ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Previous studies by others have shown that transplanted rat kidneys have abnormally low clearances of paraaminohippuric acid, inulin, and creatinine, due to rejection and/or to warm-ischemia-induced injury. In the present studies, randomly bred Sprague-Dawley rats were used as donors and recipients. The left kidneys of recipients were removed, and the right kidneys were left intact. Donor kidneys were flushed with an ice-cold hypertonic solution (150 mM NaCl, 200 mM mannitol, pH 6.4), and the kidneys were kept cold during surgery. Renal function was assessed 1 week later. The left transplanted kidneys in untreated recipients exhibited morphologic evidence of rejection, and the clearances of PAH and inulin were approximately 50% of those of the right native kidneys. CsA-treated rats did not reject the transplants, and the PAH and inulin clearances of the left transplanted kidneys were identical to those of the right native kidneys. Untreated and CsA-treated rats with both native kidneys intact served as controls. The amount of CsA given during the 7-day period produced no measurable change in renal function. This is the first demonstration of virtually normal hemodynamics in transplanted rat kidneys when randomly bred animals are used as donors and recipients. Moreover, the results indicate that if both rejection and warm ischemia are avoided, the presence of a functioning native kidney does not have a detrimental effect on the function of a transplanted kidney.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The effects of total lymphoid irradiation, cyclosporine and splenectomy alone and in combination have been studied in liver transplants from the LVG hamster to the LEW rat. Neither CsA alone, splenectomy alone, nor TLI alone prolonged graft survival. CsA/splenectomy and TLI/CsA produced significant prolongation of graft survival. TLI/CsA/splenectomy prolonged graft survival by over sixfold compared with controls. While CsA alone was ineffective in reducing lymphocytotoxic antidonor antibody, splenectomy alone or CsA/splenectomy did significantly suppress production of antibody. Only very low levels of antibody could be detected in animals treated with TLI/CsA/splenectomy. TLI/CsA/splenectomy has an immunosuppressive effect sufficient to significantly prolong liver graft survival in the LVG hamster to LEW rat combination and may represent a promising treatment protocol in experimental cross-species transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Administration of cyclosporine to rats has been shown to impair testicular function, resulting in a decrease in sperm counts and fertility. In order to determine whether or not the deleterious effects of CsA could be reversed by hormonal therapy, mature male Sprague Dawley rats were treated with CsA (40 mg/kg/day, s.c.) alone or in combination with human chorionic gonadotropin (hCG) (5 μg/day/r; s.c.) for 14 days. Cyclosporine administration decreased the body weight (290±5.30 vs. 339±8.7 g;P<0.05) and reproductive organ weights (testis 1.49±0.42 vs. 1.60±0.03 g; epididymis 0.41± 0.02 vs. 0.49±0.002 g; seminal vesicle 0.61±0.09 vs. 1.60±0.05 g; prostate 0.28±0.04 vs. 0.60±0.06 g;P<0.05) testicular sperm counts (5.80±0.42 vs. 8.49±0.48 ×107/100 mg tissue;P<0.05) and epididymal sperm counts, (28.2±0.95 vs. 51 51.62±2.17 ×107/100 mg tissue;P<0.05) and fertility (25% vs. 100%). Serum levels of LH were elevated (101.98±21.48 vs. 25.6±5.18 ng/ml;P<0.05) and testosterone was decreased (0.48±0.07 vs. 2.06±0.56 ng/ml;P<0.05). The administration of hCG to the CsA-treated rats restored the reproductive organ weights (testis 1.56±0.043 g; seminal vesicle 1.04±0.05 g; prostate 0.70±0.06 g) and sperm counts (testicular 7.88±1.0 ×107/100 mg tissue; epididymal 59.86±4.16 ×l07/100 mg tissue;P<0.05) Serum levels of testosterone (18.63±4.45 ng/ml) and LH (431.65±31.41 ng/ml) were significantly elevated, as compared with control and CsA-treated groups (P<0.05). All the rats in the gonadotropin-treated group were fertile, as compared with 25% in the CsA-treated group.CsA reduced the kidney weight (1.17±0.02 vs. 1.27±0.03 g;P<0.05) and increased the levels of serum creatinine (0.97±0.07 vs. 0.59±0.03 mg/dl;P<0.05): these changes were ameliorated by the administration of hCG (kidney weight 1.35±0.03 g; creatinine 0.76±0.09 mg/dl).

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Combination CsA with corticosteroids is the most commonly used maintenance immunosuppressive regimen after cardiac transplantation, although their high-toxicity profiles frequently limit their clinical benefit. Immunosuppressive agents that would act synergistically with CsA but without the toxicity profile of corticosteroids would be clinically useful. Thalidomide was removed from the market due to its teratogenic effects, although it has known immunomodulatory activity. The purpose of this study was (1) to determine whether maintenance immunosuppression with thalidomide and subtherapeutic doses of CsA can help prevent rat cardiac allograft rejection; and (2) to compare its synergism with CsA to the commonly used corticosteroid, methylprednisolone.ACI-LEW allografts were all treated with subtherapeutic doses of CsA (10 mg/g/day, s.c.) for 4 days. When CsA was then discontinued, severe rejection developed by posttransplant day 14. Group 1 received CsA alone. Group 2 received in addition oral thalidomide 100 mg/day for 14 days. Groups 3, 4, and 5 received CsA and methylprednisolone (low dose: 0.2 mg/kg/day s.c; moderate dose: 2.0 mg/kg/day s.c; and high dose: 20 mg/kg/day s.c. Twelve histologic parameters of rejection were semiquantitatively graded 0–4, and total pathology scores were determined.The combination of thalidomide and subtherapeutic CsA significantly reduced the severity of myocardial necrosis, interstitial inflammation, interstitial edema, and the total pathology score. Thalidomide was found to be equally as effective as low-, moderate-, and high-dose methylprednisolone. The results of this study suggest the potential clinical role of CsA and thalidomide in maintenance immunosuppressive regimens, thereby avoiding the use of corticosteroids.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The impact of haplotype match (HM), pretransplant transfusions, and cyclosporine use were examined for living-donor renal transplants performed among 49 centers in the South-Eastern Organ Procurement Foundation (SEOPF) from November 1983 to June 1988 with follow-up through March 1989. During this period, 750 2-HM, 1246 1-HM, and 120 0-HM living-donor transplants were performed at 46, 47, and 27 centers, respectively. Demographic comparisons of the HM categories demonstrated the greatest use of cyclosporine and donor-specific transfusions in the 0-HM group, and the greatest use of random blood transfusions (RBT) or no blood transfusions (NBT) in the 2-HM group. By univariate and multivariate (Cox regression) analyses, actuarial graft survival was significantly associated with haplotype match, although excellent 3-year graft survival was seen for 0-HM as well as 1-HM and 2-HM first transplant recipients: 74 ± 5%, 80 ± 2%, and 85 ± 2%, respectively. Comparisons were also made among patients receiving DST±CsA, RBT±CsA, and NBT±CsA for each HM group by univariate and mutivariate analyses. For 0-HM recipients, DST+CsA was most frequently used and associated with the best long-term survival (86±5% at 3 years) by univariate analysis. For 1-HM recipients, there were no apparent differences in graft survival between DST and RBT groups ± CsA by univariate analysis, but the absence of transfusion (NBT±CsA) was associated with the poorest 3-year survival (79±4%). This was confirmed by multivariate analysis, where DST (P<0.06) and RBT (P<0.02) were each significantly associated with graft survival, and provided relative benefits (vs. NBT) of 0.56 and 0.44, respectively; CsA use was not significantly associated with outcome or a significant benefit. For 2-HM recipients, the poorest results were seen with DST+CsA (78± 6% at 3 years) by univariate analysis; multivariate analysis suggested no benefit with DST or RBT, and an increased risk of graft loss with CsA. These results indicate that the use of pretransplant transfusions and CsA therapy may have differential benefits depending upon HM in living-donor renal transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

