccompanied by fever, and resolved spontaneously without antibiotics; the platelet count of these patients was significantly higher than those of postoperative (P<0.01) or infectious leukocytosis (P<0.05). Resolution of pretransplant hypersplenism, with the release of sequestered splenic granulocytes and platelets, was the likely cause. Rejection and corticosteroid boluses accounted for 4% and 8% of the episodes, respectively.Conclusions.Timing of onset and awareness of the patterns of leukocytosis can be valuable in the evaluation of posttransplant leukocytosis. Stable patients with leukocytosis, but without fever or documented infections, in the immediate postoperative period and between 7 and 14 days after transplantation, need not be empirically treated with antibiotics.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.The organ shortage has increased interest in the use of“expanded criteria” donors (ECDs). Although much has been written concerning the clinical outcomes associated with the use of such donors, little has been published concerning the financial results associated with their use.Methods.A retrospective cost identification study of recipients of kidneys from expanded criteria cadaveric donors was used.Results.Of a total of 78 cadaveric renal transplants in fiscal year 1995, there were 38 kidneys (49%) transplanted from ECDs. Graft survival at 1 year was not statistically different between patients who received kidneys from ECDs and those who received non-ECD kidneys (84% vs. 85%, respectively). Length of stay (P<0.05), serum creatinine at 1 year after transplantation (P<0.01), and the percentage of patients requiring hemodialysis (P<0.05) were all higher among patients who received kidneys from ECDs. Cold ischemic time was significantly longer in patients who received kidneys from ECDs(31.4±12 hr vs. 24.0±9 hr;P<0.05). The total average and median costs were $12,190 and $10,911 higher in recipients of kidneys from ECDs as compared with non-ECD controls(P<0.01). Stepwise linear regression demonstrated that length of stay was the major clinical determinant of total costs; only the use of antilymphocyte induction was otherwise significantly associated. When kidneys from ECDs were transplanted into “high-risk” recipients (age >60 or retransplant patient), the average total costs were$15,311 more than when kidneys from ECDs were transplanted into non-high-risk patients (n=16 and 21, respectively;P<0.05) and$20,680 more than when a non-ECD, non-high-risk pairing was undertaken (n=26;P<0.05).Conclusions.Kidney transplantation with organs from ECDs is significantly more expensive than with organs from non-ECDs, even in the face of similar graft survival rates. Further study is needed to determine the cost-effectiveness of renal transplantation utilizing kidneys from ECDs vis-a-vis hemodialysis.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID