摘要:

Background.Patients are at an increased risk for developing malignancies after transplantation. Lymphomas, skin malignancies, Kaposi’s sarcomas, and cervical/vulvar neoplasms are the most common, but visceral malignancies are also well documented, with a reported frequency ranging from 1% to 6%. These visceral tumors represent a mix of neoplasms that were clinically occult at the time of transplantation and those that arise de novo after transplantation. Little information, however, is available on the frequency of clinically occult malignancies at the time of transplantation and their contribution to the number of posttransplant malignancies.Methods.A retrospective study was performed of all patients who received an organ transplant from January 1981 to June 1997 and died within 100 days, a time interval in which epithelial malignancies found at autopsy were presumed to have been present, but clinically occult, at the time of transplantation.Results.A total of 375 patients were studied who received the following organ transplants: 231 liver, 52 heart, 26 heart and lung, 32 lung, and 34 kidney. Eleven malignancies were identified for an overall frequency of 2.9% and included three thyroid carcinomas, three carcinoids of the small bowel, two lung carcinomas, one laryngeal carcinoma, one renal cell carcinoma, and one seminoma.Conclusion.The 2.9% frequency of malignancies seen in this study suggests that a small, but significant, number of patients have occult malignancies at the time of transplantation and that these occult tumors contribute substantially to the number of malignancies that present clinically after transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary endpoints of the present, prospective, randomized multi-center, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade ≥3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation.Methods.A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher’s exact test were used for comparisons between groups.Results.After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%,P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%,P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day,P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups.Conclusions.The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.The aim of this study was to establish the outcome of renal transplantation in patients given pretransplant erythropoietin (EPO) treatment targeted at reaching a normal hemoglobin concentration (Hb), compared to those given EPO-treatment aimed at maintaining subnormal Hb.Methods.A total of 416 patients from Scandinavian countries and with renal anaemia were enrolled to examine the effects of increasing Hb from a subnormal level (90–120 g/liter) to a normal level (135–160 g/liter) by EPO treatment. Half of the patients were randomized to have their Hb increased, with the other half randomized to maintain a subnormal Hb. Thirty-two patients from the normal Hb group and 24 patients from the subnormal group received a renal graft during the study period. The outcomes of these transplantations were examined prospectively for 6 months.Results.Preoperative Hb levels were 143±17 and 121±14 g/liter in the two groups, respectively(P<0.0001). The Hb remained higher in the normal Hb group during the first 2 weeks after transplantation. The percentage of patients requiring postoperative blood transfusions in the normal Hb group was 16%, compared with 50% in the subnormal group (P<0.01). No statistically significant difference in the proportion of functioning grafts or in the serum creatinine levels could be detected. No correlation between EPO treatment and creatinine levels after transplantation was found. The frequency of adverse events was similar in the two groups.Conclusions.EPO treatment aimed at reaching a normal Hb in renal transplant recipients reduces the postoperative requirement for blood transfusions and has no deleterious effects on kidney graft function.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Simultaneous pancreas-kidney transplantation (SPK) ameliorates the progression of microvascular diabetic complications but the procedure is associated with excess initial morbidity and an uncertain effect on patient survival when compared with solitary cadaveric or living donor renal transplantation. We evaluated mortality risks associated with SPK, solitary renal transplantation, and dialysis treatment in a national cohort of type 1 diabetics with end-stage nephropathy.Methods.A total of 13,467 adult-type 1 diabetics enrolled on the renal and renal-pancreas transplant waiting list between 10/01/88 and 06/30/97 were followed until 06/30/98. Time-dependent mortality risks and life expectancy were calculated according to the treatment received subsequent to wait-list registration: SPK; cadaveric kidney only (CAD); living donor kidney only (LKD) transplantation; and dialysis [wait-listed, maintenance dialysis treatment (WLD)].Results.Adjusted 10-year patient survival was 67% for SPK vs. 65% for LKD recipients (P=0.19) and 46% for CAD recipients (P<0.001). The excess initial mortality normally associated with renal transplantation and the risk of early infectious death was 2-fold higher in SPK recipients. The time to achieve equal proportion of survivors as the WLD patients was 170, 95, and 72 days for SPK, CAD, and LKD recipients, respectively (P<0.001). However, the adjusted 5-year morality risk (RR) using WLD as the reference and the expected remaining life years were 0.40, 0.45, and 0.75 and 23.4, 20.9, and 12.6 years for SPK, LKD, and CAD, respectively. There was no survival benefit in SPK recipients ≥50 years old (RR=1.38,P=0.81).Conclusions.Among patients with type 1 DM with end-stage nephropathy, SPK transplantation before the age of 50 years was associated with long-term improvement in survival compared to solitary cadaveric renal transplantation or dialysis.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Because of the poor outcome of hepatic retransplantation, it is still debated whether this procedure should be performed in an era of donor organ scarcity. The aim of this study was to analyze outcome of hepatic retransplantation in children, to identify risk factors influencing this outcome, and to assess morbidity and causes of death.Methods.A series of 97 children after a single transplantation and 34 children with one retransplantation was analyzed.Results.The 1-, 3-, and 5-year survival of children with a retransplantation was 70, 63, and 52%, respectively, compared with 85, 82, and 78%, respectively, for children after a single transplantation (P=0.009). Survival of children with a retransplantation within 1 month after primary transplantation was worse (P=0.007) and survival of children with a late retransplantation was comparable (P=0.66) with single transplantation. In early retransplantations, the Child-Pugh score was higher, donors were older and weighed more, and more technical variant liver grafts were used compared with single transplantations. Biliary atresia and a high Child-Pugh score were associated with decreased patient survival after retransplantation. Sepsis was the most important complication and cause of death after retransplantation.Conclusions.Retransplantation is a significant event after pediatric liver transplantation. Outcome after hepatic retransplantation in children is inferior compared with single transplantation. This difference is explained by low survival after early retransplantation and can be explained by the poor clinical condition of the children at time of retransplantation, especially in children with biliary atresia, and by the predominant use of technical variant liver grafts in retransplantations.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Preliminary results of short-term famciclovir and lamivudine therapy in patients with hepatitis B virus (HBV) infection after liver transplantation revealed promising results. In a retrospective study the efficacy of long-term treatment with these substances was compared.Methods.A total of 53 HBV-infected adults (48 reinfections and 7 de novo infections) received antiviral treatment. A total of 32 of these patients were treated with famciclovir 3×500 mg, 20 of them were later switched to lamivudine. Fourteen patients received lamivudine, 150 mg/day orally, as first line therapy and 7 patients after failure of famciclovir-prophylaxis. Follow-up time was 8 to 62 months (mean 35 months). Response to therapy (HBV-DNA negative) was compared using Kaplan-Meier estimates. Potential influence factors (HBV-DNA and HBeAg pretransplant, HDV coinfection, pretreatment with famciclovir and immunosuppression) on treatment response were analyzed by log. Rank test (univariate); then a multivariate analysis (Cox multiple stepwise regression model) was applied.Results.A total of 19 and 76% of the patients treated with famciclovir and lamivudine resp. became HBV-DNA negative; 0 and 24% HBsAg negative. Lamivudine was also effective as second line therapy. In a multivariate analysis of all 73 treatment courses, lamivudine treatment and HDV-coinfection were significant factors for better treatment response; regarding only the lamivudine group, negative HBeAg pretransplant was significant. Viral breakthrough after prolonged treatment occurred in 55% (lamivudine) to 80% (famciclovir) of treatment courses but was only accompanied by mild hepatitis.Conclusions.Lamivudine and famciclovir are potent drugs for the treatment of HBV-infection after liver transplantation. The antiviral capacity of lamivudine is superior even after pretreatment with famciclovir but after prolonged treatment viral breakthrough is often observed.