It has been reported that initial cyclosporine levels over 400 ng/ml posttransplantation result in an increased incidence of delayed graft function (DGF). Several studies have shown early graft function to be a major determinant for long-term graft survival. Continuous intravenous infusion (CIVI) has been employed to induce immunosuppression establishing therapeutic drug levels while minimizing toxicity in renal allograft recipients. This study examines the impact of the achieved serum CsA steady-state concentration (C88) levels upon transplant outcome in 228 patients given CsA by CIVI. In spite of administration of a specific drug dose, interindividual variation in elimination rates yields a broad range of C88levels. Six groups were stratified by CsA C88levels: group A 0–75 ng/ml, group B 76–100 ng/ml, group C 101–150 ng/ml, group D 151–200 ng/ml, group E 201–250 ng/ml, and group F >250 ng/ml. Group A showed a significantly lower age and greater incidence of rejection at 0–10 days. Group F had significantly higher incidences of nephrotoxicity, hepatotoxicity, and delayed graft function. The findings suggest that the antirejection C88threshold for CsA may be at least 75 ng/ml, and the toxicity threshold above 250 ng/ml. Controversy exists about whether CsA influences the incidence of DGF, therefore risk factors for DGF were examined among the groups stratified by CsA C88levels. While cold ischemia time for all 228 patients as a group was highly correlated with DGF (P<0.001), neither cold ischemia time nor donor age was significantly different among the groups. There does appear to be a synergistic effect between CsA C. and CIT, since the incidence of DGF was significantly higher when the cold ischemia time was 21–24 hr and CsA C88>200 ng/ml. Long-term graft function did not appear to be affected by early CsA C88levels. The C88of 100–250 ng/ml appears to achieve a satisfactory outcome with a 19.5% incidence of rejection within 10 days, 29.7% DGF, and 5.1% nephrotoxicity. Only 118/228 patients (52%) in this study achieved that range despite a fixed low CIVI of CsA. Thus potential renal allograft recipients may benefit from a pretransplant pharmacokinetic study to predict the proper CIVI dose.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Of 704 renal transplant recipients receiving long-term cyclosporine immunosuppression, 71 patients experienced proteinuria >1 g/24 hr beyond the first month posttransplant. Eight patients displayed transient proteinuria, defined as lasting less than 3 months. In most cases this condition was attributed to biopsy-proved acute rejection. The transient proteinuria cohort experienced good graft outcome—namely, 87.5% one-year and 52.5% five-year actuarial graft survivals, which was similar to that observed in patients without proteinuria. In contrast, 52.4% of the 63 patients with nontransient proteinuria experienced graft loss within a median time of 6.1 months. The one- and five-year actuarial graft survivals in patients with nontransient proteinuria were 75.3% and 37.5%, respectively. Among the 63 patients with nontransient proteinuria, histopathologic diagnosis included chronic rejection in 19, transplant glomerulopathy in 14, acute rejection in 9, glomerulonephritis (GN) in 7 including 2 cases of membranous GN, and nonspecific interstitial fibrosis in 10 cases. Despite the overall poor prognosis for graft survival among the entire cohort of patients with nontransient proteinuria, the seven with allograft GN maintained prolonged graft function. They showed an 83.3% five-year actuarial graft survival versus 31.2% in patients with other causes of proteinuria (P= 0.043). These results suggest that posttransplant proteinuria in CsA-treated renal transplant recipients arises primarily as a consequence of allograft rejection and portends a poor graft outcome.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The acute renal failure associated with cyclosporine may result from vasoconstriction of intrarenal arterioles. To evaluate the mechanism of cyclosporine-induced nephrotoxicity, we acutely administered cyclosporine to eight healthy female volunteers with normal blood pressure and renal function. Cyclosporine (4 mg/kg) in 250 ml of 5% dextrose in water (D5W) was administered as a steady intravenous infusion over 6 hr. Glomerular filtration rate and renal plasma flow were measured by serum disappearance of99mTcDTPA and131I hippuran, respectively, during the last 3 hr of the infusion. D5W was given to the patients on separate days before the cyclosporine infusion to obtain control data. Systolic and diastolic blood pressure measured every hour during the infusions and renal vascular resistance were slightly higher during cyclosporine administration, but the increases were not statistically significant. Renal plasma flow was not affected by cyclosporine, being 479.6±24.9 ml/min during the control infusion and 463.3±12.7 ml/min during the cyclosporine infusion. However, glomerular filtration rate was reduced by cyclosporine in all patients (control, 108.8±2.5 ml/min, vs. cyclosporine, 91.1±2.2 