摘要:

The shortage of organs for transplantation is especially severe for the critically ill newborn infant, for whom donors of the appropriate size are particularly scarce. One way to overcome this problem is to use animals in lieu of humans as organ donors. The major limitation to using animals for this purpose is the susceptibility of animal organs to hyperacute rejection, a violent rejection reaction thought to be mediated by antidonor antibody and complement. To evaluate the potential application of xenotransplantation to newborns, we tested neonatal humans and neonatal baboons and found that neither population expressed significant levels of xenoreactive anti-pig antibodies. We transplanted heterotopically hearts from newborn pigs into unmanipulated newborn baboons (n=4). There was no evidence of hyperacute rejection in any of the grafts; the animals were killed with functioning grafts at 15, 81, 82, and 82 hr. This outcome contrasts with that of newborn pig-to-mature baboon and mature pig-to-mature baboon cardiac xenografts, which were rejected within 1 hr of transplantation. The histology of pig graft biopsies from the newborn recipients was normal. Immunohistochemistry revealed only traces of IgM, C3, C4, and the membrane attack complex along graft endothelium. Fibrin deposition along endothelial surfaces was observed early after transplantation and became more extensive with time; in the absence of endothelial bound antibody or complement, this change may represent preservation injury. This study suggests that due to low levels of natural antibody, the newborn infant may permit prolonged xenograft survival.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Glutathione is important in cellular defense against oxidative stress. We postulated that administration of N-acetylcysteine (NAC), a glutathione precursor, might help maintain or replenish hepatic glutathione stores, thereby reducing reperfusion injury in liver grafts after warm ischemia. Eighteen pigs were subjected to 2 hr of warm hepatic ischemia and divided into a control group (group A, n=6), a preischemia treatment group (group B, n=6: NAC, 150 mg/kg, continuous i.v. infusion 1 hr before ischemia), and a postischemia treatment group (group C, n=6: NAC, 150 mg/kg continuous i.v., begun 20 min before reperfusion and continued for 1 hr). At initiation of laparotomy, we measured hepatic levels of reduced glutathione (GSH), its oxidized form (GSSG), ATP, aspartate aminotransferase (AST), and lactate dehydrogenase (LDH). Before reperfusion, after 2 hr of warm ischemia, GSH, GSSG, and ATP were measured. One hour after reperfusion, we measured GSH, GSSG, ATP, AST, and LDH. Bile output was recorded every 10 min. Postreperfusion AST and LDH were significantly lower in both treatment groups than in controls. In group B, hepatic glutathione was maintained at significantly higher levels than in controls, even after ischemia (P<0.05). In group C, although hepatic GSH levels fell until reperfusion, after administration of NAC, hepatic GSH reached the level of the preischemia treatment group. In both treatment groups, GSH 1 hr after reperfusion was significantly higher than in the controls (P<0.01): regeneration of glutathione was seen in all 6 animals in group C, compared with 2/6 in group B and none in the control group. ATP recovery, bile output, and survival were all better in the treatment groups thait in the control group. Pretreatment with NAC helps maintain hepatic glutathione during warm ischemia.; given after ischemia, NAC is effective in replenishing depleted glutathione stores. Adjunctive use of NAC was associated with improved glutathione homeostasis, improved bile output and ATP regeneration, and increased survival.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

To investigate the role of platelet-activating factor (PAF) in the preservation/reperfusion injury of the liver graft, the effect of treatment with a potent PAF antagonist (E5880) was evaluated in a pig orthotopic liver transplantation model. The graft liver was flushed out and preserved for 8 hr at 4°C using a simplified University of Wisconsin solution. The PAF antagonist was administered into the University of Wisconsin solution (1 mg/L), into the rinsing solution (1 mg/L), and to a recipient pig (0.3 mg/kg d.i.v.) in group 1. The PAF antagonist was not given in the control group (group 2). Postoperative survival of more than 12 hr was 100% (9/9) in group 1 and 56% (5/9) in group 2 (P<0.05). At 12 hr after reperfusion of the graft (RPF), the arterial ketone body ratio (acetoacetate to 3-hydroxybutyrate) increased to 1.54±0.15 (mean ± SEM) in group 1, compared with 0.95±0.09 (P<0.05) in group 2. In group 2, blood leukocyte count decreased to 8.3±0.9 (x103/μl) at 2 hr after RPF, in contrast to a slight increase in group 1 (14.3±1.8 x 103/μl,P< 0.01). At 4 hr after RPF, glutamic oxaloacetic transaminase (461±59 vs. 712±97 U/L,P< 0.05), glutamic pyruvic transaminase (65±4 vs. 82±5 U/L,P< 0.05), and the lactate level (6.2±1.1 vs. 9.4±1.0 mmol/L,P< 0.05) in arterial blood were significantly lower in group 1 than in group 2. Light and electron microscopic study at 1 hr after RPF showed neutrophil sludging in the sinusoids and sinusoidal endothelial cell damage in group 2, while these findings were attenuated in group 1. It is suggested that PAF plays a key role in microcirculatory disturbance of the liver graft manifested on reperfusion, and that the treatment with E5880 has a protective effect against preservation/reperfusion injury of the graft in liver transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Oxidative damage is thought to play an important role in ischemia/reperfusion injury, including the outcome of transplantation of the liver and intestine. We have investigated oxidative DNA damage after combined transplantation of the liver and small intestine in 5 pigs. DNA damage was estimated from the urinary excretion of the repair product 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). In the first 1–3 hr after reperfusion of the grafts, 8-oxodG excretion was increased 2.9-fold (1.7–4.1; 95% confidence intervals;P<0.05). A control experiment included sham surgery with clamping of the suprarenal inferior caval vein in 2 pigs during steady state infusion of 8-oxodG. While the caval vein was clamped, the urinary excretion of 8-oxodG was almost blocked, whereas after removal of the clamp, the excretion returned to and did not exceed the preclamp levels. In a separate experiment with 2 pigs, the elimination of injected 8-oxodG was shown to adhere to first-order kinetics with a clearance and a terminal elimination half-life of approximately 4 ml min-1kg-1and 2½ hr, respectively. The injected dose was completely excreted into the urine within 4 hr. It is concluded that substantial oxidative damage to DNA results from reperfusion of transplanted small intestine and liver in pigs, as estimated from the readily excreted repair product 8-oxodG.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The Collaborative Corneal Transplantation Studies are a pair of multicenter prospective clinical trials evaluating the effectiveness of histocompatibility matching in high risk keratoplasty patients. The antigen matching study (AMS) evaluated HLA matching in patients without circulating lymphocytotoxic antibody to HLA antigens and the cross-match study (CS) evaluated the effect of using cross-match-negative donors in patients with identified circulating lymphocytotoxic antibodies to HLA antigens. Sera from 510 patients considered for enrollment in the studies were screened preoperatively for the presence of anti-class I lymphocytotoxic antibodies (LA). The 42 patients (8%) found to have detectable LA entered the CS. The 468 patients found not to have detectable LA preoperatively entered the AMS. Fifteen of the 37 transplanted CS patients were found to have donor-specific anticlass I antibody (before or after surgery). These patients were also screened for anti-class II LA and 25 had anti-class II panel reactive antibody ≥ 5%.Forty-nine of the 419 transplanted AMS patients (12%) were found to have produced anti-class I LA after surgery, and in 19 patients, antibody specificities were those of donor HLA antigens. There was a significant association between the number of mismatched class I antigens and the number of donor-specific LA produced. The production of LA by AMS patients was significantly associated with reaction episodes; eighty-two percent of patients (40 of 49) with LA had reaction, compared with 63% of patients (230 of 365) without LA (P=0.02). Likewise, production of donorspecific LA was significantly associated with immunemediated graft failure (P=0.025).For CS patients, there was no correlation between the production of donor-specific anti-class I or nonspecific anti-class II antibodies and graft outcome. However, the CS patients had poorer graft survival than did AMS patients at 3 years (57% vs. 66%,P=0.01). These data demonstrate that LA, especially directed against donor class