摘要:

The management of the liver transplant (OLT) candidate with portopulmonary hypertension (PPHTN) has dramatically changed in the past 3 years. Careful preoperative evaluation with functional characterization of right ventricular function plays a critical role. The pulmonary vascular response to epoprostenol infusion serves as a deciding factor for OLT candidacy. Careful perioperative attention to avoid right ventricular failure from acutely elevated pulmonary artery pressures or sudden increases in right ventricular preload is a key physiologic tenet of management. With increased surgical expertise, anesthetic sophistication, and availability of epoprostenol, PPHTN is no longer considered an absolute contraindication for OLT.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.The presentation of donor MHC class II-derived peptides by host antigen-presenting cells in the context of self-MHC class II molecules has been suggested as a mechanism for the chronic rejection of kidney and heart allografts. The aim of this study was to determine whether indirect allorecognition of HLA class I-derived peptides occurred in lung transplant (LTx) recipients and whether it correlated with the development of bronchiolitis obliterans syndrome (BOS).Methods.Peripheral blood mononuclear cells from LTx recipients were cultured with synthetic peptides corresponding to the hypervariable regions of the mismatched HLA class I antigens of the donor. Proliferation and precursor frequency (PF) of allopeptide reactive T cells were determined by the incorporation of [3H]thymidine into DNA and limiting dilution analysis.Results.Peripheral blood leukocytes of LTx recipients with BOS mismatched for HLA class I molecules showed a proliferative response three- to fourfold higher than those observed in mismatched recipients without BOS and in normal control individuals (P<0.001). Similarly, the PF of allopeptide-reactive T cell was 3- to 24-fold higher in recipients with BOS compared with recipients without BOS (P<0.05) as well as normal control individuals (P<0.03). The T cell PF to donor-specific allopeptides, as well as irrelevant allopeptides, was not significantly different in LTx recipients without BOS and normal control individuals.Conclusions.These data suggest that T cells from LTx recipients are sensitized to mismatched HLA class I antigens. The sensitization was significantly higher in LTx recipients with BOS compared with LTx recipients without BOS. Strategies to block T-cell responses generated by indirect allorecognition after lung transplantation may provide a means for the prevention or treatment of BOS in LTx recipients.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.Ischemic injury of the liver is generally considered to result in necrosis, but it has recently been recognized that mediators of apoptosis are activated during ischemia/reperfusion. This study was designed to characterize the extent and the type of cells within the liver that undergo apoptosis at different periods of ischemia and reperfusion.Methods.Male Wistar rats were subjected to 30 or 60 min of normothermic ischemia. Liver sections were evaluated at the end of ischemia and at 1, 6, 24, and 72 hr after reperfusion. Apoptosis was determined by DNA fragmentation as evaluated by laddering on gel electrophoresis, in situ staining for apoptotic cells using TdT-mediated dUTP-digoxigenin nick-end labeling (TUNEL), and morphology on electron microscopy.Results.In situ staining of liver biopsy specimens using TUNEL showed significant apoptosis after reperfusion. Sinusoidal endothelial cells (SEC) showed evidence of apoptosis earlier than hepatocytes. For example, at 1 hr of reperfusion after 60 min of ischemia, 22±4% of the SEC stained TUNEL positive compared with 2±1% of the hepatocytes (P<0.001). With a longer duration of ischemia, a greater number of SEC and hepatocytes became TUNEL positive. An increase in TUNEL-positive cells was also noted with an increasing duration of reperfusion. The presence of apoptotic SEC and hepatocytes was supported by DNA laddering on gel electrophoresis and cell morphology on electron microscopy. Several Kupffer cells were seen containing apoptotic bodies but did not show evidence of apoptosis. Only rare hepatocytes showed features of necrosis after 60 min of ischemia and 6 hr of reperfusion.Conclusion.These results suggest that apoptosis of endothelial cells followed by hepatocytes is an important mechanism of cell death after ischemia/reperfusion injury in the liver.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.The use of immunoisolation to protect transplanted cells from the immune system of the host has broad application to the treatment of major diseases such as diabetes and a wide range of other disorders resulting from functional defects of native cell systems. In most cases, limitations in functional cell longevity will necessitate periodic replenishment of the cells. We describe a hydrogel-based microcapsule that breaks down at a rate that can be adjusted to correspond to the functional longevity of the encapsulated cells. These injectable capsules can be engineered to degrade over several weeks to months for short-term drug delivery, or to remain intact and immunoprotective for more extended periods. When the supply of cells needs to be replenished, no surgery will be required to localize and remove the old capsules.Methods.Porcine and bovine islets were immobilized in "composite" microcapsules fabricated from alginate and low-relative molecular mass (Mr) poly (L-lysine[PLL]) (Mrexclusion <120 Kd) and implanted into the peritoneum of normal and streptozotocin-induced diabetic rats. In addition to demonstrating long-term islet viability and function, a series of in vitro studies were carried out to determine the permeability and biodegradability of the microcapsules used in the present system.Results.Xenogeneic islets implanted in nonimmuno-suppressed rats remained in excellent condition indefinitely (>40 weeks) (viability was comparable to that of preimplant control specimens). In contrast, no islets survived in uncoated alginate spheres after 2 weeks postimplantation. By changing the concentration of the alginate, it was possible to vary the rate of capsule breakdown in rats from mechanically unstable (outer matrix <0.5-0.75% alginate) to stable for >1 year (≥1.5% alginate). In addition to in vivo breakdown studies, the biodegradability of the capsular components was verified in vitro using a mixture of tritosomes (enzymes isolated from animal cells).Conclusions.We have designed a microcapsule system with controllable biodegradability which allows breakdown and absorption of implants when the cells die or become functionally inactive. These results may have application to other alginate-PLL encapsulation systems. The ability to cross species lines using these biodegradable microcapsules has the potential to expand dramatically the number of patients and the scope of diseases that can be successfully treated with cellular therapy.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.Previous studies have demonstrated that long-term tolerance of class I mismatched renal allografts in miniature swine is induced by a short course of cyclosporine (CyA), and that a total thymectomy 21 days before transplantation abrogates the induction of stable tolerance. We have now examined the effects of surgical manipulation of the thymus, with or without a reduction in the thymic volume, on the induction of tolerance.Materials and Methods.Miniature swine receiving a transplant of a class I-mismatched renal allograft and 12 days of CyA underwent either (1) a partial thymectomy 21 days before kidney transplantation (day −21), (2) serial thymic biopsies (to evaluate the effect of surgical trauma and reduction in volume of the thymus) or serial incisions of the thymus thymus (to evaluate the effect of surgical trauma without changes in thymic volume), (3) a sham thymectomy on day −21, or serial sham thymic surgery on the same POD as the thymic biopsies and incisions (control animals).Results.Control animals had a stable plasma creatinine, had donor-specific unresponsiveness in cell-mediated lympholysis (CML) assays, had absence of rejection in kidney biopsy specimens, and did not develop anti-donor class I immunoglobulin (Ig)G alloantibodies. Animals undergoing a partial thymectomy on day −21 or serial thymic biopsies showed severe renal dysfunction, histological evidence of rejection in kidney biopsy specimens and anti-donor reactivity in CML assays; all but one animal developed anti-donor class I IgG alloantibodies. Serial incisions of the thymus induced an increase in plasma creatinine and histological rejection in 1 of 3 animals and anti-donor cytotoxic T cells in vitro in all 3 animals.Conclusions.A partial thymectomy or serial thymic biopsies markedly interfere with the induction of tolerance to renal allografts. Serial thymic incisions also interfere with the induction of tolerance, but to a lesser degree. These studies may have implications for tolerance-inducing protocols that involve thymic manipulation.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.The present study examined the potential role of gene therapy in the induction of tolerance to anti-porcine major histocompatibility complex (SLA) class II-mediated responses after porcine renal or skin xenografts.Methods.Baboons were treated with a non-myeloablative or a myeloablative preparative regimen before bone marrow transplantation with autologous bone marrow cells retrovirally transduced to express both SLA class II DR and neomycin phosphotransferase (NeoR) genes, or the NeoRgene alone. Four months or more after bone marrow transplantation, the immunological response to a porcine kidney or skin xenograft was examined. Both the renal and skin xenografts were SLA DR-matched to the transgene, and recipients were conditioned by combinations of complement inhibitors, adsorption of natural antibodies, immunosuppressive therapy, and splenectomy.Results.Although the long-term presence of the SLA transgene was detected in the peripheral blood and/or bone marrow cells of all baboons, the transcription of the transgene was transient. Autopsy tissues were available from one animal and demonstrated expression of the SLA DR transgene in lymphohematopoietic tissues. After kidney and skin transplantation, xenografts were rejected after 8-22 days. Long-term follow-up of control animals demonstrated that high levels of induced IgG antibodies to new non-αGal epitopes developed after organ rejection. In contrast, induced non-αGal IgG antibody responses were minimal in the SLA DR-transduced baboons.Conclusions.Transfer and expression of xenogeneic class II DR transgenes can be achieved in baboons. This therapy may prevent late T cell-dependent responses to porcine xenografts, which include induced non-αGal IgG antibody responses.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.Prostaglandins have been shown to protect against a variety of liver insults, including ischemia-reperfusion injury. Decreased graft injury and improved survival have been demonstrated in animal studies of liver transplantation after donor pretreatment with prostaglandin before organ retrieval. This potential clinical application has not been examined in human subjects.Patients and Methods.One hundred and six liver donors were randomly assigned to receive either prostaglandin I2(epoprostenol, 500 μg intravenous bolus) immediately before cold perfusion or no drug as control. Donor and recipient characteristics were recorded, and liver function tests were monitored after transplant to assess the effect of epoprostenol on graft injury.Results.Donor pretreatment with epoprostenol significantly improved the rapidity and homogeneity of graft reperfusion. Epoprostenol pretreatment also significantly reduced peak values of transaminases after transplantation: serum glutamic-pyruvic transaminase, control (851±121 international units [IU]/L) and epoprostenol (463±78 IU/L); serum glutamic-oxalaacetic transaminase, control (870±127 IU/L) and epoprostenol (463±78 IU/L); serum glutamate dehydrogenase, control (458±95 IU/L) and epoprostenol (170±30 IU/L);P<0.01 for all, byttest. Serum levels of bilirubin and alkaline phospatase were not significantly altered by donor pretreatment with epoprostenol.Conclusions.Reduction of ischemia-reperfusion injury by administration of epoprostenol before graft retrieval may have important applications in liver transplantation. Further studies are required to establish the mechanism of this effect and to define its precise role in clinical practice.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.Despite two decades of use, there are limited data on the best way to administer and monitor cyclosporine (CsA) for liver transplantation. The present study was undertaken (1) to determine whether treatment with a new formulation of CsA, Neoral, would improve the results of liver transplantation; and (2) to study the relationships between pharmacokinetic parameters and clinical outcomes after transplantation.Methods.A double-blind, randomized, comparison of Sandimmune (SIM) with Neoral (NEO) was conducted at five Canadian centers in 188 consecutive adults undergoing primary orthotopic liver transplantation. Patients were induced with intravenous CsA then switched to NEO or SIM. Dose adjustments were made daily, or as needed, to reach a target trough CsA level of 350 ng/ml in both groups. Pharmacokinetic studies were performed on days 5, 10, 15, and 16 weeks after transplantation.Results.The NEO group was slightly younger, with a median age of 50 years (range: 23-70) versus 55 years (range: 24-71) for SIM (P=0.007); otherwise the two groups were well balanced. The NEO group stopped intravenous CsA earlier (5.8±2.6 days vs. 8.7±4.7 days,P<0.0001). This group required a lower median daily oral dose (7.5 mg/kg vs. 9.0 mg/kg,P<0.01) to maintain comparable trough CsA levels. Five SIM patients, but no NEO patients, discontinued the study due to the inability to reach target trough levels of CsA within the prescribed time (P<0.05). At 4 months, there were no differences between the two groups with respect to patient survival (93% NEO vs. 91% SIM), graft survival (90% NEO vs. 86% SIM), and rejection-free survival (54.1% NEO, 51.8% SIM). The incidence of serious adverse events was also similar and did not correlate with CsA pharmacokinetic profiles. The NEO group had a higher area under the drug concentration curve for the first 6 hr after the dosing interval (AUC0-6) and peak CsA levels (Cmax). There was a strong correlation between freedom from graft rejection during the first month after transplantation and (a) AUC0-6and (b) Cmaxat days 5 and 10 after transplantation, but only in the NEO group did this reach statistical significance. In contrast, there was a poor correlation between trough CsA and graft rejection. In patients on NEO, the concentration of CsA 2 hr after dosing (C2) closely reflected AUC0-6(r2=0.93), whereas there was a poorer correlation in patients on SIM (r2=0.73)Conclusions.Cmaxand/or AUC0-6may provide better markers than trough levels for monitoring CsA-based immune suppression after orthotopic liver transplantation. Prospective studies are underway to determine whether dosing to C2, which provides a good estimation of Cmax, can be used to take full advantage of NEO's improved absorption profile.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.A frequent dilemma is discerning the likelihood of pneumonia and the need for empiric antibiotic therapy in liver transplant recipients with pulmonary infiltrates in the intensive care unit (ICU).Methods.We performed a prospective, observational study of consecutive liver transplant recipients developing pulmonary infiltrates in the ICU.Results.Of 90 consecutive liver transplant patients in the ICU over a 3-year period, 44% (40) developed pulmonary infiltrates. The etiologies were pneumonia (38%, 15 of 40), pulmonary edema (40%, 16 of 40), atelectasis (10%, 4 of 40), adult respiratory distress syndrome (8%, 3 of 40), contusion (3%, 1 of 40), and unknown (3%, 1 of 40). Pneumonia was due to methicillin-resistantStaphylococcus aureusin 27% (4 of 15),Pseudomonas aeruginosa(27%, 4 of 15), invasive aspergillosis (20%, 3 of 15), andEnterobacter cloacae, Serratia marcescens, Pneumocystis carinii pneumonia,and unknown (7%, 1 of 15) in one each. None of the patients had cytomegalovirus or herpes simplex virus pneumonia. Seventy-five percent of methicillin-resistantStaphylococcus aureusand allAspergilluspneumonias, but only 14% of the Gram-negative pneumonias, occurred within 30 days of transplantation. Twenty-seven percent of the pneumonias occurred >365 days after transplantation; all of these were in patients with recurrent viral hepatitis C virus or hepatitis B virus, disseminated posttransplant lymphoproliferative disorder, or late rejection. Of patients with pneumonia, 87% were ventilated and 40% had bacteremia. Clinical pulmonary infection score (Pugin score) >6 (73% vs. 6%,P=0.0001), abnormal temperature (73% versus 28%,P=0.005), and creatinine level >1.5 mg/dl (80% versus 50%,P=0.05) were predictors of pneumonia versus other etiologies of pulmonary infiltrates. Overall mortality in patients with pulmonary infiltrates was 28% (11 of 40); pneumonia as etiology (P=0.06), creatinine level >1.5 mg/dl (P=0.028), higher blood urea nitrogen (P=0.017), and worse APACHE neurological score (P=0.04) were predictors of poor outcome.Conclusions.Our data have implications not only for identifying pneumonia as a potential cause of pulmonary infiltrates, but for the likely etiology of the pneumonia and thus the selection of empiric antibiotic therapy in critically ill liver transplant recipients. Pugin score >6 in patients with pulmonary infiltrates warrants antimicrobial therapy. Early onset within 30 days after transplantation raises the spectra of aspergillosis.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Background.In the last few years, rare cases of acute quadriplegic myopathy (AQM*) with myosin-deficient muscle fibres occurring after solid organ transplantation has been reported. The aim of the present study was to review all cases of AQM with myosin deficient fibres seen at our institution among a large series of patients after orthotopic liver transplants (OLT), with special attention to clinical aspects and associated risk factors. Additionally, an extensive review of all ultrastructurally demonstrated cases of AQM in transplant recipients is also included.Patients and Methods.Among patients involved in 281 consecutive liver transplant procedures performed in a 4-year period, 3 men and 1 woman developed an arreflexic, flaccid quadriplegia in the immediate postoperative period of OLT. After ruling out other causes of weakness, a muscle biopsy was performed and a loss of thick (myosin) filaments was confirmed by ultrastructural analysis in all cases. Accurate clinical, epidemiological, and evolutive data were recorded.Results.Corticosteroids had been used at usual dosage given to liver transplant recipients; all four patients had several intra- and postoperative complications leading to receiving significantly higher amounts of hemoderivates, to develop renal failure in all cases, and to require a significantly higher number of reoperations within a few days after transplantation than our contemporaneous global series of liver transplant recipients. AQM patients required a significantly longer intensive care unit and hospital stay. Muscular recovery was the rule, but currently a mild myopathic gait remains in three patients. These and other reported cases of AQM do not histologically and clinically differ from AQM seen in other critically ill patients who have not had transplants.Conclusions.Patients with a complicated intra- and postoperative course of OLT who develop newly acquired acute muscle weakness should be suspected as having acute AQM with myosin-deficient muscle fibres. In this setting, differential diagnosis with other causes of weakness should be carried out, because the prognosis of this myopathy is good with early muscle rehabilitation therapy.

ISSN:0041-1337    

出版商:OVID    

年代:1999

数据来源: OVID