摘要:

Chronic tubulointerstitial nephropathy during long-term cyclosporine A (CsA) use has led to a search for equally effective but safer analogues. In this study we evaluated one of these analogues, cyclosporine G (CsG), in a rat model of chronic cyclosporine nephrotoxicity. CsG has immunosuppressive effects equivalent to CsA when dosed on a weight basis. Pair-fed Sprague-Dawley rats kept on a low-salt rice diet were given CsA 15 mg/kg, CsG 15 mg/kg, CsG 25 mg/kg, or vehicle subcutaneously. After 21 days, CsA animals had a lower glomerular filtration rate, measured by inulin clearance (0.16±0.04 ml/min/100 g) and higher serum creatinine (0.94±0.06 mg/dl) than CsG 15 mg/kg (GFR: 0.41±0.10 ml/min/100 g and serum creatinine: 0.68±0.09 mg/dl), CsG 25 mg/kg (GFR: 0.39±0.16 ml/min/100 g) or control rats (GFR: 0.62±0.06 ml/min/100 g; serum creatinine: 0.56±0.03 mg/dl), respectively (P<0.05). The CsA group had considerable cortical and medullary injury (interstitial fibrosis and tubular atrophy), whereas both groups of CsG animals had more limited changes. Despite the same or larger doses of CsG on a weight basis, cyclosporine blood levels were significantly lower in CsG than CsA rats. We conclude that CsG, an analogue of cyclosporine with immunosuppressive activity equivalent to that of CsA, produced less nephrotoxicity in a model of chronic renal injury in rats, using both functional and structural parameters.

ISSN:0041-1337    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Tumor necrosis factor α and β are polypeptide cytokines with a wide range of metabolic, immunologic, and inflammatory activities. TNF is known to participate in immune meditated injury of native lungs, but a role for TNF in mediating lung allograft rejection (AR) has not been established. In experiments reported here, we assessed the role of TNF in mediating lung AR in a rat model of lung transplantation (BN→Lew) (RT1n→WRT11). This model shows florid AR with all grafts completely destroyed by day 6 posttransplant. Graft pathology is characterized by massive lymphocytic infiltrates and hemorrhagic necrosis. Initially, 5 lung allograft recipients in each group were sacrificed on days 1 to 6 post-transplant. Allografts were removed, mRNA isolated, and Northern blotting or RT-PCR performed with blots probed with cDNAs or oligos specific for rat TNF-α cyclophylin and γ-actin. Data were compared with syngeneic transplants (Lew→Lew) and with normal controls. In addition, frozen lung allograft tissue was examined by indirect immunofluorescence, using antibodies specific for TNF. TNF-α mRNA levels were detectable on day 2 posttransplant, and peaked on days 6–7 posttransplant. IF studies snowed TNF protein expression in mononuclear cells of rejecting allografts on day 3, peaking on day 6. Both TNF-α mRNA and protein levels correlated with maximal AR and hemorrhagic necrosis of grafts. Minimal TNF-α mRNA or protein was detected in syngeneic grafts or in contralateral native lungs. We than examined the ability of a rabbit polyclonal anti-TNF-α (7000 U/day) and anti-TNF-β (5000 U/day) with 30% crossreactivity with rat TNF to modify the AR response. For each group, 4–5 left lung transplants were performed as described, and animals treated with anti-TNF-α, anti-TNF-β, (anti-TNF-α + anti-TNF-β) or with preimmune rabbit sera. All animals were sacrificed on day 6 posttransplant. Several pathological categories of inflammation were examined and scored (0–4), with a score of 0=0% involvement; 1=1–25% involvement; 2=26–50% involvement; 3=51–75% involvement; and 4=76–100% involvement. The mean and SD scores were obtained for all animals in the treatment categories mentioned above, and compared with preimmune—treated controls. Briefly, no differences in perivascular, peribronchial, or peribronchiolar cell infiltrates or edema were seen in treatment groups compared with controls. However, profound differences were seen in scores for vasculitis (1.6±0.5 vs. 3±0), (P< 0.0001), necrosis (0±0 vs. 3.0±0.71) (P<0.00001), and interalveolar hemorrhage (0.6±0.5 vs. 3.5±0.71) (P< 0.00001) in the (anti-TNF-α + anti-TNF-β) treatment group compared with preimmune controls. Both anti-TNF-α and anti-TNF-β treatment groups showed ameliorative effects on hemorrhagic necrosis and vasculitis, but not to the degree seen with the combination of both antibodies. These data suggest that TNF-α and β are important mediators of lung AR in the rat. Although the intensity of cellular infiltration was not affected by anti-TNF therapy, there were profound reductions in vasculitis and hemorrhagic necrosis of the grafts.

ISSN:0041-1337    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Flushing hepatic grafts immediately before revascularization with a specially designed rinse solution such as “Carolina rinse” has been reported to improve survival after liver transplantation in the rat. This study investigated the influence of Carolina rinse and adenosine rinse on early graft function, microcirculation, and leukocyte (WBC)-endothelial cell interaction of arterialized syngeneic orthotopic liver transplants in Lewis rats. Livers were preserved for 24 hr in University of Wisconsin solution and flushed immediately before re-perfusion with either Ringer's lactate (group A: n = 7), Ringer's lactate + 0.2 mmol/liter adenosine (group B: n = 6), or Carolina rinse (group C: n = 7). Microvascular perfusion and WBC accumulation were assessed by intravital fluorescence microscopy. In group C, acinar perfusion was significantly improved, accompanied by a lower percentage of nonperfused sinusoids 1 hr after reperfusion (mean → SEM: 26±2% [group A], 21±2% [B], 11±1% [C],P<0.01 for C vs. A or B). In addition, Carolina rinse and, to a lesser extent, adenosine rinse reduced the number of WBC sticking in sinusoids and postsinusoidal venules. Better graft function in group C was indicated by increased bile flow during the observation period of 90 min after reperfusion (0.5±0.3 ml/100 g liver [group A], 1.5±0.7 [B], 3.7±0.6 [C],P<0.01 for C vs. A or B). We conclude that Carolina rinse is able to improve early excretory hepatocellular function, microvascular perfusion, and intrahepatic WBC accumulation after prolonged cold ischemia and reperfusion, but adenosine is unlikely to be the key component of this rinse solution.

ISSN:0041-1337    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The expression of some genes has been comparatively studied in transplanted rat liver and in liver reperfused after ischemia in situ. Experiments on protein synthesis by tissue slices from cold-stored or transplanted livers show that rat livers that retain a good capacity for protein synthesis during storage undergo a profound impairment in the capacity for protein synthesis during the first hours after transplantation. This recovers in the following hours. There is never any indication of synthesis of stress proteins, and of hsp 70 in particular. The steady-state level of mRNAs for albumin, transferrin, and β-actin, which are well expressed in reperfused postischemic livers in vivo, are reduced early after transplantation and recover only many hours later. Run-on analysis shows that an early defect in transcription and a partial recovery of this process later on are responsible for these changes. The steady-state levels of the same mRNAs are well maintained in donor livers preserved in University of Wisconsin solution for at least 12 hr, and less satisfactorily in Euro-Collins solution. Results of run-on analysis parallel the data on mRNA levels. The behavior of these mRNAs is, therefore, clearly different in reperfused and transplanted liver.The early stages of liver transplantation seem to be characterized by a depressed capacity of gene expression, without the reactive phenomenon of activation of stress protein genes that occurs in reperfused postischemic livers.

ISSN:0041-1337    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

We have retrospectively analyzed the glomerular filtration rate by125-I iothalamate clearance and creatinine clearance in a group of 661 persons evaluated as potential kidney donors. The average GFR in this population is lower than that reported in previous studies and ranges from 102±15 and 114±17 ml/min for males and females age 21–30 to 84±13 and 79±15 ml/min for males and females age 51–60. Furthermore, there has been a gradual decrease in GFR in this population from 1970 to 1990 in both the entire population and in those under the age of 40. The cause of this drop is not apparent. These data can be utilized to determine the appropriateness of a potential donor for donation, and may indicate that our current standards are too high.

ISSN:0041-1337    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The influence of cyclosporine pharmacokinetic parameters on clinical events and outcome after transplantation was studied in 100 renal transplant recipients who underwent a pre-as well as posttransplant CsA pharmacokinetic evaluation. Among the patients, 30 were black and 50 were white. Black recipients had significantly lower bioavailability (F) pre-as well as posttransplantation than white recipients, the post-transplant mean F values being 25.8±9.0% and 38.1→ 16.7%, respectively (P<0.002). The posttransplant CsA clearance rate (CL) and oral clearance (clearance/bio-availability; CLoral) were significantly higher in patients who had acute rejection than in those who did not, with CL mean values of 425±141 ml/min and 359±131 ml/min, respectively (P<0.02). The initial posttransplant F was significantly lower, and the CLoralhigher in patients who eventually lost their grafts than in those who did not, the mean F values being 26.5±12.8% and 38.7± 17.5%, respectively (P<0.002). Thus, several important relationships between CsA pharmacokinetic parameters and clinical events following renal transplantation were documented. The CLoraldecreased during the first 3 months after transplantation (P<0.0001), but it was stable thereafter. Neither the bioavailability nor the clearance of CsA showed a correlation with administered dose. These results indicate that certain recipient groups, such as black patients, and individuals with rapid CL, may benefit from larger CsA doses and/or shorter dosage intervals, in order to compensate for these interpatient variabilities.

ISSN:0041-1337    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

We studied the effect of acute renal allograft rejection and its timing on the development of chronic rejection and subsequent graft loss. Between January 1, 1987 and April 30, 1991, 424 patients at the University of Minnesota received a primary kidney transplant (minimum follow-up, 1 year). Patients were subdivided by donor source, presence or absence of acute rejection, and the timing of acute rejection onset (early, ≤ 60 days vs. late, > 60 days post-transplant).For living donor (LD) transplant recipients (n=219), the incidence of chronic rejection is 0.8% in those who had no acute rejection (n=130), 20% in those with acute rejection ≤60 days (n=59) (P<0.001 vs. no acute rejection), and 43% in those with acute rejection > 60 days (n=30) (P<0.001 vs. no acute rejection,P=0.04 vs. early acute rejection). For cadaver (CAD) transplant recipients (n=205), the incidence of chronic rejection is 0% in those who had no acute rejection (n=109), 36% in those with acute rejection ≤ 60 days (n=69) (P<0.001 vs. no acute rejection), and 63% in those with acute rejection > 60 days (n=27) (P<0.001 vs. no acute rejection,P=0.03 vs. early acute rejection).For both LD and CAD recipients, no grafts have been lost to chronic rejection among those who did not first have at least 1 acute rejection episode. In contrast, 23 patients with acute rejection have had graft loss to chronic rejection. For both LD and CAD recipients, those with > 1 acute rejection episode had significantly more chronic rejection than those with only 1 rejection (P<0.05). There was no significant difference in the incidence of chronic rejection based on whether the first acute rejection episode was steroid resistant or steroid responsive.We conclude that acute rejection is strongly related to the development of biopsy-proven chronic rejection and subsequent graft loss. Patients undergoing their first acute rejection episode > 60 days (vs. ≤ 60 days) have an increased incidence of chronic rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The pretransplant sera of 27 IgA nephropathy (N) kidney transplant patients were investigated for antibodies to the HLA molecule, together with 104 sera from non-IgA N patients and 60 controls. IgA antibodies to HLA were found in 61% of IgA N patients and 2% of non-IgA N patients. IgA N patients with IgA antibodies to HLA had a 100% 2-year cadaver donor graft survival rate compared with 70% in those without IgA antibodies. Patients with IgG antibodies to HLA without accompanying IgA antibodies had the worst graft survival rates. We propose that IgA anti-HLA contributes to the high kidney graft survival in IgA N patients by blocking IgG antibodies or inhibiting cellular immune response.

ISSN:0041-1337    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Forty-three renal transplant recipients receiving cyclosporine were started on 200 mg/day of oral ketoconazole 10 days to 75 months posttransplant. The cyclosporine dose was reduced by 70% when ketoconazole was started. The mean cyclosporine dose was 5.6 mg/kg/day preketoconazole, and 0.9, 0.8, and 0.7 mg/kg/day at one, two, and three years after addition of ketoconazole (cyclosporine dose reduction 84%, 86%, and 88% at one, two, and three years, respectively). Two patients died after two years of combination therapy, six patients returned to dialysis, and ketoconazole was discontinued in four. Renal function in patients on ketoconazole remained stable (serum creatinine 1.8, 1.7, 1.7, and 1.8 mg/dl preketoconazole and at one, two, and three years, respectively).In a second study, 52 patients were randomized to standard doses of cyclosporine (n=28), or reduced doses of cyclosporine with ketoconazole (n=24); seven of the patients were not started on ketoconazole. In 28 patients on standard-dose cyclosporine, there were two deaths and one graft loss. In 17 patients receiving ketoconazole there were two deaths and no graft losses. Renal function and the frequency of rejection episodes was similar in the two groups. In the ketoconazole group, the cyclosporine dose was <20% of that in the patients on standard doses.In both studies addition of ketoconazole to cyclosporine-treated patients resulted in significant inhibition of cyclosporine metabolism and decrease in dosage in patients followed for up to four years. This drug interaction provides a significant reduction in cost of immuno-suppressive therapy in organ transplant recipient.

ISSN:0041-1337    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The causes of failure were studied for 1386 cadaver kidney transplants shared through the UNOS 6-antigen match program from November 1987 to February 1992. The one-year graft survival for 1004 HLA-matched first cadaver transplants was 88% compared with 90% for parent donor and 78% for 22, 188 HLA-mismatched first cadaveric donors reported to the UNOS Scientific Renal Transplant Registry. The cause of graft loss was immunological in 55% of HLA-mismatched cadaver kidney failures, whereas only 39% of the HLA-matched graft failures were immunological. The fraction of immunological failures in HLA-matched first transplant recipients younger than age 17 was 57% and decreased with increasing age to 14% for recipients older than age 60. Death with a functioning graft accounted for 50% of failures in the older age group. Sensitization was associated with an increased incidence of immunological failures in matched first graft recipients from 36% in nonsensitized to 53% in broadly sensitized patients, and 55% of failures were immunological in second graft recipients compared with 39% in first transplants. Some immunological failures may have been due to tissue typing, since only 18% of failures in kidneys with well-defined HLA antigens were immunological, whereas 44% of kidneys matched with more difficult HLA antigens were lost due to immunological causes. The results indicate that phenotypically identical cadaver renal transplants have a reduced rate of immunological failures. As the accuracy of this tissue typing for the more difficult HLA antigens improves, immunological failures in this group of transplants will decline even further.

ISSN:0041-1337    

出版商:OVID    

年代:1993

数据来源: OVID