I HLA antigens following corneal transplantation in high risk patients, are associated with immune graft rejection and can be an indicator of allograft rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Results of 34 recipients of living related renal allografts initially treated with cyclosporine, azathioprine, and prednisolone and later electively converted to AZAand PRED are presented. Thirteen (group A), 14 (group B), and 7 (group C) patients were converted before 9 months, between 9 and 12 months, and after 12 months, respectively. Thirty-four patients who were on AZA and PRED and had never received CsA served as controls. Of the 34 patients, 33 were HLA haploidentical with their donors and 1 was HLA identical. All patients received a mean 8.62±7.39 third-party blood transfusions. In the control group, 29 patients received haploidentical grafts. The number of blood transfusions given to this group was 7.09±9.13. Of the 34 patients receiving triple-drug therapy, 9 (26%) had acute rejection within 3 months after conversion, as compared with 5 (14.7%) in the control group (P> 0.05). Although 1 case had acute rejection before conversion, all recipients had stable graft function at the time of conversion. Of these 9 recipients, 7 had conversion over 4–7 weeks, while 2 had rapid conversion. Following treatment of the rejection episodes, 4 patients in the study group responded to therapy, as compared with 3 cases in the control group (P>0.05). After a mean follow-up of 18.62 ±10.31 months (range 3-41 months) following conversion, 4 patients were normal, 4 had chronic rejection (mean serum creatinine = 3.0 mg/100 ml), and 1 was back on regular dialysis. Eventually, of the 34 patients who were converted from triple-drug to double-drug therapy, 25 were normal, 5 had stable chronic rejection, 2 were back on regular dialysis, 1 was retransplanted, and 1 died due to failed graft. At the end of follow-up, graft survival in the study group was 88.2%, as compared with 85.5% in controls (P> 0.05).We conclude that conversion from triple-drug to double-drug therapy is not without risk, even in living related primary renal transplantation. Degree of HLA matching, number of pretransplant blood transfusions,and rejection before conversion did not have any significant effect on rejections following conversion, and the graft loss following conversion is unpredictable.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

FK506 has been proven effective for prevention and treatment of liver allograft rejection. Herein, we compare FK506-based immunosuppression with an effective quadruple immunosuppressive regimen, including cyclosporine and antithymocyte globulin. The results of a single center participating in the European multicenter FK506 study are reported, including immunosuppressive efficacy as well as toxicity. Oneyear patient and graft survival was 96.7% and 90.0% for the CsA group and 90.2% and 88.5% for the FK506 group, which is not statistically different. The incidence and severity of acute rejection episodes during the first postoperative year was similar in both treatment groups with 34.4% and 33.3% for the FK506 and CsA treatment group, respectively. Immunosuppressive potency was better for the FK506 group compared with the CsA group according to the incidence of chronic rejection. Furthermore, 5 patients (8.3%) required conversion to FK506 for immunological reasons, i.e., refractory acute or chronic rejection. The incidence of moderate and severe neurotoxicity during the early postoperative period was higher in the FK506 group (21.3%) compared with the CsA group (11.7%), while the incidence of renal insufficiency and acute renal failure was similar (18.0% and 18.3% for the FK506 and CsA treatment groups, respectively). The incidence of CMV infection was significantly higher under treatment with CsA (25.0%) than with FK506 (6.6%) (P≤0.05), while the incidence of pneumonia (13.1% and 13.3%), cholangitis (29.5% and 26.7%), and urinary tract infection (39.3% and 28.3% for the FK506 and CsA treatment groups, respectively) was similar in both treatment groups. However, infection was more serious in some cases treated with FK506, and evolved as the main cause of death in the FK506 treatment group. Therefore, caution should be paid to overimmunosuppression and toxicity in FK506-treated patients. Regarding the monitoring of FK506, FK506 plasma level failed to be a reliable indicator, and therefore we recommend measurement of whole blood FK506 levels. Our data indicate that immunosuppressive potency of FK506 is greater than that of CsA, especially concerning the incidence of chronic rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

We have determined accompanying events and reviewed the management and outcome of late acute cellular rejection episodes in 384 consecutive liver recipients. A significant proportion of patients experienced concomitant viral infection (group 1, n=15 [41%]), with CMV infection comprising the largest group and smaller contributions from other viruses (CMV, 30%; HSV, 5%; EBV, 3%; varicella zoster virus, 3%). Thirteen (35%) patients (group 2) developed late rejection associated with low maintenance immunosuppression, and in a further 10 patients (group 3), no accompanying factor could be identified. Refractory rejection was higher in late compared with early rejection episodes in our series (29% vs. 9.2%,P< 0.05). Antiviral chemotherapy administered in rejection episodes with concomitant viral infection, either as sole treatment in cases with accompanying hepatitis or as adjunctive therapy to further supplemental immunosuppression in episodes of steroid-resistant rejection, controlled the rejection process in all treated patients.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Eighty-six consecutive liver transplant recipients were prospectively randomized in a double-blind, placebo-controlled antifungal prophylaxis study. Seventy-seven patients received 5 days of prophylaxis starting during the transplantation with either liposomal amphotericin B (AmBisome) 1 mg/kg/day or placebo. Among 40 AmBisome-treated patients, no invasiveCandidainfection was seen during the first month, compared with 5 invasiveCandida albicansinfections among 37 control patients (P< 0.05). Furthermore, 1 placebo patient experienced Aspergillus niger pneumonia. Thus, the overall incidence of invasive fungal infections was 0/40 (0%) in the AmBisome group versus 6/37 (16%) in the placebo group (P<0.01). Patient survival at 30 days was 92% versus 94% for AmBisome-and placebo-treated patients, respectively. One patient experienced backache related to AmBisome infusion. Two patients had transient thrombocytopenia possibly caused by AmBisome treatment. AmBisome was otherwise well tolerated. The total cost for all antifungal drugs used in both groups was equal. However, prophylaxis with AmBisome was $5000 less expensive than treatment of proven invasive fungal infections among placebo patients.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Thirty-six renal transplant biopsies were obtained from 20 diabetic patients 1–6.5 years after successful combined pancreatic and renal transplantation (PKtx).1An additional 36 renal transplant biopsies were obtained from 30 diabetic recipients 1–6.8 years after kidney transplantation only (Ktx). Light microscopic lesions indicating diabetic nephropathy were evaluated by a semiquantitative score ranging from 0 to 9. Within 2.5 years after transplantation, light microscopy showed no or only slight diabetic changes in both groups (nephropathy score = 0–2). Later, a nephropathy score ≥ 3 was seen in only 1 of 15 biopsies (6.7%) in the combined PKtx group, but in 11 of 24 biopsies (45.8%) in the Ktx group (P< 0.05).Twenty-eight of the biopsies from the PKtx group and 26 of them from the Ktx patients were examined with electron microscopic morphometry to evaluate the glomerular basement membrane thickness (BMT) and the relative volume of the mesangial tissue (Vv). Of the biopsies taken < 2½ years after transplantation in PKtx patients, and of those similarly taken in the Ktx patients, 93.8% vs. 88.9% had BMT values within 2 SD of the normal (NS). Of the kidney biopsies taken ≥ 2.5 years after transplantation, 91.7% in the PKtx group still had a normal BMT, while only 35.3% of the biopsies in the Ktx group had a normal BMT (P< 0.01). In the PKtx group, the Vvwas normal in 12/16 (75.0%) of the biopsies taken <2½ years after transplantation, and in 9/11 (81.8%) of the biopsies obtained ≥ 2.5 years after transplantation. In contrast, the Vvwas normal in only 1/9 (11.1%) and 2/17 (11.8%) of correspondingly obtained biopsies from Ktx patients (biopsies < 2.5 years after transplantation,P<0.01, and biopsies ≥ 2.5 years after transplantation,P<0.001, respectively). We conclude that a functioning pancreatic transplant can prevent or reduce the various signs of diabetic nephropathy that eventually develop in diabetic patients with a kidney graft only.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID