摘要:

Background.Pancreatic islets are susceptible to myriad insults that occur during islet isolation and transplantation. Studies demonstrated the role of Akt in regulating pancreatic &bgr;-cell growth and survival. Activation of Akt maintains Bad phosphorylation and prevents its binding to mitochondrial targets, decreases caspase-9 activity, and prevents the translocation of forkhead transcription factors (FKHR). Simvastatin activates Akt in mammalian cells; therefore, we investigated the role of simvastatin on human pancreatic islets (HPI) survival.Methods.HPI were treated with simvastatin, with and without LY294002, an inhibitor of phosphoinositide 3-kinase. PI viability was examined with ethidium bromide–acridine orange, and apoptosis was examined using a quantitative assay. Akt, Bad, FKHR phosphorylation, and mitochondrial cytochromecrelease were analyzed by Western blots. Caspase-9 activity was assessed by a fluorometric assay. A limited number of HPI were transplanted after simvastatin treatment in diabetic NOD-SCID mice.Results.Low levels of Akt phosphorylation (activation) were demonstrated early after islet isolation. Akt activation; increase in islet viability; and decrease in Bad phosphorylation, cytochromecrelease, caspase-9 activation, and translocation of FKHR were observed after simvastatin treatment, effects reversed by LY294002. Among recipients of islets without simvastatin, none demonstrated reversal of diabetes after the transplant. In contrast, 58% of the recipients given islets treated with simvastatin remained euglycemic 30 days after the transplant.Conclusions.Targeting the survival pathway with simvastatin exerts a cytoprotective effect on isolated PI. Activation of the Akt pathway is a potential new therapeutic approach to reduce loss of functional islet mass to bolster success in clinical islet transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Background.Progressive nephrotoxicity caused by calcineurin inhibitor drugs contributes to the long-term decline in renal function in kidney transplant patients.Methods.We conducted a randomized, prospective trial of calcineurin inhibitor drug avoidance in 61 adult primary kidney transplant recipients. Each patient received induction therapy with 20 mg basiliximab on days 0 and 4, and maintenance therapy with mycophenolate mofetil 1 g two times per day and steroids. Thirty-one patients received sirolimus, 5 mg daily after a 15-mg loading dose. Doses were then concentration-controlled to keep 24-hr trough levels at 10 to 12 ng/mL for 6 months and 5 to 10 ng/mL thereafter. Thirty patients began cyclosporine therapy at 6 to 8 mg/kg per day in divided doses and were then concentration-controlled to keep 12-hr troughs of 200 to 250 ng/mL.Results.Mean follow-up is 18.1 months (range, 12–26 months). The percentages of 1-year patient survival, graft survival, and biopsy-confirmed acute rejection rates were not significantly different between the sirolimus-treated patients (96.7%, 96.7%, and 6.4%, respectively) and the cyclosporine-treated patients (100%, 95.4%, and 16.6%, respectively). At 6 and 12 months, respectively, the sirolimus-treated patients enjoyed significantly better (P=0.008 andP=0.004) mean serum creatinine levels (1.29 and 1.32 mg/dL) and calculated creatinine clearances (77.8 and 81.1 mL/min) than cyclosporine-treated patients (1.74 and 1.78 mg/dL, and 64.1 and 61.1 mL/min, respectively). Sirolimus-treated recipients have significantly (P=0.001) higher 1-year trough levels of mycophenolic acid (4.16 ng/mL) than cyclosporine-treated patients (1.93 ng/mL). Sirolimus also delays the repopulation of basiliximab-depleted CD25+T cells compared with cyclosporine.Conclusions.Calcineurin inhibitor drug avoidance with basiliximab induction and sirolimus provides comparable 1-year transplant outcomes, with significantly better renal function in primary renal allograft recipients.

ISSN:0041-1337    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Background.Thrombotic microangiopathy (TMA) is a well-known complication after renal allograft transplantation. In most cases, calcineurin inhibitor is believed to play a role in the development of this disorder. Recent studies have shown that a deficiency in the activity of the von Willebrand factor–cleaving metalloprotease ADAMTS13 causes thrombotic thrombocytopenic purpura. A similar mechanism occurring in patients who develop TMA after renal transplantation has not been described.Methods.Analysis of plasma samples from a patient who developed TMA after receiving a cadaveric renal allograft revealed undetectable ADAMTS13 activity and the presence of its inhibitors.Results.Discontinuation of cyclosporine and daily plasma exchange increased the ADAMTS13 activity, which was followed by resolution of the microangiopathic hemolysis and improvement of the graft function. At 3-month follow-up, the ADAMTS13 activity remained in the normal range and no inhibitors were detected.Conclusions.This is the first case to demonstrate a correlation between the presence of ADAMTS13 inhibitors and transplant-associated TMA. Autoimmune inhibitors of ADAMTS13 should be considered in patients with transplant-associated thrombotic microangiopathy. The role of calcineurin inhibitor in the formation of autoantibodies to ADAMTS13 remains to be explored.

ISSN:0041-1337    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Objective.We compared the enzyme release from preserved and ex vivo reperfused livers after acute injury or inflammatory stimulus with organ function.Methods.Acute injury was induced by carbon tetrachloride and inflammation was induced by turpentine oil treatments. Livers were exsanguinated and preserved for 8 or 24 hr. Enzymes were measured in preservation and reperfusion solutions, and reperfused liver function was evaluated by O2consumption and bromsulphalein clearance.Results.The release of lysosomal enzymes was negligible in the preservation solution, and that of alanine aminotransferase and lactate dehydrogenase was similar in all groups. Release of aspartate aminotransferase and of EC 3.4.24.15 was more than that of the controls. During reperfusion liver function was normal in the injured group.Conclusion.Release of enzymes, mainly aspartate aminotransferase and EC 3.4.24.15, into the preservation solution is a sensitive and early indicator of either inflammatory or acute injury alterations of the preserved liver, but does not reflect organ malfunction.

ISSN:0041-1337    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Background.The aim of the present study was to examine the effect of tacrolimus (TAC) and prednisolone (PRE) in islet xenotransplantation and to use the immunosuppressive effects of these drugs and others to further characterize the mechanisms behind islet xenograft rejection.Methods.Fetal porcine islet-like cell clusters (ICCs) were transplanted under the kidney capsule in Lewis rats. The animals were treated with TAC, cyclosporine A (CsA) plus 15-deoxyspergualin (DSG), CsA plus sirolimus (SIR) or CsA plus leflunomide (LEF), with or without the addition of PRE. Rejection was assessed by immunohistological evaluation 12 days after transplantation. In selected groups, the intragraft cytokine mRNA expression was analyzed with real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR).Results.In untreated rats, the ICC xenografts were completely rejected. Treatment with PRE alone had no, or only a marginal, protective effect. TAC alone at a dose of 1 or 0.5 mg/kg of body weight (BW) prevented xenograft rejection. The addition of PRE to TAC treatment had a paradoxical unfavorable effect. In contrast, when PRE was added to CsA-based protocols (CsA+DSG, CsA+SIR, or CsA+LEF), the immunosuppressive effect was slightly enhanced. In comparison with untreated rats, the messengers for interleukin (IL)-1&bgr;, IL-2, IL-4, IL-10, interferon (IFN)-&ggr;, and tumor necosis factor (TNF)-&agr; were reduced in both CsA and TAC treated rats. Notably, the amount of IL-12p40 transcripts was only inhibited in rats given TAC alone, whereas this messenger was increased to approximately the same levels in untreated, CsA treated, and TAC plus PRE treated rats.Conclusions.TAC exerted a pronounced immunosuppressive effect in the pig-to-rat islet xenotransplantation model. So far, no other single drug protocol has shown a comparable efficacy. Notably, the graft protective effect of TAC was markedly abrogated when PRE was added to the treatment protocol, suggesting that TAC exerts its effect by a unique mechanism of action. In contrast with the other studied immunosuppressive regimens, treatment with TAC alone inhibited intragraft mRNA expression of all the Th1 associated cytokines, indicating that Th1 response is one important rejection mechanism that needs to be inhibited to achieve islet xenograft survival.

ISSN:0041-1337    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Background.Patients who undergo orthotopic liver transplantation (OLT) for Budd-Chiari syndrome (BCS) traditionally have been anticoagulated with warfarin postoperatively. Because a significant proportion of BCS patients are found to have an underlying myeloproliferative disorder (MPD), antiplatelet therapy may be a more rational treatment strategy for this subgroup.Methods.All patients who underwent OLT for the diagnosis of BCS at our institution through March 2000 were included in this analysis. Posttransplant therapy consisted of hydroxyurea and aspirin for those with MPDs. Standard anticoagulation or no antithrombotic treatment was given to BCS patients with other causes. Major posttransplantation complications (thrombosis and bleeding) and mortality were determined.Results.Seventeen patients underwent OLT for BCS at our institution. The mean follow-up was 68.4 months. Two of seventeen patients died; one patient died of recurrent thrombosis (124 months after OLT) and the other patient died of acute hepatitis B (7 months after OLT). Twelve patients (71%) had evidence of a MPD. Two of the MPD patients were treated with warfarin before the initiation of hydroxyurea and aspirin therapy. The remaining 10 MPD patients were placed on only hydroxyurea and aspirin after OLT. Anagrelide was used in place of hydroxyurea in two patients because of cytopenias caused by the latter agent. The mean follow-up of this group of 10 patients was 59.9 months. Only one patient experienced recurrent thrombosis, which occurred more than 10 years after the original transplant. There were no major bleeding complications and posttransplant liver biopsies were well tolerated.Conclusions.Antiplatelet therapy that consists of hydroxyurea and aspirin is a safe and effective alternative to anticoagulation to prevent recurrent thrombosis in MPD patients with BCS after liver transplantation. For patients with a hypercoagulable state corrected by OLT, antithrombotic therapy probably is not required. For those patients with conditions not corrected by OLT or with idiopathic BCS, anticoagulation or other therapy to control the hypercoagulable state should be given.

ISSN:0041-1337    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Background.Posttransplant lymphoproliferative disorders (PTLDs) that occur late after solid-organ transplantation are usually a monoclonal proliferation frequently characterized by the lack of the Epstein-Barr virus genome in tumor cells. The clinical outcome and the best management for patients who present with late PTLDs still remain unclear.Patients and Methods.Thirty patients who developed PTLDs more than 12 months (range 13–156) after heart, kidney, or liver transplantation were retrospectively evaluated. Median age was 36.7 years (range 1–70). Fifty-five percent of patients presented with advanced-stage (III–IV) lymphoma, 43% of patients presented with B symptoms, and 40% of patients showed extranodal involvement. Twenty-four cases (75%) were categorized as monoclonal monomorphic PTLD.Results.Three patients died of progressive multiorgan failure before any treatment was initiated. Overall, 17 (63%) patients obtained a clinical response (14 patients had complete remission [CR] and 3 patients had partial remission [PR]). Eight (47%) patients are still alive and in CR, two (12%) patients died in CR, and seven (41%) patients relapsed. With a median follow-up of 6 months (range 0.5–42.8), the median overall survival was 6.2 months. Both clinical response and survival were significantly influenced by the treatment. Indeed, all patients treated for limited disease with surgery or radiotherapy in combination with modulation of immunosuppression obtained CR and are still alive and in CR. On the contrary, 33% of patients who received chemotherapy obtained a clinical response, whereas 15% of patients who received chemotherapy showed progressive disease and 50% of patients who received chemotherapy died of toxicity (infectious or multiorgan failure).Conclusions.We suggest that patients with late PTLDs and limited disease may benefit from local treatment. For patients who require chemotherapy, we suggest that it should be administered to minimize the risk of infection complications.

ISSN:0041-1337    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Background.Posttransplant lymphoproliferative disorder (PTLD) is a well-known complication of organ transplantation that leads to death in more than 50% of cases. The aim of this work was to identify specific risk factors for lymphoproliferative disorders after liver transplantation in adults.Methods.A total of 480 consecutive patients who underwent transplantation between 1986 and 1997 were studied (323 men, 157 women; mean age: 49.8±10.4 years). Demographics, the indication for transplantation, the immunosuppressive regimens, the incidence of rejection episodes, and Epstein-Barr virus infection were analyzed. Univariate and multivariate analysis were used to identify factors predictive of PTLD.Results.Sixteen cases of PTLD (3.3%) occurred at a median of 5.5 (range, 1–39) months after liver transplantation. All 16 cases occurred in patients with evidence of exposure to Epstein-Barr virus before transplantation. In multivariate analysis, the use of antilymphocyte antibodies (P=0.007, relative risk [RR]=4.2, 95% confidence interval [CI]=1.5–11.7), age older than 50 years (P=0.037, RR=3.5, 95% CI=0.95–13.0), liver transplantation for hepatitis C virus cirrhosis (P=0.015, RR=8.7, 95% CI=1–78.3), and liver transplantation for alcoholic cirrhosis (P=0.015, RR=9.6, 95% CI=1.2–77.2) were independently associated with the onset of PTLD.Conclusion.Liver transplantation for hepatitis C virus-related and alcoholic cirrhosis and age older than 50 years are three additional risk factors for lymphoproliferative disorder independent of the use of antilymphocyte antibodies. The use of antilymphocyte antibodies after liver transplantation should be avoided in these categories of patients, especially those older than 50 years.

ISSN:0041-1337    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Background.Posttransplantation diabetes mellitus (PTDM) is a metabolic complication of renal transplantation. A high prevalence of DM has been recently reported in patients with chronic hepatitis C virus (HCV) infection in the nontransplant population. The aim of this study was to investigate possible factors that may have a role in the development of DM, including HCV infection in renal transplant recipients.Patients and Methods.This case-control study included 43 patients with PTDM (36 men, 7 women; mean age, 44±10 years) and 43 consecutive transplant patients who did not develop PTDM (30 men, 13 women; mean age, 37±11 years). Age, body mass index, high-dose steroid use, family history for DM and HCV, and presence of HLA-DR2, -DR3, and -DR4 were considered as possible factors for predicting PTDM.Results.Patients with PTDM were older (P=0.002) and had a higher prevalence of family history of DM (61% vs. 9%,P<0.001) and a higher rate of HCV seropositivity (72% vs. 37%,P=0.002; odds ratio = 1.94; 95% confidence interval = 1.26–2.98). The prevalence of pancreatic autoantibodies (anti-glutamic acid decarboxylase, islet cell antibody) was similar between patients with and without PTDM. In logistic regression analysis (r2= 0.61,P<0.001), age, family history, and HCV infection were independent variables for predicting development of PTDM.Conclusion.HCV infection was associated with the development of PTDM, in addition to family history and increased age. The rate of autoantibodies against pancreatic cells was not increased in patients with HCV, which suggested that nonimmunologic mechanisms were likely to have a role in the pathogenesis of PTDM.

ISSN:0041-1337    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Background.Preexisting alloantibodies against the mismatched HLA class I antigens of the donor, when present in current sera, are believed to be detrimental for kidney graft survival. The relevance of a positive crossmatch with historical sera only is still a matter of debate. Previous studies showed a correlation between the presence of alloantibodies and the presence of alloactivated cytotoxic T lymphocytes (CTLs). We wondered whether the persistence of activated CTLs might explain the poor results in a proportion of patients with a historical positive crossmatch.Methods.We tested 10 sensitized patients to determine whether activated CTLs persist when the antibodies disappear. Limiting dilution assays were performed in the presence and absence of cyclosporine (CsA) to distinguish between activated (primed) (CsA resistant) and naive (CsA sensitive) CTLs. To test the clinical relevance of the persisting CTLs, eight sensitized patients, who underwent a kidney transplantation across a positive historical crossmatch, were retrospectively tested for the presence or absence of activated donor-specific CTLs at the day of transplantation.Results.In the first group, four patients had CsA-sensitive CTLs, three patients had CsA-resistant CTLs, and three other patients had CsA-sensitive CTLs for a particular HLA antigen and CsA-resistant CTLs for another HLA antigen. In the transplant group, four patients with CsA-sensitive CTLs at the day of transplantation were found to have a good graft function. In the other four patients, the presence of CsA-resistant donor-specific CTLs was associated with rejection and early graft loss.Conclusion.The present study suggests that determining the activation state of CTLs specific for the HLA mismatch against which antibodies were present in historical sera, may be relevant to transplant outcome in patients who undergo transplantation across a positive historical crossmatch.

ISSN:0041-1337    

出版商:OVID    

年代:2002

数据来源: OVID