ml/min,P<.01), except one who demonstrated no significant change. Urinary excretion of thromboxane B2during cyclosporine administration was markedly increased in all patients, being 39.9±8.2 ng/hr in the control period and 85.8±22.3 ng/hr during cyclosporine infusion (P<.05), except for the one patient in whom no decrease in GFR was noted. There was no significant change in the urinary excretion rate for 6-keto-prostaglandin Flaor prostaglandin E during cyclosporine infusion. Serum averaged levels of peripheral renin activity, angiotensin II, and aldosterone did not change during with the cyclosporine administration compared with the control. All patients demonstrated a decrease in 24-h urinary excretion of sodium and potassium on the day of the cyclosporine infusion. Verapamil SR (240 mg daily for 7 days prior to cyclosporine infusion) did not reverse the reduction in glomerular filtration rate induced by cyclosporine; however, a significant reduction in renal vascular resistance and an increase in renal plasma flow (P<.05) were noted when the volunteers were treated with both verapamil and cyclosporine compared with cyclosporine alone. Intravenous infusion of Cremophor EL, the vehicle to dissolve cyclosporine, demonstrated no significant effects on blood pressure, renal hemodynamics or urinary prostaglandin excretion. In summary, intravenous administration of a single dose of 4 mg/kg of cyclosporine acutely reduced glomerular filtration rate without affecting renal plasma flow, suggesting a predominant vasoconstrictive effect on the afferent arteriole, perhaps mediated through an increase in renal production of thromboxane A2.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

OKT3 is an IgG2a murine monoclonal antibody directed against the CD3 antigen receptor of human T lymphocytes. A major concern with OKT3 treatment in solid organ transplant recipients is the development of antimouse antibody, which may preclude retreatment with this agent. We have administered OKT3 on 215 occasions (150 renal, 34 hepatic, 26 cardiac, 5 pancreatic) in 179 patients between April 1982 and December 1988. The mean duration of treatment was 10.5 days (range, 2–22 days). Antimouse antibody data were analyzed on the most recent 133 treatment courses where the antibody status was available pretreatment. Determination of antimouse antibody production was elicited by ELISA technology at days 0, 7, 14, and 28 of OKT3 treatment. Patients were categorized according to the antibody response as follows: (a) absence of antibody; (b) low titer (1:100); or (c) high titer (≥1:1000). Our earlier experience has demonstrated that retreatment with OKT3 is successful in groups a and b. The development of antimurine antibodies was analyzed with regard to the following parameters: (1) The duration of OKT3 treatment; (2) treatment type (prophylactic, primary, or secondary); (3) primary treatment or retreatment; (4) concomitant immunosuppressive regimen (double or triple therapy); (5) dosage of concomitant immunosuppressive drugs; and (6) transplant organ type. The following results were obtained. (1) Duration of treatment had no effect on antibody production (11.0 days in antibody negative and 10.0 days in antibody positive). (2) There was no difference in antibody formation rates for the first treatment of OKT3 when it was used as prophylaxis (26%), primary (19%), or secondary (27%) therapy. (3) Antibody formation rate with first treatment was 29%; with retreatment, patients who were antibody negative following first treatment became positive in 28% of cases, and retreated patients who were low titer positive following first treatment converted to high titer in 57% of cases. (4) Antibody formation was higher in patients receiving double immunosuppressive therapy (36%) than in those receiving triple immunosuppressive therapy (21%) during OKT3 treatment. (5) Concomitant immunosuppression was lower in the antibody-positive group during OKT3 therapy: steroids, 61 mg/day vs. 52 mg/day; azathioprine, 89 mg/day vs. 66 mg/day; CsA, 317 mg/day vs. 186 mg/day. (6) Antibody formation rates were lower in nonrenal transplants following first treatment with OKT3 (liver 17%, heart 17%, kidney 28%); this reflects the higher doses of concomitant immunosuppressive therapy used in nonrenal transplants. In conclusion, anti-mouse antibody formation varies inversely with the amount of immunosuppression used during OKT3 therapy, and the ability to reuse OKT3 can be related to maintenance of baseline immunosuppressive therapy.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID