ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Introduction.This study evaluated whether cyclosporine (CsA) could be eliminated from a sirolimus (Rapamune, rapamycin, SRL)-CsA-steroid (ST) regimen at 3 months.Methods.This was an open-label study conducted in Europe, Australia, and Canada. Upon enrollment, 525 primary (90%) or secondary (10%) renal allograft recipients with cadaveric (89%) or living (11%) donors received 2 mg of sirolimus (troughs>5 ng/ml), CsA, and steroids. At 3 months±2 weeks, eligible patients were randomized (1:1) to remain on SRL-CsA-ST or to have CsA withdrawn and therapy continued with SRL (troughs 20–30 ng/ml)-ST.Results.At 12 months, overall graft and patient survival were 89.1% and 94.9%, respectively. In the 430 (82%) randomized patients, there was no difference in graft survival (95.8% vs. 97.2%, SRL-CsA-ST vs. SRL-ST) or patient survival (97.2% vs. 98.1%, respectively). The incidence of biopsy-confirmed primary acute rejection was 13.1% during the prerandomization period. After randomization, the acute rejection rates were 4.2% and 9.8% for SRL-CsA-ST and SRL-ST, respectively (P=0.035). Renal function (calculated glomerular filtration rate, 57 vs. 63 ml/min,P<0.001) and blood pressure significantly improved when CsA was withdrawn. Hypertension, CsA nephrotoxicity, hyperuricemia, andHerpes zosteroccurred statistically more frequently in patients remaining on CsA, whereas thrombocytopenia, abnormal liver function tests, and hypokalemia were reported more often for SRL-ST therapy.Conclusion.Sirolimus, CsA, and steroids for 3 months posttransplant, followed by elimination of CsA, is a safe and effective alternative to continuous therapy with sirolimus, CsA, and steroids that can result in better renal function and lower blood pressure.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Sirolimus, a promising new immunosuppressive drug for organ transplantation, is currently associated with side effects, such as thrombocytopenia and hyperlipidemia.Methods.Eight renal transplant recipients, who developed unexplained interstitial pneumonitis during sirolimus therapy, were extensively re-screened for all causes of pneumonitis.Results.Interstitial pneumonitis was constantly characterized by bilateral interstitial infiltrates on chest x-rays and lung computed tomography scans, with marked general symptoms in all patients but one. Bronchoalveolar lavage (BAL) disclosed lymphocytic alveolitis (mainly of the CD4 type) in seven patients and alveolar hemorrhage in one. Transbronchial lung biopsies, performed in two patients, showed bronchiolitis obliterans with organizing pneumonia combined with lymphocytic interstitial pneumonitis. Pulmonary infections were ruled out by specific stainings and cultures of BAL, bronchial aspirates, and blood cultures. After the elimination of all possible causes, sirolimus-induced pneumonitis was considered probable. Discontinuation of sirolimus in seven cases and dose reduction in the remaining case dramatically improved clinical and radiological status within a few weeks and led to complete resolution within 3 months.Conclusions.Sirolimus is very probably responsible for interstitial pneumonitis on the following grounds: (a) occurrence of pneumonitis during sirolimus therapy; (b) absence of any other causes; and (c) resolution within 3 months of sirolimus discontinuation or dose reduction.Sirolimus should now be added to the list of possible causes of pulmonary complications after renal transplantation. Discontinuation or dose reduction of sirolimus led to complete and lasting resolution of symptoms.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.Although prolonged composite tissue allograft (CTA) survival is achievable in animals using immunosuppressive drugs, long-term immunosuppression of CTAs in the clinical setting may be unacceptable for most patients. The purpose of this study was to develop a model for reliable CTA tolerance induction in the adult rat across a major MHC mismatch without the need for long-term immunosuppression.Methods.Mixed allogeneic chimeras were prepared by using rat strains with strong MHC incompatibility [WF (RT1Au), ACI (RT1Aa)] WF + ACI→WF, n=23. The bone marrow (BM) of recipient animals was pretreated with low-dose irradiation (500–700 cGy), followed by reconstitution with a mixture of T cell-depleted syngeneic (WF) and allogeneic (ACI) cells. Additionally, the recipient animals received a single dose of anti-lymphocyte serum (10 mg) 5 days before bone marrow transplantation (BMT) and tacrolimus (1 mg/kg/day) from the day before BMT to 10 days post-BMT. Hindlimb transplants were performed 12 months after BMT. Five animals received a limb allograft irradiated (1000 cGy) just before transplantation. Rat chimeras were characterized (percentage of donor cells present within the bloodstream) by flow cytometry at 3 and 12 months after BM reconstitution and after hindlimb transplantation.Results.Peripheral blood lymphocyte chimerism (WF/ACI) remained stable >12 months after BM reconstitution in 18/23 animals. Multi-lineage chimerism of both lymphoid and myeloid lineages was present, suggesting that engraftment of the pluripotent rat stem cell had occurred. In animals with donor chimerism >60% (n=18) no sign of limb rejection was present for the duration of the study. All animals with chimerism <20% (n=5) developed moderate signs of rejection clinically and histologically. Gross motor and sensory reinnervation (weight bearing, toe spread) developed at >60 days in 14/21 rats. Postoperative flow cytometry studies demonstrated stable chimerism in all animals studied (n=10). Five out of five animals with irradiated limb transplants showed no sign of GVHD at >100 days.Conclusions.Stable mixed allogeneic chimerism can be achieved in a rat hindlimb model of composite tissue allotransplantation. Hindlimb allografts to mixed allogeneic chimeras exhibit prolonged, rejection-free survival. Partial functional return should be expected. The BM transplanted as part of the hindlimb allograft plays a role in the etiology of GVHD. Manipulating that BM before transplantation may influence the incidence of GVHD. This represents the first reliable rat hindlimb model demonstrating rejection-free CTA survival in an adult animal across a major MHC mismatch without the long-term need for immunosuppressive agents.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background.A recent clinical study demonstrated that in renal allografts preserved in the cold apoptosis occurred soon after reperfusion. The mode of cell death during cold storage is generally considered necrotic. Whether apoptosis occurs as a part of cold storage is uncertain. The objective was to determine in human renal tubular cells whether apoptosis is specific for rewarming or it also occurs during cold storage and whether it could be modified.Methods and Results.Cold storage (4°C) of primary human renal proximal tubular epithelial (RPTE) in University of Wisconsin (UW) solution up to 48 hr caused a time-dependent increase in cell death measured by lactic dehydrogenase (LDH) release and vital dye exclusion methods. Transmission electron microscopy (TEM) demonstrated that cell death in the cold was necrotic, involving considerable mitochondrial disruption, and was not apoptotic. The TUNEL assay that provides a specific, quantitative measure for apoptosis showed no increase in TUNEL-positivity during flow cytometry of cells stored in cold: 37°C, 0.23±0.14%; 24 hr cold, 0.23±0.1%; 48 hr cold, 1.79±0.58%. Annexin-V staining, a sensitive method for detecting early apoptosis, similarly showed no increase in positively stained cells during cold storage. Addition of antioxidants 2-methyl aminochroman and deferoxamine to UW solution inhibited necrotic cell death and preserved mitochondrial structure. In contrast to cold storage alone, rewarming (37°C for 24 hr) of cold stored cells, however, resulted in significant apoptosis (TUNEL positive: 48 hr cold: 2±0.6%, 48 hr cold and 24 hr rewarming: 54±17%), which was confirmed by the TEM based on typical apoptotic features. Addition of 2-MAC and DFO significantly inhibited rewarming-induced apoptotic cell death (plus 2-MAC: 3±1%, plus DFO: 3±2%).Conclusion.Our study in human tubular cells provides evidence that cold storage per se does not result in apoptosis, but is primarily necrotic. However, rewarming is associated with significant apoptosis in the presence of ongoing necrosis, speculatively due to the activation of the apoptotic enzymic process of sublethally injured cells. Inclusion of antioxidants in the storage solution confers protection against both cold storage and rewarming-induced necrosis and apoptosis.

ISSN:0041-1337    

出版商:OVID    

年代:2001

数据来源: OVID