ISSN:0041-1337    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

We utilized a canine renal transplant model to estimate the first-pass extraction of mizoribine (MZB) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (i.a.) versus intravenous (i.v.) MZB delivery, with and without a background of oral cyclosporine. Five autotransplanted mongrel dogs with programmable, implantable pump/catheter systems were given MZB by both i.v. bolus (5 mg/ kg) and i.a. infusion (5.0 mg/kg/day). Mean ± SD elimination half-life was 3.02±0.81 hr, and the transplanted kidney removed as much as 47–59% (mean 56%) of locally infused MZB. With increasing local and systemic MZB delivery in a single autografted dog undergoing both i.a. and i.v. pump/catheter placement, renal extraction decreased from at least 47% (5.0 mg/kg/day) to 33% (7.5 mg/kg/day), and finally to 18% (10.0 mg/kg/day). A dose of 3.0 mg/kg/day MZB did not significantly prolong survival of renal allograft recipients over that of untreated controls (median survival time [MST]=8 days) when administered either locally (MST=9 days) or systemically (MST=12 days). All dogs receiving 4.0 mg/kg/ day MZB i.a. died from rejection, and a survival advantage was still not realized (MST=7 days). In contrast, 4.0 mg/kg/day i.v. prolonged survival over controls (MST=14 days; P=0.03) but not when directly compared with the i.a. group (P=0.30), and produced death from severe debility in five of seven animals with significantly higher mean systemic MZB levels (P=0.02). Four of six dogs receiving 5.0 mg/kg/day MZB i.a. (MST=14 days) and two of four dogs receiving 5.0 mg/kg/day i.v. (MST=14 days) died from severe debility, though survival in both groups was prolonged over control values (P=0.01 and P=0.05, respectively). Coad-ministration of a subtherapeutic dose of oral CsA (5 mg/ kg/day) significantly prolonged the overall survival of dogs receiving MZB 4.0 mg/kg/day i.a. (MST=23; P=0.01) but not i.v. (MST=11; P=1.00), so that a significant difference in overall survival between the combined MZB i.a. + CSA and MZB i.v. + CSA groups was now realized in favor of the former (P=0.04). We conclude that at local doses required to achieve immunosuppression, the transplanted kidney was not able to extract enough MZB to prevent death from systemic toxicity, presumably as a result of saturation of renal elimination mechanisms, so that an overall survival benefit was not realized. However, combination of oral CsA with i.a., but not i.v., MZB infusion conferred a survival advantage with lower systemic MZB concentrations, suggesting mediation via a local immunosuppressive effect.

ISSN:0041-1337    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Rejection remains a major obstacle to long-term success of pulmonary transplantation. Direct delivery of cyclosporine to lung allografts may produce better control of rejection by generating high intragraft concentrations of drug with decreased systemic delivery and toxicity. The efficacy of inhaled cyclosporine in preventing allograft rejection was compared with systemic delivery by intramuscular injections in a rat model of lung transplantation (Brown-Norway to Lewis). Group 1 animals were given no immunosuppression. Group 2 received a single i.m. injection of 25 mg/kg CsA on the day of operation while group 3 received daily doses on postoperative days 0–3. Groups 4–7 received aerosolized CsA daily for seven days. The aerosol generator produced an airborne concentration of CsA of 180 mg/ m3with a mean particle size of 0.7 μ and estimated pulmonary depositions of CsA of 0.98–3.6 mg/kg/day. Animals were killed on POD 7, and the transplanted lungs graded histologically in a blinded fashion. All control animals showed destructive grade 4 changes by POD 7. Animals receiving high-dose aerosolized CsA (groups 6 and 7) showed minimal changes with a mean rejection grade of 1.3. A single i.m. dose of CsA (group 2) failed to prevent rejection; the mean grade was 2.2. Animals given four i.m. doses of CsA had a mean grade of 1.8. Aerosolized CsA provided significantly better control of rejection than did systemic CsA (groups 6 and 7 vs. groups 2 and 3; P<0.0002 and <0.0054, respectively). Local delivery of CsA by aerosol inhalation is effective in limiting acute rejection of the rat lung allograft.

ISSN:0041-1337    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Graft pancreatitis and allograft rejection were both accompanied by increased serum levels of immunoreactive anionic trypsin (ir AT) in a porcine pancreatic allograft transplantation model. Characterization of this immunoreactivity by gel filtration revealed different elution profiles in these conditions that can be helpful in the differentiation between them. During graft pancreatitis, a major part of the immunoreactivity was found within the high-molecular-weight fraction corresponding to the formation of complexes between trypsin and protease inhibitors. During allograft rejection, virtually all serum ir AT increase could be attributed to the release of anionic trypsinogen without any evidence of activation. Since this transplantation model includes urinary diversion of the exocrine secretions, ir AT and immunoreactive cationic trypsin (irCT) can also be measured in the urine. Characterization of this immunoreactivity showed that most of both irAT and irCT was found as active trypsin but a minor part was probably complexed with some protease inhibitor (possibly pancreatic secretory trypsin inhibitor [PSTI]).

ISSN:0041-1337    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Adequate immunosuppression remains a major obstacle to successful xenotransplantation, with early xenograft rejection appearing to be mediated by humoral factors. Total-lymphoid irradiation (TLI) and 15-deoxyspergualin (DOSP) have been shown to be effective immunosuppressive agents in allografts. In this study, TLI alone and in combination with DOSP and cyclosporine were evaluated in the hamster-to-rat heterotopic cardiac xenograft model. The animals were divided into four groups: group 1—control (n=9); group 2—TLI alone, administered pretransplant at 125 cGy/ day, four days per week, for three weeks (n=12); group 3—TLI plus CsA at 10 mg/kg/day (n=17); and group 4—TLI plus DOSP at 2.5 mg/kg/day (n=10). Tissue sections were taken from rejected xenografts in all treatment groups for histological examination. Complement-dependent cytotoxicity assays were performed on the control group and also the TLI-DOSP group. The control animals were found to have a mean graft survival of 3.2±0.4 days. TLI alone (5.8±0.7 days) did not significantly improve graft survival in comparison with the control group. Combination of TLI with DOSP (26.3±5.9 days) results in significantly improved survival (P<0.05) in comparison with the control, TLI alone, and combination of TLI and CsA (13.6±8.6 days). Complement-dependent cytotoxicity assays revealed that control groups have low rat antihamster lymphocytotoxic antibody titer (1/1–1/10) prior to xenografting, and that these antibody titers show a precipitous rise to a level of 1/640–1/1280 by day 3, the time at which rejection occurred. This correlates with the histological findings of the rejected hearts showing a severe humoral type of rejection and no evidence of cellular rejection. In contrast, animals in the TLI-DOSP group had markedly lowered rat antihamster lymphocytotoxic antibody titers (1/20–1/40) on day 3, and these titers only increased to 1/160 at time of rejection. This correlates with the histological findings of a lesser degree of humoral rejection in the TLI-DOSP group. Combination therapy with TLI and DOSP results in a marked increase of survival in xenografts in this model not seen with any other drug combination studied in over 500 xenografts in our laboratory. This study indicates that TLI combined with DOSP results in prolonged suppression of the antixenograft antibody response. This combination of agents appears to have the potential to prevent early xenograft rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1992

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Withdrawal of steroid therapy in renal transplant recipients is associated with a risk of acute allograft rejection. To define clinical risk factors for rejection associated with steroid withdrawal, we analyzed the clinical characteristics of 107 patients with drawn from steroid therapy at various times after transplantation. Both univariate and multivariate analyses suggested that the timing of steroid withdrawal is an important predictor of steroid withdrawal failure. Withdrawal of steroids was successful in only 13 of 32 patients (41%) in whom prednisone was discontinued shortly after transplantation. In contrast, steroid withdrawal has been successful in 59 of 75 patients (79%) in whom prednisone was discontinued at least 6 months after transplantation. Black race and donor-recipient racial mismatch also were significant predictors of rejection associated with steroid withdrawal. In patients undergoing steroid withdrawal at least 6 months posttransplant, serum creatinine concentration also correlated independently with the risk of rejection. Neither age, sex, HLA match, pretransplant PRA, source of the allograft (cadaver vs. living relative), acute tubular necrosis, nor the presence of diabetes was predictive of the outcome of steroid withdrawal.

ISSN:0041-1337    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Cyclosporine has improved the results of renal transplantation. In 1984, we began using it as part of a sequential immunosuppression protocol (MALG, AZA, P, and delayed administration of CsA) in our pediatric renal transplant recipients. We studied the outcome of the 131 pediatric renal transplants (≤18 years of age at transplant) performed at our institution between June 1984 and March 1991. We compared these results with the 144 similar transplants performed since January 1980 that did not involve CsA immunosuppression.In the sequential immunosuppression group, there were 97 primary (74%) (26 [27%] cadaver, 71 [73%] living donor [LD]) and 34 (26%) retransplant (23 [68%] CAD, 11 [32%]) recipients. Age at transplant (mean± SD) was 7.4±5.5. Overall, 1-year actuarial graft survival was 93%; 1-year patient survival was 100%. The mean number of hospital readmissions was 3.0±3.5; 26 (20%) were readmission-free. The mean number of rejection episodes was .87±1.3 per patient; 73 (56%) were rejection-free. Importantly, LD (vs. CAD) recipients had fewer rejection episodes (P = 0.06). In the first posttransplant year, the serum creatinine level was significantly lower in primary (vs. retransplant) recipients and in LD (vs. CAD) recipients (P < 0.05).In the 144 patients not receiving CsA, there were 129 (90%) primary (27 CAD, 102 LD) and 15 (10%) retransplant (7 CAD, 8 LD) recipients. Age at transplant was 6.9±5.3 years. The 1-year actuarial graft survival rate was 82%; the 1-year patient survival rate was 94%. The mean number of hospital readmissions was 3.3±2.3; 5 (8%) were readmission-free. The mean number of rejection episodes was 1.2±1.5; 27 (45%) were rejection-free. There was no difference in the serum creatinine level based on donor source or transplant number.Sequential immunosuppression has significantly improved patient (P = 0.003) and graft survival (P = 0.004) rates. Comparing sequential vs. non-CsA immunosuppression, there was no difference in the number of readmissions (P = 0.47), number of rejection episodes (P = 0.17), or serum creatinine level. The number of rejection-free patients was significantly lower in LD (vs. CAD) recipients (P < 0.05). There was no evidence of progressive deterioration in renal function in the sequential (vs. non-CsA) recipients.

ISSN:0041-1337    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The present analysis was undertaken to evaluate the influence of primary allograft nephrectomies on the early function, incidence of rejection, and short-term graft survival of subsequent renal retransplants. Among 95 consecutive cyclosporine treated retransplant recipients, 52 were retransplanted without primary allograft nephrectomy; 35 had removal of their primary grafts prior to retransplantation for fever and graft tenderness (30 patients) and persistent hematuria (5 patients); and 8 patients had an elective primary graft nephrectomy at the time of retransplantation. Demographic characteristics and immunosuppressive regimens were otherwise similar in all three groups. Nephrectomy of the primary allograft prior to retransplantation was associated with a significant subsequent rise in preformed cytotoxic antibody levels (57% having PRA > 30% compared with 33% in those with retention of primary grafts), a significantly higher incidence of delayed graft function among retransplants (63% compared with 30% in those who did not undergo primary allograft nephrectomy) and a trend toward decreased allograft survival in the subgroup who lost their primary allografts in the first year poattranaplant. The incidence of acute rejection and 3-year posttransplant renal function in retransplants were not, however, influenced by nephrectomy of the primary allograft.

ISSN:0041-1337    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

We retrospectively analyzed 526 primary cadaver recipients transplanted at a single center to identify pre-transplant variables that predict long-term survival with multivariate analysis. All recipients received atleast three random blood transfusions and were treated under a quadruple-therapy protocol consisting of ALG, azathioprine, prednisone, and cyclosporine.Of 526 consecutive transplants, 86 grafts were lost from acute or chronic rejection. Thirteen grafts were lost for nonimmunologic reasons and 35 recipients died with a functioning graft. A total of 273 patients (52%) experienced at least one episode of acute rejection.Donor age ranged from 3 to 64 years, with 62% of donors less than 30 years of age and 9% of donors over 50 years of age. Donor age was not predictive of long-term graft survival and neither was the difference be-

ISSN:0041-1337    

出版商:OVID    

年代:1992

数据来源: OVID