摘要:

Background.Induction therapy with antithymocyte globulin (ATG) reduces the incidence of acute rejection after transplantation. A study was undertaken to assess the efficacy and safety of ATG induction on tacrolimus-based and cyclosporine A (CsA)-based therapies compared with immediate tacrolimus triple therapy in kidney transplant recipients.Methods.In a 6-month, open-label, randomized, prospective study conducted in 30 European centers, 555 renal transplant patients were randomly assigned to tacrolimus triple therapy (Tac triple, n=185), ATG induction with tacrolimus (ATG-Tac, n=186), or ATG induction with CsA microemulsion (ATG-CsA, n=184); all were combined with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection episode confirmed by biopsy.Results.Patient demographics and clinical parameters at baseline were similar. Patient and graft survival rates were similar in all groups. The incidence of clinically apparent acute rejection was significantly higher (P=0.003) for Tac triple (33.0%) compared with ATG-Tac (22.6%) and the incidence for ATG-Tac was significantly lower (P=0.004) than for ATG-CsA (37.0%). The incidences of acute rejection confirmed by biopsy (primary endpoint) were 25.4%, 15.1%, and 21.2% for Tac triple, ATG-Tac, and ATG-CsA, respectively (Tac triple vs. ATG-Tac,P=0.004). The incidences of corticosteroid-resistant acute rejection were 7.0% (Tac triple), 4.8% (ATG-Tac), and 10.9% (ATG-CsA) (ATG-Tac vs. ATG-CsA,P=0.038). In the ATG groups, the incidences of leukopenia, thrombocytopenia, serum sickness, fever, and cytomegalovirus infection were significantly higher (P<0.05).Conclusions.Acute rejection was significantly lower in the ATG-Tac group compared with the ATG-CsA and Tac triple groups. Significantly more hematologic and infectious adverse events were observed in both ATG induction groups.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Posttransplant lymphoproliferative disorder (PTLD) remains a difficult management issue; therefore, many studies focus on the identification of risk factors to allow for preventive strategies. We investigated risk factors for PTLD in the adult renal transplant setting.Methods.A single-center, matched case-control study design was used. Cases were identified from patients who underwent a first renal transplant between January 1, 1985, and December 1, 2001. Two controls were chosen per case, matched (±1 year) by date of transplant and graft survival. Clinical and demographic data were ascertained from medical records. Pretransplant serology for Epstein-Barr virus (EBV) and cytomegalovirus was confirmed on frozen, stored sera. Statistical analysis included univariate and multivariable examination of putative risk factors using conditional logistic regression.Results.Twenty cases of PTLD were identified, an incidence of 2.4%. Median time from transplant to diagnosis was 55 months (range, 3–168 months), with 16 cases of late-onset PTLD (>1 year posttransplant). The only significant risk in univariate analysis was EBV-negative status at transplant (risk ratio 6.0,P=0.03). In multivariable analysis, EBV-negative status remained significant (adjusted risk ratio 8.9,P=0.01). The risk related to EBV status held true when late cases were analyzed separately (adjusted risk ratio 7.1,P=0.03).Conclusions.Pretransplant EBV-seronegative status is a strong risk for development of PTLD in adult renal allograft recipients, even in late disease. These results indicate that primary infection with EBV may have a pathogenic role in some cases of late PTLD.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Alveolar echinococcosis (AE) of the liver is a rare and severe parasitic disease. It behaves like a slow-growing liver cancer, and liver transplantation (LT) has been proposed in advanced cases since 1985. The aim of this retrospective study was to collect all AE transplant cases in Europe, analyze the results, and specify the usefulness of LT for this unusual indication.Methods.A questionnaire was sent to 83 LT centers from July 1996 to December 1999.Results.Sixty-five centers responded: 45 AE patients (mean age, 45.8 years) underwent an LT procedure at 16 LT centers. The mean interval between diagnosis and LT was 5 years. One patient died during the hepatectomy phase. Five-year survival was 71%. Five-year survival without recurrence was 58%. The nine early deaths were mostly related to bacterial or fungal infections, or both, in patients in bad condition when LT was performed. Six patients had a graft AE reinfection. Five late deaths were related directly to ongoing AE. In the other cases, benzimidazole (BZM) therapy seemed to stabilize AE residues.Conclusions.This unique experience indicates that LT is feasible for life-threatening AE. Specific management is needed to optimize the results: earlier decision for LT in incurable symptomatic biliary AE, pre- and post-LT BZM therapy, meticulous pre-LT evaluation to identify extrahepatic extension, and an immunosuppressive regimen kept to a minimum.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The rapid and massive death of cultured donor myoblasts after injection in vivo is a major problem for clinical myoblast transfer therapy (MTT). This study shows blood-borne factors are responsible and that ablating the host natural killer (NK) cell response greatly enhances the survival of such donor myoblasts.Methods.Cultured male donor myoblasts were injected into muscles of female host mice and surviving donor male DNA (myoblasts) quantified using a Y-chromosome specific (Y1) probe. Survival of donor myoblasts transfected with m144, a murine major histocompatibility complex (MHC) class I homologue that protects against NK attack, was quantified. In addition, donor myoblast survival was investigated in host mice following initial (before MTT) and sustained (repeatedly for 3 weeks after MTT) depletion of host NK1.1+and CD4+/CD8+cells using specific monoclonal antibodies (either alone or in combination) for up to 3 weeks after MTT, as well as in beige (deficient in NK activity) and in perforin-deficient mdx host mice.Results.A major role for blood-borne factors (especially cells) was confirmed by MTT experiments in irradiated and perfused host mice. Substantially enhanced myoblast survival was seen with donor myoblasts modified by transfection with the m144 molecule or following antibody depletion of host NK1.1+cells and in beige host mice. Other studies support some role for CD8+but not CD4+cells.Conclusions.These combined data support a central role for host NK cells in the rapid initial death of donor myoblasts. The demonstrated role of NK cells provides strategies to enhance the efficacy of clinical myoblast transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Before kidney transplantation, a serological crossmatch is routinely performed between donor and recipient to prevent hyperacute rejection by donor-specific anti-human leukocyte antigen (HLA) antibodies. After transplantation, the presence of these antibodies is not routinely monitored. We wanted to know whether donor-specific anti-HLA antibodies are detectable during acute rejection (AR), before or after reduction of immunosuppression in kidney transplant recipients who were converted from cyclosporine A (CsA) to the less nephrotoxic azathioprine (AZA) or mycophenolate mofetil (MMF) at 1 year after transplantation.Methods.Plasma samples were collected before transplantation, at several time points after transplantation, and during AR. Antibodies were measured in 29 patients: 5 patients with AR during the first year after transplantation (before conversion), 14 patients with AR after conversion or dose-reduction of AZA or MMF, and a control group of 10 patients without AR during a follow-up of 2 years (1 year before and 1 year after conversion of immunosuppression). Antibodies were measured by complement-dependent cytotoxicity assay, enzyme-linked immunosorbent assay (ELISA), and flow-cytometry in a crossmatch with donor spleen cells.Results.Donor-specific antibodies were not detectable after transplantation in the control group without AR, nor in patients with AR shortly after transplantation during CsA therapy. After conversion from CsA to AZA or MMF, antibodies appeared only in one patient after graft failure followed by transplantectomy and in patients during AR on AZA but not on MMF therapy.Conclusion.In this patient group, we could not detect donor-specific antibodies during CsA treatment, not even at the time of AR using three different techniques. Donor-specific antibodies were primarily present during AR in patients converted from CsA to AZA and were not found in the sera from patients converted to MMF.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The authors previously showed that intratracheal delivery (ITD) of donor splenocytes induced prolonged survival of fully allogeneic cardiac grafts in mice. In this study, this treatment protocol was combined with blockade of the CD40 pathway in an attempt to induce operational tolerance.Methods.CBA mice were given donor splenocytes (1×107) or Kbpeptide (100 &mgr;g) by ITD with or without antibody specific for mouse CD40 ligand (MR1, 200 &mgr;g) 7 days before transplantation of a C57BL/10 heart. Also, splenocyte (5×107) from primary recipient CBA mice given ITD of donor splenocytes or Kbpeptide plus MR1 were adoptively transferred into naive CBA secondary recipients 7 days after the pretreatment and C57BL/10 hearts were transplanted into those recipients the same day.Results.ITD of donor splenocytes and Kbpeptide induced prolonged survival of cardiac grafts (median survival time [MST], 74 and 56 days, respectively), whereas naive control mice and mice pretreated with syngeneic splenocytes had acute graft rejection (MST in both groups, 7 days). When MR1 was included, all grafts survived indefinitely (>200 days), but mice pretreated with MR1 alone had graft rejection (MST, 54 days). Mice bearing cardiac grafts had acceptance of skin grafts from C57BL/10 but not BALB/c mice, demonstrating that operational tolerance was induced. Secondary recipients given adoptive transfer of splenocytes from primary recipients of the combined treatment had acceptance of C57BL/10 grafts, suggesting that regulatory cells were generated within 7 days of pretreatment.Conclusions.ITD of donor splenocytes or Kbpeptide under blockade of the CD40 pathway induced operational tolerance and generated regulatory cells.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.HLAMatchmaker is a recently developed computer-based algorithm to determine donor-recipient HLA compatibility at the molecular level. Originally designed for highly alloimmunized patients, this algorithm is based on the concept that immunogenic epitopes are represented by amino acid triplets on exposed parts of protein sequences of HLA-A, -B, and -C chains accessible to alloantibodies. Donor HLA compatibility is determined by intralocus and interlocus comparisons of triplets in polymorphic sequence positions. For most patients, HLAMatchmaker can identify certain mismatched HLA antigens that are zero-triplet mismatches to the patient’s HLA phenotype and should, therefore, be considered fully histocompatible. The present study was designed to determine how class I HLA matching at the triplet level affects kidney transplant outcome.Methods.We analyzed two multicenter databases of zero-HLA-DR–mismatched kidneys transplanted from 1987 to 1999. One database consisted of 31,879 primary allografts registered by U.S. transplant centers in the United Network for Organ Sharing database and the other consisted of 15,872 transplants in the Eurotransplant program.Results.HLA-A,B mismatched kidneys that were compatible at the triplet level exhibited almost identical graft survival rates as the zero-HLA-A,B antigen mismatches defined by conventional criteria. This beneficial effect of triplet matching was seen for both nonsensitized and sensitized patients and also for white and nonwhite patients.Conclusions.These findings suggest that the application of HLAMatchmaker will increase the number of successful transplants, at least in the HLA-DR match combinations.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.HLAMatchmaker is a computer algorithm that determines human leukocyte antigen (HLA) compatibility at the level of polymorphic amino acid triplets in antibody-accessible sequence positions. Recent studies have shown that HLA-DR–matched kidney transplant recipients with zero to two triplet mismatches had almost identical graft survival rates as those with zero HLA-A,B,DR antigen mismatches. This report describes how HLAMatchmaker can be used to identify more compatible donors for highly sensitized patients.Methods.The HLAMatchmaker program was used to calculate the probability of finding a donor (PFD) with zero, one, or two triplet mismatches for 54 highly sensitized patients waiting for a kidney transplant and having panel reactive antibody (PRA) values greater than 85% and 50 randomly selected nonsensitized patients with PRA values less than 3%.Results.There was a wide variability for PFD values for the two patient cohorts. If only donors with zero HLA-A,B mismatches were deemed acceptable for recipients, the median PFD of a zero-antigen mismatch was 0.046% for nonsensitized patients and 0.009% for highly sensitized patients (P=0.007). Half of the highly sensitized patients had a PFD below 0.01%, or fewer than 1 in 10,000 donors would have zero antigen mismatches. Application of HLAMatchmaker identified additional HLA antigens with zero-triplet mismatches for 27 patients, resulting in a 1.8-fold increase in PFD. Considering additional antigens with one-triplet or two-triplet mismatches increased the PFD by an additional 3.8-fold and 13.7-fold, respectively. Acceptable antigen mismatches for 37 of the 54 highly sensitized patients were identified by consistently negative reactions in serum screens, and their addition resulted in a 12.7-fold increase of the PFD to a median of 0.141%. Applying these acceptable antigens to the HLAMatchmaker algorithm identified additional antigens with zero or acceptable triplet mismatches and their inclusion increased the PFD by 3.3-fold to 0.347%.Conclusions.HLAMatchmaker offers a valuable strategy for identifying more suitably HLA-matched donors and has the potential for alleviating the problem of accumulation of highly sensitized patients on the transplant waiting list.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Severe sepsis in immunosuppressed recipients of solid-organ transplants is associated with a high mortality. Conventional management of sepsis in this patient population has not specifically attempted to treat the underlying inflammatory or procoagulant responses that contribute to the development of multisystem organ failure. Drotrecogin alfa (activated, human activated protein C) has been shown to be a safe and effective adjuvant in the treatment of severe sepsis; however, experience in recipients of solid-organ transplants has not been addressed. The treatments and outcomes of three solid-organ transplant recipients (liver, kidney, and kidney-pancreas) who experienced episodes of severe sepsis are presented and demonstrate initial success with the use of drotrecogin alfa (activated).

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID