摘要:

Background.Portopulmonary hypertension, defined as mean pulmonary artery pressure >25 mmHg in the presence of a normal pulmonary capillary wedge pressure and portal hypertension, is a known complication of end-stage liver disease that has been associated with high morbidity and mortality at the time of liver transplantation. We have recently reported the successful treatment of portopulmonary hypertension with chronic intravenous epoprostenol and now report the first patient with severe portopulmonary hypertension successfully treated with epoprostenol who subsequently underwent successful liver transplantation.Methods.A patient with severe portopulmonary hypertension was treated with intravenous epoprostenol, 23 ng/kg/min, for a 4-month period, after which the portopulmonary hypertension resolved and the patient underwent successful liver transplantation.Results.The patient was discharged, continues to do well, and at 3 months is off epoprostenol with near normal pulmonary artery pressures.Conclusions.Chronic epoprostenol, in conjunction with a multidisciplinary, well-planned perioperative evaluation and treatment plan, may be the answer to a heretofore untreatable disease.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Nitric oxide (NO) is considered to be one of the endogenous inhibitory factors of ischemic reperfusion injury. In this study, the NO-producing ability of the preserved lung, flushed at various pulmonary artery pressures (flushing pressure), was studied during reperfusion using an ex vivo rabbit lung perfusion model.Methods.The lungs were flushed with 200 ml of preservation solution with flushing pressures adjusted to 15, 15, 20, and 25 mmHg for groups 1, 2, 3, and 4, respectively (n=5 in each group). In the control group (group 1), the heart-lung block was harvested after flushing and the lungs were assessed without preservation. In the other groups, the harvested blocks were preserved at 8°C for 24 hr and reperfused with homologous blood for pulmonary functional assessment. Pulmonary function was assessed by measuring mean airway pressure, mean pulmonary arterial pressure, partial oxygen tension of pulmonary venous effluent blood, and pulmonary wet-dry weight ratio. The sequential changes in the concentration of NO-related substances (NO-RS) in the serum of reperfused blood were also measured by chemiluminescence.Results.During reperfusion, biphasic increases in NO-RS were observed in all groups. In groups 3 and 4, the increases in NO-RS were significantly lower than those of groups 1 and 2, and pulmonary function deteriorated.Conclusion.These data suggest that in order to maintain the endogenous NO-producing ability of preserved lung, the flushing pressure must be less than 20 mmHg.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.One intravenous injection of freshly heparinized donor blood 7 days before transplantation significantly prolongs hepatic allograft survival from ACI (RT1a) to LEW (RT1l) rats. The aim of this study was to investigate hepatic allograft expression of neutrophil chemoattractant and tumor necrosis factor in immunologic unresponsiveness.Methods and Results.Cytokine-induced neutrophil chemoattractant levels in untreated hepatic allografts were significantly higher than in allografts treated with donor-specific transfusion. Additionally, more neutrophils infiltrated untreated than transfusion-treated hepatic allografts. The number of chemoattractant-positive cells was significantly lower in donor-specific transfused allografts than in untreated hepatic allografts. The number of ED1+mononuclear cells infiltrating portal areas of untreated allografts increased over time and expressed abundant cytokine-induced neutrophil chemoattractant mRNA during acute rejection. This correlated with significantly higher levels of chemoattractant mRNA in untreated allograft livers on postoperative day 5 as compared with transfusion-treated allografts. Serum concentrations of tumor necrosis factor-α in untreated hepatic allograft recipients increased over time and peaked on day 7, while those in transfused allografts were maintained at lower levels. Moreover, in vitro chemoattractant production by peritoneal macrophages responded in a dose-dependent manner to tumor necrosis factor-α.Conclusion.Donor-specific transfusion treatment decreases tumor necrosis factor-α and chemoattractant expression as well as neutrophil accumulation in hepatic allografts.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Posttransplant donor-specific bone marrow (BM) infusion in mice treated with antilymphocyte serum (ALS) induces specific unresponsiveness(tolerance) to skin allografts, which can be augmented by the adjuvant administration of chemotherapeutic immunosuppressive agents. The purpose of this study was to determine the optimal dose and timing of administration of sirolimus (rapamycin) to induce maximal skin allograft survival in ALS-treated, BM-infused recipients.Methods.DBA/2 donor skin grafts were placed on B6AF1 recipients (class I- and II-disparate). Groups of recipient mice (n=10 each) received combinations of the following treatment protocols: ALS, 0.5 ml on days -1 and 2; BM, 25×106donor-specific cells on day 7; sirolimus, 6, 12, 18, or 24 mg/kg at times indicated; and cyclosporine, 50 mg/kg at times indicated. The immune status of putatively tolerant animals was examined with mixed lymphocyte cultures, cell-mediated lympholysis assays (CML), and limiting dilution analyses.Results.When administered in conjunction with ALS/BM, a single dose of sirolimus (6 mg/kg) on days 21, 18, 14, 10, or 7 resulted in median skin graft survival times of 35, 26, 40, 46, and 103 days, respectively, versus a median survival of 27 days in mice given ALS and BM alone. The addition of cyclosporine to sirolimus (6 mg/kg) given on day 7 or days 7 and 10 did not significantly increase graft survival over that achieved with sirolimus alone. A single dose (18 or 24 mg/kg) of sirolimus administered on day 7 to ALS/BM-treated recipients resulted in 100% 200-day skin graft acceptance. Tolerant mice demonstrated nonspecific suppression of the mixed lymphocyte culture assays at 90 and 200 days and a nonspecific reduction of the CML assay at 50 days. By 200 days, the third-party CML response was restored, whereas donor-specific cell-mediated cytotoxicity remained suppressed. There was a donor-specific reduction in the number of alloreactive cytotoxic T lymphocyte clones by limiting dilution assay at 120 days. In vivo specificity of immunosuppression induced with this protocol was demonstrated by indefinite survival of second donor-specific skin grafts placed on putatively tolerant mice at day 90, whereas third-party skin grafts were rejected in 14 days.Conclusion.A single dose of sirolimus (18-24 mg/kg) administered on day 7, within the context of an ALS/BM immunosuppressive regimen, reliably induces permanent skin allograft acceptance in this model. In vitro measures of immunocompetence demonstrated an early nonspecific suppression of the recipients immune status and later recovery of third-party immunoreactivity. In vivo testing indicates an operationally tolerant state that is donor-specific 90 days after treatment.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.The influence of donor hematopoietic cell microchimerism on organ allograft survival has been studied largely in vascularized transplant models. Here, we examine the impact of donor bone marrow (BM) cells administered intravenously together with transient systemic tacrolimus therapy on microchimerism, the survival of nonvascularized cardiac allografts, and growth of donor antigen-presenting cells (dendritic cells [DCs]) from recipient BM.Methods.Adult male C3H (H2k) mice received heterotopic heart transplants from B10 (H2b) donors in the dorsal ear pinna. They were given no further treatment, or either a short course of tacrolimus (FK506; 2 mg/kg i.p. from day 0 to day 13), unmodified donor BM cells(50×106i.v. on day 0) or both treatments. Grafts were examined daily for contractile activity. Anti-donor cytotoxic T lymphocyte responses were determined in recipients' spleens. Microchimerism (IAb+cells) was demonstrated by immunocytochemical staining of spleens, and of cells expanded from recipient BM using cytokines and culture conditions that promote the growth of DCs.Results.Tacrolimus alone significantly prolonged median heart graft survival time from 10 to 22 days (P<0.001). BM alone failed to prolong graft survival. By contrast, tacrolimus + donor BM resulted in a mean survival time of 42 days (P<0.01 compared with tacrolimus treatment alone). This marked increase in heart allograft survival was associated with reduced anti-donor cytotoxic T lymphocyte responses attributable to a nonspecific effect of tacrolimus. In addition, however, a link was observed between the beneficial effect of donor BM and comparatively large numbers of donor major histocompatibility complex class II(IAb+)-positive cells in recipients' spleens, and in cultures of granulocyte-macrophage colony-stimulating factor + interleukin-4-stimulated DCs from recipients' BM. No donor-derived cells were propagated from heart graft recipients given either tacrolimus or donor BM alone.Conclusions.This nonvascularized organ transplant model demonstrates the positive effect on allograft survival of donor BM given at the time of transplant to transiently immunosuppressed recipients. The findings also reveal links between hematopoietic cell chimerism, the presence of donor DC progenitors in recipient BM, and organ allograft survival.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Ligament injuries of the knee are common and, if severe, can predispose to joint pain, instability, reinjury, and, ultimately, osteoarthritis. Xenograft replacement of ligaments could have potential; however, a limited understanding of the immunology of ligament xenograft rejection has inhibited their use. The purpose of this study was to characterize the antigenic elements of a fresh porcine tendon xenograft in a rabbit model and to provide a better understanding of what would need to be done to either block or extract these antigenic elements.Methods.Three experimental situations were evaluated in a pig to rabbit ligament transplantation model: subcutaneous implantation of fresh porcine patellar tendon (PPT), implantation of fresh PPT into a medial collateral ligament midsubstance gap, and replacement of the entire medial collateral ligament complex with either fresh or guanidinium hydrochloride-extracted PPT. Preimmune and immune sera were collected from rabbits and used to localize antigenic targets in PPT, meniscus, and cartilage with indirect immunofluorescence techniques. The reactivities of the same rabbit sera towards tissue extracts of PPT, meniscus, and cartilage by Western immunoblot analyses were used to characterize the antigenic components.Results.Indirect immunofluorescence with preimmune rabbit sera on PPT showed staining of tendon fibroblasts. Immune sera from rabbits transplanted with xenografts stained regions of the extracellular matrix of PPT. Fresh PPT induced antibodies that consistently recognized six extracellular matrix components with molecular masses of >200 kDa, 180 kDa, 135 kDa, 108 kDa, 63 kDa, and 59 kDa.Conclusions.Our results suggest that naturally occurring rabbit anti-pig antibodies of the IgG isotype recognize immunogenic components on tendon fibroblasts, whereas induced rabbit anti-pig antibodies recognize a specific subset of six extracellular matrix components of PPT. PPT xenografts appeared to induce a similar humoral immune response irrespective of graft location. Finally, our results indicate that selective extraction of PPT xenograft components before implantation altered the induced rabbit anti-pig antibody response; however, such extraction did not change the ultimate fate of the transplant tissue.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.In order to clarify the risk of hepatitis B virus (HBV) transmission from hepatitis B core antibody-positive (HBcAb(+)) donors and to evolve a new strategy to counter such a risk, we undertook a retrospective (1990-1995) and prospective (1995-1996) analysis of our experience with living related liver transplantation involving HBcAb(+) donors.Methods.Between June 15, 1990, and June 30, 1995, HBcAb(+) individuals were not excluded as donor candidates at our institutions. For 171 liver transplants, 16 donors were HBcAb(+). Between July 1, 1995, and June 30, 1996, HBcAb(+) individuals were generally excluded as donor candidates; however, three recipients were given liver grafts from HBcAb(+) donors because other donor candidates presented even higher risks. In the latter period, recipients with transplants from HBcAb(+) donors underwent prophylactic passive immunization with hyperimmune hepatitis B immunoglobulin (HBIG). The serum of 10 HBcAb(+) donors was examined by nested polymerase chain reaction for the presence of HBV-DNA, but it was not detected in any of them. However, the same examination of the liver tissue of five such donors yielded positive results in all cases.Results.In the first 5-year period, out of 16 recipients with HBcAb(+) donors, 15 became hepatitis B surface antigen-positive after transplant. The three recipients with HBcAb(+) donors during the second 1-year period, who were treated by prophylactic passive immunization with HBIG, remained hepatitis B surface antigen-negative and negative for serum HBV-DNA after transplant.Conclusions.HBV exists in the liver of healthy HBcAb(+) individuals, but not in the blood. Therefore, HBV is thought to be transmitted to recipients by liver grafts from the HBcAb(+) donors at a significantly high rate. The prevention of viral activation and clinical disease development by means of passive immunization with HBIG seems promising, although the follow-up period in our study may be too short for any definitive conclusions.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.One of the most controversial areas in patient selection and donor allocation is the high-risk patient. Risk factors for mortality and major infectious morbidity were prospectively analyzed in consecutive United States veterans undergoing liver transplantation under primary tacrolimus-based immunosuppression.Methods.Twenty-eight pre-liver transplant, operative, and posttransplant risk factors were examined univariately and multivariately in 140 consecutive liver transplants in 130 veterans (98% male; mean age, 47.3 years).Results.Eighty-two percent of the patients had post-necrotic cirrhosis due to viral hepatitis or ethanol (20% ethanol alone), and only 12% had cholestatic liver disease. Ninety-eight percent of the patients were hospitalized at the time of transplantation (66% United Network for Organ Sharing [UNOS] 2, 32% UNOS 1). Major bacterial infection, posttransplant dialysis, additional immunosuppression, readmission to intensive care unit(P=0.0001 for all), major fungal infection, posttransplant abdominal surgery, posttransplant intensive care unit stay length of stay (P<0.005 for all), donor age, pretransplant dialysis, and creatinine (P<0.05 for all) were significantly associated with mortality by univariate analysis. Underlying liver disease, cytomegalovirus infection and disease, portal vein thrombosis, UNOS status, Childs-Pugh score, patient age, pretransplant bilirubin, ischemia time, and operative blood loss were not significant predictors of mortality. Patients with hepatitis C (HCV) and recurrent HCV had a trend towards higher mortality (P=0.18). By multivariate analysis, donor age, any major infection, additional immunosuppression, posttransplant dialysis, and subsequent transplantation were significant independent predictors of mortality(P<0.05). Major infectious morbidity was associated with HCV recurrence (P=0.003), posttransplant dialysis(P=0.0001), pretransplant creatinine, donor age, median blood loss, intensive care unit length of stay, additional immunosuppression, and biopsy-proven rejection (P<0.05 for all). By multivariate analysis, intensive care unit length of stay and additional immunosuppression were significant independent predictors of infectious morbidity (P<0.03). HCV recurrence was of borderline significance (P=0.07).Conclusions.Biologic and physiologic parameters appear to be more powerful predictors of mortality and morbidity after liver transplantation. Both donor and recipient variables need to be considered for early and late outcome analysis and risk assessment modeling.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.There has been concern that the increased drug exposure associated with treatment with cyclosporine microemulsion (CsA-ME) would lead to an increase in adverse events.Methods.The long-term safety and tolerability of conventional cyclosporine(CsA) and CsA-ME were compared in a randomized, multicenter, pharmacoepidemiologic study involving 1097 stable renal transplant patients after 18 months of follow-up.Results.No significant difference was seen in change in serum creatinine or calculated creatinine clearance between the two groups. Episodes of deterioration in renal function (change in serum creatinine ≥20%) were categorized with the following results for CsA-ME versus CsA, respectively: acute rejection, 4.5% vs. 4.5%; chronic rejection, 8% vs. 11%; CsA nephrotoxicity, 12% vs. 7% (P=0.008); transient changes, 17% vs. 12%; other causes, 4% vs. 6%. During the first 6 months of the study, a transient increase in the incidence of gastrointestinal and neurological adverse events was seen in the CsA-ME group compared with the CsA group. Up to 18 months, patients in the CsA group reported significantly fewer hearing and vestibular disorders, but more cardiovascular problems than those in the CsA-ME group (P=0.035).Conclusions.Tolerance to CsA and CsA-ME was similar. Renal function over 18 months was not adversely affected by the increased drug exposure with CsA-ME, although there was a transient increase in nephrotoxicity. The frequency of acute and chronic rejection did not change.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Tumors of the bladder termed nephrogenic adenomas in kidney allograft recipients are believed to develop as urothelial metaplastic proliferations in response to mechanical trauma, chemical noxae, irradiation, and bacterial or viral pathogens. We report on the incidence of nephrogenic adenoma of the bladder in patients who received renal transplants during a period of 7 years and 3 months at the University Hospital of Vienna.Methods.Diagnosis was obtained by cystoscopy and histological analysis. Nephrogenic adenoma was treated by transurethral electroresection and administration of antibiotics in case of urinary tract infections. Follow-up consisted of cytological controls of urine and bladder irrigation fluid as well as of cystoscopy every 3 months.Results.In 7 of 1328 renal allograft recipients, nephrogenic adenoma could be detected after 7 to 60 months following renal transplantation. In five patients, recurrence was detected 9 to 23 months after diagnosis of the initial lesion. No evidence of malignant degeneration was observed in any patient. Nephrogenic adenoma was not related to immunosuppressive therapy, cytomegalovirus disease, or gancyclovir therapy.Conclusions.We suggest that after successful transurethral electroresection of nephrogenic adenomas, cytological controls are adequate every 3 months. Only in renal transplant patients with recurrence of voiding disturbances, macrohematuria, or urinary tract infection are cystoscopy and biopsy indicated in the routine follow-up regimen.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID