Beneficial effect of HLA-A and B matched pretransplant blood transfusions on primary cadaveric kidney graft survival

The effects of HLA-A and B matched pretransplant blood transfusions on the survival of a primary cadaveric kidney graft were studied prospectively in a group of 15 patients who had never received a transfusion and had never been pregnant. Kidney graft survival at one year was 87%, whereas a group of 14 nontransfused patients who underwent transplantation in the same center (before this study was initiated) had a graft survival of only 7%. Twenty-six patients who received a transplant in the same center just before and after each protocol patient served as controls. There were no prior pregnancies in this group; all patients had received blood transfusions from random blood bank donors. Kidney graft survival at one year was 76% for this control group, which is not statistically different from that found for the protocol group. Graft survival for the 13 contralateral kidneys from the protocol group donors was only 50% at one year. These kidneys, however, were transplanted in various other centers. From our study, prolongation of kidney graft survival could be demonstrated for patients receiving pretransplant HLA-A-and-B-matched blood transfusions. Sera screening indicated that lymphocytotoxicity might be reduced by pretransplant HLA-A-and-B-matched blood transfusions. The presence of pretransplant antibodies with specificities for HLA-A and/or B could be significantly correlated with poor graft survival.     

Beneficial effect of HLA-DR matching on the survival of corneal allografts

BACKGROUND: Although HLA typing and matching have been used for 3 decades, that practice has been poorly implemented in corneal transplantation, mainly because of inconclusive or contradictory analytical results. Consequently, we studied the immune response of corneal transplant recipients to HLA histoincompatibilities in a large homogeneous study. METHODS: All corneal transplantations performed by a single surgeon between 1976 and 1996 were studied. HLA-AB matching was used for recipient selection. All HLA typings were performed by a single experienced laboratory. Population genetic techniques were used to assess the validity of the HLA typings. Mono- and multivariate analyses were performed to identify the factors which significantly influence the survival of corneal allografts. Simulation studies were carried out to demonstrate the effects of mis-typed donor and recipient HLA-DR typings on analytical results. RESULTS: Retransplantation, degree of vascularization, HLA-AB and DR matching, endothelial cell count, graft size, recipient gender, and storage method were identified as significant factors by our monovariate analyses. A Cox proportional hazards survival analysis model identified degree of vascularization and HLA-AB and DR matching as significant prognostic factors when all immunological rejection episodes were used, P=0.000001. When only irreversible immunological rejection episodes were used, panel reactive antibodies, retransplantation, and number of rejection events were also identified, P=0.000001. Simulation studies showed that the effects of HLA-DR matching are abrogated by poor HLA-DR typings. CONCLUSIONS: Corneal allograft recipients have a normal alloimmune response to histoincompatibilities. Demonstration of that fact requires accurate HLA typings.     

HLAmatchmaker: a molecularly based algorithm for histocompatibility determination. III. Effect of matching at the HLA-A,B amino acid triplet level on kidney transplant survival

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.     

The effect of HLA-A, -B matching on cadaver renal allograft rejection comparing public and private specificities

Data collected prospectively on 3811 cadaver renal transplants performed between June 1977 and July 1982 by the 42 member institutions of the South-Eastern Organ Procurement Foundation (SEOPF) were analyzed to determine whether donor-recipient compatibility based on public rather than private HLA-A,-B specificities influenced the beneficial effect of HLA matching on outcome. HLA compatibility was calculated considering match and mismatch based on common private or various public (crossreactive group, [CREG]) specificities. Donor-recipient compatibility using certain CREG assignments provided an equivalent means of stratifying graft outcome by the degree of HLA-A,-B match or mismatch, and other CREGs assignments did not. Multivariate Cox regression analysis of donor-recipient compatibility based on certain public antigens showed as high an association (P less than 10(-5) between good matching and decreased graft rejection as did matching for private antigens alone. Patient stratification by HLA match provided a stronger association with graft outcome than by HLA mismatch, irrespective of whether private or public antigens were considered. The likelihood of finding a better match was significantly increased using CREG assignments, and patients with at least one matched private antigen had equivalent or better graft survival when additional public antigens were matched. These findings indicate that with conventional immunosuppressive therapy: (1) matching of private or public HLA-A,-B antigens plays a highly significant role in decreasing renal allograft rejection; (2) matching based on certain public antigens can provide the same or a better association with outcome as private antigens; and (3) the association (crossreactivity) of various HLA specificities can be defined on a functional basis in terms of graft survival.     

Anti-IL2 induction in liver transplantation with 93% rejection-free patient and graft survival at 18 months

BACKGROUND: Induction with the use of monoclonal antibodies targeting the alpha-chain (CD25) of the high-affinity IL2 receptor may avoid many of the adverse events associated with polyclonal antibodies and significantly impact on rejection-free long-term survival in orthotopic liver transplantation (OLT). METHODS: Forty-two consecutive deceased donor primary OLT were retrospectively analyzed. All patients received two 20-mg doses of basiliximab (days 0 and 4 after OLT) followed by tacrolimus (0.15 mg/kg/day; 10-15 ng/mL target trough levels), and steroids (methylprednisolone 1 g intraoperatively followed by tapering doses). Mycophenolate mofetil (MMF) 1 g every 12 h was added to the drug combination as needed. The mean follow-up period was 19.3 months (range: 4.8-35.9 months). RESULTS: The average Model for End-Stage Liver Disease score was 26 (range: 15-40). A total of 39 patients (93%) remained rejection-free during follow-up with an actuarial rejection-free probability of 95% within 3 months. The actuarial patient and graft survival rate (Kaplan-Meier estimated) at 2 years was 93%. Twenty-five patients (60%) were completely off steroids within 3 months post-OLT (mean: 51.1 days, range: 10-90 days). By the 10th month post-OLT, 30/39 (77%) of the patients were completely off steroids. At last follow-up, 30/39 (77%) are on tacrolimus monotherapy with an average dose of 4 mg per day. Six patients (15%) are on double therapy, receiving a combination of tacrolimus and prednisone (two patients) or tacrolimus and MMF (two patients) or tacrolimus and mycophenolic acid (two patients). Only three patients (8%) are receiving triple therapy at last follow-up. Nine patients (21%) experienced at least one episode of infection. Only six (26%) of a total of 23 hepatitis C virus (HCV) recipients developed histology-proven HCV recurrence, with a mean onset of recurrence post-OLT of 3.2 months (range: 1.3-6.3 months). Of these six patients, two are presently undergoing treatment with interferon and ribavirin, one was treated and became HCV RNA negative, one was not treated, one declined treatment, and two died of HCV recurrence. None of the 42 study patients developed cytomegalovirus infection or posttransplant lymphoproliferative disease. CONCLUSIONS: These preliminary data suggest that basiliximab, given in combination with a tacrolimus-based immunosuppressive regimen, is safe and associated with a low incidence of acute rejection and excellent short-term rejection-free graft and patient survival rate after OLT.     

Basiliximab induction in adult liver transplant recipients with 93% rejection-free patient and graft survival at 24 months

Induction with the use of interleukin-2 receptor monoclonal antibodies may avoid many of the adverse events associated with polyclonal antibodies and significantly impact on rejection-free long-term survival in orthotopic liver transplantation (OLTx). We describe our experience with the use of basiliximab induction therapy in adult OLTx recipients on tacrolimus-based immunosuppression. Forty-six consecutive deceased donor primary OLTx were analyzed. All patients received standard doses of basiliximab, tacrolimus, and steroids. Mycophenolate mofetil was also used as indicated. The mean follow-up period was 17.9 months. Forty-three patients remained rejection-free during follow-up. The actuarial patient and graft survival rate at 2 years was 93%. The rate of histology-proven hepatitis C virus (HCV) recurrence was 24%, with two progressing to severe cholestatic recurrent HCV. None of the study patients developed (cytomegalovirus (CMV) infection or posttransplant lymphoproliferative disease (PTLD). Results were compared to a historical group of 46 OLTx recipients on tacrolimus-based immunosuppression without basiliximab induction. The historical group had a rejection rate of 34% with lower patient and graft survival rates of 71.74% and 69.5%, respectively, at 24 months as well as a higher histological HCV recurrence rate of 77% (17/22), with three patients progressing to graft failure within 2 years. CMV infection and disease developed in 4.5% of the patients. Although PTLD was not observed, three recipients with hepatocellular carcinoma (HCC) developed and died of metastatic HCC. Induction with basiliximab in combination with tacrolimus-based immunosuppressive regimen reduces the incidence of rejection and improves rejection-free survival rate after OLTx without increasing the incidence of CMV, PTLD, or HCV recurrence.     

The impact of center variation on the HLA-DR matching effect in kidney graft survival

Data from 7436 cases of first-cadaver transplants between 1981 and 1986 from 50 transplant follow-up centers within Eurotransplant, were analyzed with respect to the effect of HLA-DR matching on graft prognosis within the first year posttransplant. The use of cyclosporine was allowed for as well as the variation in graft survival rate between transplant follow-up centers. After adjustment for these variables, HLA-DR matching was still very significant. The effect of CsA on graft survival varied between centers--i.e., interaction was observed--but the effect of HLA-DR mismatching did not vary significantly between centers. Over all the centers there was a 1.4-fold increase in relative risk for each increase in HLA-DR mismatch, corresponding to predicted one-year graft survivals of 86.5%, 81.9%, and 75.4% for 0, 1, and 2 HLA-DR mismatches respectively, in patients receiving CsA, and 72.5%, 64.2%, and 53.6% in patients not receiving CsA.     

The influence of HLA-A, B, and DR matching on graft survival in primary cadaveric renal transplantation in Belfast

HLA-DR matching has been shown in a retrospective study of 72 renal transplant patients to significantly enhance graft survival at 12 months. HLA-A and -B antigen matching also increased the graft survival rate significantly. Analysis of combined HLA-A, -B and -DR matching suggested an improvement in graft survival rate with better matching, but this did not attain statistical significance. It is now our policy to use HLA-DR matching prospectively and to ensure that all recipients receive a kidney with a maximum of 1 HLA-DR incompatibility and a minimum of 2 HLA-A and -B antigens shared.     

The effect of HLA matching on kidney graft survival in separate posttransplantation intervals

The effect of matching for the HLA antigens has been well established as important in the prognosis of kidney grafts. By analyzing the effect of matching on first transplants from unrelated donors in specific intervals up to 3 years posttransplantation, we show that the effect of HLA-DR matching is strongest in the first 5 months following transplantation (relative risks of graft failure 1.31 and 1.77 for 1 and 2 HLA-DR mismatches, respectively, compared with no mismatches). For patients whose grafts remained functioning after 5 months, there was no significant further improvement in graft survival to 3 years (relative risks 1.16 and 0.98 for 1 and 2 HLA-DR mismatches, respectively, compared with no mismatches)--i.e., the gain in graft survival by matching for HLA-DR appears to be due to its influence in the first 5 months following transplantation. For HLA-B, the matching effect was evident both before and after 5 months (relative risks 1.11 and 1.27 for 1 and 2 HLA-B mismatches, respectively, compared with no mismatches and modelled as constant over the 3-year period), whereas no effect of HLA-A matching was evident in the period up to 3 years.     

Influence of HLA-A, B, C, and D matching and pretransplant blood transfusions on kidney graft survival.

A significant influence of matching both for the HLA-A and B and the D/DR antigens on graft survival in patients transplanted with kidneys from living related or cadaveric donors is demonstrated. A generally reduced survival of cadaveric grafts during the last few years may at least in part be explained by the use of more three and four antigen-mismatched donors. The beneficial effect of pretransplant blood transfusions on graft survival in our material is almost nulled when uremic patients, dying while waiting for a transplant, are also considered. In addition, significantly more high-risk patients are included in the nontransfused patient group.     

Donor age and delayed graft function as predictors of renal allograft survival in rejection-free patients.

BACKGROUND: Transplant recipients of kidneys harvested from old donors have a high incidence of delayed graft function (DGF) and a poor graft outcome. This result is partly explained by the increased incidence of acute rejection in patients suffering from DGF. However, the long-term impact of donor age and DGF in rejection free renal transplants is not well established. The aim of the present work is to evaluate the impact of donor age and DGF on long-term outcome in renal transplants with or without acute rejection. PATIENTS: We review all cadaveric kidney transplants performed in our centre between April 1984 and December 1995 treated with a cyclosporin-based immunosuppression. RESULTS: Five hundred and ninety-five patients were included. The overall incidence of DGF was 29.1%, and this event was associated with an increased donor age and cold ischaemia time. Univariate and multivariate analysis showed that graft loss was associated with acute rejection (relative risk (RR) 2.24, 95% confidence interval (CI) 1.62-3.01); DGF (RR 1.83, 95% CI 1.32-2.54); donors >50 years (RR 1.65, 95% CI 1.13-2.38); and retransplantation (RR 1.52, 95% CI 1.01-2.31). In rejection-free patients there were two independent predictors of graft failure: donor >50 years (RR 2.40, 95% CI 1.45-4.01); and DGF (RR 2.42, 95% CI 1.53-3.84). CONCLUSIONS: Regardless of the presence of acute rejection, delayed graft function amplifies the detrimental effect of advanced donor age on long-term graft outcome.     

Influence of HLA-A, -B, -C, and -D matching on the outcome of clinical kidney transplantation.

The influence of HLA matching has been studied in the Norwegian material of 142 living related and 311 cadaveric transplants. Graft survival corresponded closely to the degree of HLA haplotype disparity between donors and recipients. Furthermore, graft survival was less in combinations being incompatible for the serologically defined HLA-A and -B antigens as compared to compatible combinations. A weak MLC response, indicating a possible sharing of the HLA-D determinants between donor and recipient, was also associated with superior graft survival, even in the presence of HLA-A and -B disparity. Matching for HLA-C in addition to HLA-A and -B did not seem to improve graft survival.     

The effect of individual HLA-A and -B mismatches on the generation of cytotoxic T lymphocyte precursors

In order to study the correlation between HLA mismatches and the cytotoxic T lymphocyte precursor frequency, we used a limiting dilution analysis to determine the CTLp frequencies against individual mismatched HLA-A and -B alloantigens in 21 patients waiting for a renal transplant. Altogether, thirty-three mismatched HLA-A antigens and 55 HLA-B antigens were tested. The CTLp frequencies against mismatches of HLA-B locus antigens were found to be significantly higher than those against HLA-A antigens (P less than 0.002). This may explain why matching for HLA-B antigens is more important for a good renal allograft survival than matching for HLA-A antigens.