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Liver allografts in spontaneously tolerant strain combinations can protect other organs of the same donor origin from rejection and reverse ongoing rejection in previously placed grafts. The aims of this study were to examine whether liver allografts have the same protective effect on islet allografts and to investigate the underlying mechanisms.Methods.PVG islets were transplanted beneath the kidney capsule of streptozotocin-induced diabetic DA rats with or without liver allografting. The cellular infiltrate, and the extent of apoptosis and of Fas ligand (FasL) expression in the islet grafts were evaluated on days 2, 4, and 7 after transplantation by means of immunostaining and the in situ terminal deoxynucleotide transferase-mediated dUTP nick end labeling assay. Donor and recipient mixed lymphocyte reactions (MLR) were determined at 7 days or 100 days after islet transplantation.Results.Islet allografts transplanted alone were rapidly rejected within 5-8 days. Rejection was delayed, but not prevented, when islets were transplanted simultaneously with the liver. Liver transplantation 1 month before islet transplantation resulted in long-term survival (>100 days) of islet grafts in three of seven animals, whereas the other four died of liver rejection with functional islet grafts. Liver transplantation on day 4 after islet grafting reversed ongoing islet rejection and led to indefinite islet graft survival in three of seven cases. There was a progressive increase of cellular infiltration in all of the islet allografts, but the intensity of the infiltrate did not correlate with the outcome of the islet allografts. Islet rejection was characterized by an early dominance of monocytes/macrophages and CD25+T cells in the infiltrates, a high incidence of apoptotic &bgr; cells in grafts, and a sensitized status in the MLR. Tolerance of islet allografts was associated with increased numbers of dendritic cells in the graft infiltrates, up-regulation of FasL, and prominent apoptosis of alloreactive leukocytes in the islet grafts, as well as donor-specific MLR suppression in long-term survivors.Conclusions.These results demonstrate that the extent of the protective effect of liver transplantation on islet allografts varies with the time of liver grafting, ranging from delay in islet rejection to complete islet acceptance. Islet graft tolerance induced by liver transplantation is the result of an immune process that involves up-regulation of Fas ligand expres-sion on, and apoptosis of, islet graft infiltrating lymphocytes.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Hepatic ischemia/reperfusion (I/R) injury is associated with early and late graft failure after liver transplantation. A major mechanism is leukocyte adhesion to endothelium followed by release of reactive oxygen intermediates. We examined whether desferriexochelin 772SM (D-Exo), a lipid soluble iron chelator that prevents hydroxyl radical formation, can enhance the capacity of recombinant P-selectin glycoprotein ligand immunoglobulin (rPSGL-Ig), a glycoprotein that binds to P-selectin and inhibits neutrophil adhesion, to protect against I/R injury in an ex vivo rat liver model.Methods.Rat livers were harvested and stored for 6 hr at 4°C in University of Wisconsin solution and then perfused with oxygenated whole blood for 2 hr. Three groups were studied (n=6 rats/group): an untreated control group; a group that received 0.4 mg/kg rPSGL-Ig intraportally at the time of harvest; and a group that received 0.4 mg/kg rPSGL-Ig plus 1 &mgr;mol D-Exo intraportally both at the time of harvest and at the onset of reperfusion. Liver portal venous blood flow was assessed during perfusion, and at the end of each experiment, liver samples were collected for blinded histological evaluation and biochemical analyses.Results.Livers treated with D-Exo + rPSGL-Ig had significantly higher blood flow than livers treated with rPSGL-1Ig alone (P<0.05), and both treatment groups had higher blood flow than controls (P<0.001). Production of carbonyl proteins, a protein oxidation product, was significantly reduced in the D-Exo + rPSGL-1Ig group (P<0.02 vs. controls), but not in the rPSGL-Ig alone group. Total reduced glutathione was significantly higher than controls in the D-Exo + rPSGL-Ig group (P<0.001 vs. controls), but not in the rPSGL-Ig alone group, indicating less oxidative stress in the D-Exo-treated group. Production of malondialdehyde, an index of lipid peroxidation, was significantly less than controls in both treatment groups (P<0.03). Histopathological findings paralleled these results with Banff’s scores of 3.3±0.5, 1.8±0.4, and1.3±0.5 in the control, rPSGL-Ig alone, and D-Exo plus rPSGL-Ig groups, resp.Conclusion.rPSGL-Ig provides partial protection against I/R injury to ex vivo rat livers; however, the addition of D-Exo substantially increases protection by reducing oxidative injury. These findings may have clinical relevance in preventing the consequences of I/R injury after liver transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is a potent immunosuppressive agent used in clinical organ transplantation.MPA preferentially inhibits the type II isoform of inosine monophosphate dehydrogenase, depletes GTP, suppresses transfer of mannose and fucose to glycoproteins, and prevents lymphocyte proliferation in vivo. Whether MMF can also delete activated T cells in vivo by triggering an apoptotic signal was addressed in this study. To this end we analyzed the activity of MMF in mice injected with the bacterial superantigen staphylococcal enterotoxin B (SEB). Superantigens bind to MHC class II molecules without requirement for processing, and activate subsets of CD4+and CD8+T cells whose T cell receptor &bgr; chains express V&bgr; family-specific homologous sequences. This model that shares several features with direct allorecognition has the unique advantage of allowing a precise monitoring of activated T cells.Methods.BALB/c mice treated with MMF (100 mg/kg/day) or vehicle were injected with SEB. Serum cytokines, CD4+and CD8+V&bgr;8+cells were monitored in blood and lymphoid tissues, and apoptosis was determined by externalization of membrane phosphatidyl serine, double strand DNA breaks, and expression of B220 antigen by V&bgr;8+cells.Results.MMF treatment decreased tumor necrosis factor &agr;, interferon &ggr;, and interleukin-10 secretion induced by SEB. It did not modify other early activation events (blast transformation, CD69 and CD25 expression) but completely inhibited SEB-induced expansion of V&bgr;8+cells by inducing apoptosis of SEB-reactive T cells. A similar effect was observed in CD95-ligand-deficient mice. Repeated SEB injections associated with MMF resulted in a marked decrease of CD8+V&bgr;8+T cells. SEB-induced increase of V&bgr;8+thymocytes was not prevented by MMF treatment.Conclusion.Results obtained in this in vivo model suggest that MMF treatment may induce deletion of activated peripheral T cells and decrease early cytokine responses.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Primary nonfunction resulting in immediate graft loss is responsible for the failure of a large number of islet transplants. Evidence is accumulating to single out endotoxin contamination of the various reagents needed for islet isolation as a major cause of early graft loss.Methods.Islets isolated with endotoxin-containing (400 endotoxin units/ml) collagenase type V and “endotoxin-free” (3.1 endotoxin units/ml) Liberase™ were compared. Graft function was assessed using a syngeneic murine model of marginal islet mass transplantation. Pro-inflammatory cytokine production by islets was measured by ELISA in culture supernatants, and quantitative reverse transcriptase-PCR. Islet cell apoptosis was measured using the annexin assay.Results.Graft function was significantly delayed when islets were isolated with endotoxin-containing collagenase. Addition of endotoxin to the Liberase™ solution similarly delayed graft function. After 18 hr in culture, collagenase-isolated islets released higher amounts of proinflammatory cytokines compared with Liberase™-isolated islets (interleukin-6: 2185±1174 pg/ml vs. 520±201 pg/ml; tumor necrosis factor-&agr;: 304±298 pg/ml vs. 0; IL-1&bgr;: 12.5 pg/ml±12.5 vs. 0). This observation correlated with higher cytokine mRNA expression in collagenase-isolated islets. The percentage of apoptotic islet cells immediately after isolation was 17.2%±9.4 in collagenase-isolated islets and 7.1%±2.1 in Liberase™-isolated islets.Conclusions.We propose that endotoxin contamination is the primum movens of a chain of events that involves intra-islet cytokine production and release and islet cell apoptosis, and endotoxin contamination can ultimately lead to primary nonfunction in vivo. This emphasizes the fact that using endotoxin-free reagents during isolation is a key factor for successful islet transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID