摘要:

Background.Reperfusion injury plays a pivotal role in the occurrence of delayed graft function and chronic rejection. Heme oxygenase-1 (HO-1), an inducible heat shock protein, is known to have cytoprotective effects against reperfusion injury. We report on the potential for ex vivo induction of HO-1 expression during acellular warm perfusion of canine kidneys, using cobalt protoporphyrin (CoPP) as an HO-1 inducer and zinc protoporphyrin as an HO-1 inhibitor.Methods.Canine kidneys were used to evaluate HO-1 increase after exposure to warm ischemia (WI), hypothermic perfusion (mechanical perfusion [MP], 4°C), warm perfusion (exsanguineous metabolic support [EMS], 32°C), or various combinations.Results.WI alone, MP, or EMS with or without WI, had no effect on HO-1 activity. However, the presence of CoPP during EMS perfusion resulted in a significant increase in kidney HO-1 activity, whereas zinc protoporphyrin reduced HO-1 activity. The presence of CoPP during MP did not induce elevated HO-1 expression. The results of our study demonstrate that sufficient metabolism supporting new protein synthesis resulting in the expression of the protective gene, HO-1, can be accomplished during an acellular near-normothermic perfusion using CoPP. Most importantly, the time required for ex vivo HO-1 induction with this method is compatible with the current time frame for which organs are preserved clinically.Conclusions.The ability to induce HO-1 expression ex vivo eliminates the need for donor therapy to induce HO-1 increase before retrieving organs and also prevents the potential of decreasing HO-1 enzyme activity that is known to occur with temperature-mediated inhibition of oxidative metabolism during hypothermic organ storage.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.A difference in short- and long-term function between living-related and cadaveric donor organs is consistently shown in kidney- and liver-transplant studies. We hypothesize that this is caused by induction of apoptosis and inflammation of the potential graft because of the phase of brain death (BD) in the cadaveric donor that predisposes for additional transplant injury. Previously, we have shown inflammation in the liver of brain-dead donors by increased expression of cell adhesion molecules and influx of leukocytes. The key inflammatory mediator in inflammation is tumor necrosis factor (TNF)-&agr;. In addition to being involved in inflammation, TNF-&agr; also activates the potential detrimental process of apoptosis and, on the other hand, activates an antiapoptotic survival pathway by way of NF-kB. The aim of the present study was to investigate whether the inflammatory response in the liver of brain-dead donors is accompanied by changes in apoptosis and in expression of apoptosis-related proteins, in particular those regulated by NF-kB.Methods.BD was induced by inflation of an intracranially placed balloon. Apoptosis was assessed by caspase-3 enzyme activity and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay. Changes in expression of proteins involved in pathways leading to apoptosis were studied by determination of mRNA levels using semiquantitative reverse-transcriptase polymerase chain reaction followed by image analysis. TNF-receptor (TNFR), Fas, and Fas-ligand (FasL) were used as indicators for activation of the death receptor mediated pathway. Bcl-2, Bax, Bak, Bid, and A1 were used as indicators for activation of the mitochondrial pathway.Results.After 6 hours of normotensive BD, the number of apoptotic cells and caspase-3 activity were significantly increased compared with non–brain-dead control rats. TUNEL staining revealed that the apoptotic cells were primarily hepatocytes. mRNA levels of all NF-&kgr;B induced activators (Fas, bid) and inhibitors (A1, BCl-xl, cIAP2) of both apoptotic pathways were significantly increased in liver tissue of BD donors versus non-BD controls.Conclusions.The phase of BD in the donor induces increased apoptosis of hepatocytes despite an enhanced expression of NF-kB-dependent antiapoptotic genes.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Acute graft-versus-host disease (GVHD) remains a significant impediment to successful hematopoietic stem-cell transplantation (HSCT). Here, we examined the effectiveness of 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720), an immunosuppressant that retraffics activated lymphocytes to secondary lymphoid organs, for the treatment of acute GVHD in an established dog leukocyte antigen-nonidentical unrelated canine HSCT model.Methods.Dogs were given HSCT after conditioning with 920 cGy total body irradiation. The dogs received methotrexate 0.4 mg/kg/day on days 1, 3, 6, and 11 and FTY720 (5 mg/kg/day orally) after developing GVHD.Results.Five of six dogs achieved engraftment, developed acute GVHD, and were treated with FTY720. FTY720 resulted in a profound decrease in lymphocytes and a temporary mitigation of clinical GVHD; however, GVHD recurred in all dogs. Four of five dogs were euthanized because of severe GVHD and the fifth because of severe inanition associated with moderate GVHD.Conclusions.Compared with controls, treatment of GVHD with FTY720 did not control this complication or significantly increase survival.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Some immunosuppressive drug therapies inhibit transplant tolerance in animal models, and we have shown that treatment of recipients with methylprednisolone, but not cyclosporine, inhibits spontaneous acceptance of liver transplants. This study investigates the effects of mycophenolate mofetil (MMF) on liver acceptance and rejection.Methods.Piebald Virol Glaxo rat livers were transplanted into Dark Agouti recipients, which spontaneously tolerate (TOL) the liver, or into Lewis recipients, which reject (REJ) the liver. MMF (40 mg/kg/day subcutaneously) was given for 5 days from days 0 to 4 (early) or from days 3 to 7 (late). In separate experiments, liver grafts were collected for assessment of infiltrate and of interleukin (IL)-2, IL-4, IL-10, and interferon-&ggr; mRNA expression.Results.TOL liver transplants had a median survival time (MST) of more than 100 days (n=6), and neither early nor late MMF treatment of TOL transplants reduced survival (MST 85 days,P=0.19 and 78 days,P=0.08, respectively). Liver failure in most of these animals was the result of biliary problems, not rejection. There were few consistent differences between treated and untreated TOL animals in infiltrate or liver cytokine expression, although there was a moderate reduction in T-cell infiltrate in MMF-treated TOL animals (P=0.003 on day 5 TOL). In contrast, REJ transplants had an MST of 13 days (n=10), and early MMF treatment led to five of six animals surviving more than 100 days (P=0.0002), whereas late treatment was much less effective, with one of six animals surviving more than 100 days. REJ livers had significantly more IL-4 mRNA expression and immunoglobulin G1 deposition in the graft than TOL livers, and this was inhibited by early, but not late, MMF treatment.Conclusions.MMF treatment inhibited rejection but not acceptance of liver allografts. Early administration was more effective in preventing rejection and demonstrated a more marked effect on IL-4 expression and alloantibody deposition than on graft T-cell infiltrate and expression of other cytokines.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Apolipoprotein E-deficient (apoE-/-) mice spontaneously develop hypercholesterolemia and atherosclerotic lesions. This may be an appropriate background for the development of graft vessel disease. The authors therefore investigated the effects of cyclosporine A (CsA) and SDZ RAD (RAD, everolimus, Certican) on neointima formation of carotid allografts in apoE-/- mice. To ascertain that equipotent immunosuppressive doses were used, the authors also investigated their effects on cardiac allografts using the same wild-type strain combination.Methods.Heterotopic heart allotransplantation was performed in the BALB/c to C57BL/6 strain combination. Graft survival was monitored daily. Orthotopic carotid artery allotransplantation was performed from BALB/c to apoE-/- (C57BL/6) mice. Groups of mice were treated for 8 weeks with placebo; CsA 10, 20, and 30 mg/kg/d; or RAD 0.3, 1.0, and 3.0 mg/kg/d using ALZET minipumps. Body weight, CsA blood levels, serum lipids, and histology were examined 8 weeks after transplantation or on the day of rejection.Results.Compared with the placebo group, CsA or RAD did not affect body weight. Both CsA and RAD prolonged the survival of cardiac grafts in a dose-dependent manner. CsA blood levels were not different between wild-type and apoE-/- recipients. CsA increased total cholesterol and low-density lipoprotein, but not high-density lipoprotein dose-dependently and significantly, but RAD did not affect the lipids. RAD but not CsA significantly attenuated neointima formation.Conclusions.These results suggest that RAD at a dose preventing organ rejection may also prevent transplant vasculopathy even in the presence of hyperlipidemia.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Posttransplant proteinuria and hypertension are difficult to treat after renal transplantation. Therefore, we examined whether candesartan cilexetil is effective in reducing urinary protein excretion or in controlling hypertension in patients with renal allograft dysfunction.Methods.Sixty-two renal transplant recipients with proteinuria were enrolled in this study. They underwent kidney transplantation under cyclosporine or tacrolimus immunosuppression between February 1983 and December 1998. Causes of proteinuria were chronic rejection in 28, glomerulonephritis in 16, cyclosporine or tacrolimus nephrotoxicity in 9, and unknown in 9 recipients. The dose of candesartan cilexetil ranged from 4 to 12 mg/day. Eleven patients with proteinuria who had not been treated with candesartan cilexetil constituted a matched control population.Results.Hypertension was well controlled by administration of candesartan cilexetil. Both systolic blood pressure and diastolic blood pressure significantly decreased from 141.7±14.8 mm Hg to 118.7±11.9 mm Hg and 121.2±11.6 mm Hg, and from 89.0±13.0 mm Hg to 72.0±10.4 mm Hg and 74.9±9.4 mm Hg, at 2 months and 1 year after administration, respectively. Urinary protein excretion was reduced from 0.93±1.2 g/day to 0.34±0.7 g/day and 0.43±1.2 g/day at 2 months and 1 year after administration, respectively. The levels of creatinine clearance were 55.7±28.9 mL/min before treatment, 50.9±24.8 mL/min at 2 months, and 52.6±24.8 mL/min at 1 year after treatment, respectively. There was no clinically significant difference between them. Regarding the calcineurin inhibitor levels, there was no significant difference between the levels before and 1 year after treatment. There was a significant difference in all examinations (systolic blood pressure, diastolic blood pressure, proteinuria, and renal function) between the patients with and without candesartan at 1 year after treatment. No significant adverse effects occurred.Conclusions.Candesartan cilexetil can effectively control hypertension and proteinuria without deterioration in renal allograft function. These data suggest that treatment with candesartan cilexetil may be useful for maintaining long-term renal allograft function.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The survival results of patients demonstrating acute-on-chronic liver failure and undergoing live-donor liver transplantation (LDLT) have been reported to be poor. This study evaluates the survival outcomes of patients who underwent LDLT using right-lobe liver grafts for acute-on-chronic hepatitis B liver failure.Methods.The study comprised 32 patients who demonstrated acute-on-chronic hepatitis B liver failure with mean (± standard error of mean) Model for End-Stage Liver Disease scores of 36±1.8. The mean preoperative intensive care unit stay was 2.4 days. LDLT using a right-lobe liver graft including the middle hepatic vein was performed in all patients. Oral lamivudine 100 mg daily was used for hepatitis B prophylaxis.Results.The patients received liver grafts that were 52%±2% of the estimated standard liver weight. Hospital mortality occurred in two patients, and two other patients died on follow-up. At a median follow-up of 23 months, both patient and graft survival rates were 88%. The survival results were not different from those of 49 patients who underwent right-lobe LDLT for elective conditions during the same study period (graft survival=82%,P=0.55; patient survival=84%,P=0.75). Two (6.3%) patients developed hepatitis B virus DNA breakthrough 47 and 53 months, respectively, after transplantation, but they remained well after treatment with adefovir.Conclusion.Right-lobe LDLT is an effective therapeutic option for patients with acute-on-chronic hepatitis B liver failure. It results in satisfactory survival outcomes comparable to those in patients undergoing LDLT for elective conditions.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives.En bloc pediatric kidney transplants (EBPKT) are still a subject of controversy. The aim of this study was to determine whether acceptable long-term graft survival and function can be achieved in EBPKT compared with the transplant of single, cadaveric, adult donor kidneys.Methods.A retrospective review was conducted of 66 recipients of en bloc kidneys from cadaveric pediatric donors and 434 patients who underwent transplantation with a single kidney from an adult donor between January 1990 and May 2002 at the authors’ hospital. The recipients were well-matched demographically. Both transplant groups were analyzed for short- and long-term performance in terms of transplant outcome and quality of graft function.Results.Overall death-censored actuarial graft survival rates at 1 and 5 years were 89.2% and 84.6% in the adult kidney transplants (AKT) and 83.3% and 81.1% in EBPKT, respectively (P=0.56). In the EBPKT group, graft function was improved over that observed in AKT. Vascular thrombosis was the most common cause of graft loss in EBPKT. Acute rejection occurred more frequently in AKT and Cox’s regression analysis indicated that undergoing an AKT was a predictive factor for acute vascular rejection (adjusted risk ratio, 3.8; 95% confidence interval, 1.4–10.2;P=0.001).Conclusions.Overall graft survival was similar in both groups, vascular complications were the main cause of graft loss in EBPKT, and the EBPKT showed excellent long-term graft function and a low incidence of acute rejection.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Current trends in medical management of advanced heart failure and transplant medicine and the enactment of a national transplant law forced a change toward allocation driven by disease severity.Objective.The aim of this study was to create a model for predicting waiting-list survival on the basis of simple clinical parameters.Methods.The clinical profiles of all patients registered for heart transplantation in Germany in 1997 (n=889) were used as a derivation set, and the total German 1998 cohort (n=897) was used as a validation set. The model was validated by the c statistic and by comparison of risk stratified mortality rates. The validated model was fine tuned by the appropriate calibration procedures. The data were first classified into physiologic subscores: an urgency score, a left ventricular heart failure score, a right ventricular heart failure score, and a systemic heart failure score. A stepwise modeling procedure was undertaken using these subscores as factors as well as the recipient’s age, ABO blood group, and body surface area.Results.The urgency and the left ventricular subscore were found to be significantly associated with waiting-list mortality. A summary index termed German Transplant Society (GTS) score was then calculated on the basis of seven parameters contained in these two subscores. The GTS score was able to predict waiting-list mortality risks for the 1998 cohort: 1-year mortality before transplantation was 71%, 34%, 11% for the high, medium, and low risk groups, respectively.Conclusion.The use of this continuous disease severity index may improve the selection of cardiac transplant candidates.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Chronic allograft nephropathy is an important cause of late renal transplant failure. Although numerous studies on cytokines have been carried out, the pathogenetic role of cytokines in chronic renal allograft nephropathy remains unclear.Methods.In a retrospective study, the authors compared posttransplant plasma and urine cytokine levels (interleukin [IL]-1&agr;, IL-1&bgr;, soluble [s] IL-1 receptor [R] antagonist [A], IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, tumor necrosis factor-&agr;, transforming growth factor-&bgr;2, and interferon-&ggr;) in 34 matched pairs of patients with or without late graft failure and in 50 matched pairs with either normal or increased serum creatinine levels and continued stable graft function.Results.Twelve and 6 months before late graft failure, urine levels of sIL-6R were significantly increased (P=0.003 andP=0.01, respectively). Serum creatinine levels were not associated with increased urine sIL-6R.Conclusion.High urine sIL-6R appears to be predictive of late graft failure in renal transplant recipients.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID