Prospective HLA-DR matching in cadaveric renal transplants: a single center study

We reviewed 77 potential cadaveric allograft recipients who had undergone prospective HLA-A and B locus and HLA-DR antigen identification. Matching was accomplished, giving first priority to HLA-DR compatibility and relying on HLA-A and B antigen matching only in situations of total HLA-DR incompatibility. Complete HLA-DR identification occurred in 56 per cent of all patients. There were 15 patients (19.5 per cent) who received a 2/2 HLA-DR perfect match, with 86.7 plus or minus 8.8 per cent 1-year actuarial graft survival, and 41 (53 per cent) who received a 1/2 HLA-DR match, with 58.2 plus or minus 7.8 per cent 1-year actual allograft survival. Finally, 21 patients (27 per cent) received a 0/2 HLA-DR match, with 64.9 plus or minus 10.7 per cent actual survival. These results and their mirrored mismatching results showed statistically significant allograft success in only the HLA-DR 2/2 matches. Matching for HLA 2 DR donors proved a statistically significant success over the other HLA-DR allograft matches and the older controversial matching system based on HLA-A and B locus antigens. The restricted gene polymorphism of the HLA-DR systems allows for a relatively high percentage of perfect HLA-DR matches.     

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 current role of pre-transplant blood transfusions and tissue typing in cadaveric renal transplantation

In a retrospective analysis of 74 consecutive cadaveric renal transplants performed at our center during a 38-month period we assessed the influence of random blood transfusions and tissue matching on graft and patient survival. All patients received cyclosporine and low dose prednisone with or without azathioprine as immunosuppressive therapy. Actual patient survival was 100 per cent at 1 year and actuarial 1-year graft survival was 82 per cent. Random blood transfusions and histocompatibility matching at the HLA-DR locus did not influence graft survival. Matching at 2 or more HLA-A and B loci was associated with a significant detrimental influence (p less than 0.05) on graft survival. We conclude that the use of cyclosporine-based immunosuppression overcomes much of the adverse effect of poor tissue matching and may obviate the need for random blood transfusions in cadaveric renal transplantation during the first year of engraftment.     

Influence of HLA matching on survival of second kidney transplants in cyclosporine-treated recipients

In an analysis of over 4000 cyclosporine-treated recipients of second kidney transplants we observed a strong effect of HLA matching in living-related and cadaver transplants. In contrast to the results obtained in first cadaver transplants, second cadaver transplants benefited substantially from matching for HLA-A locus antigens. The strongest effect of matching was found when HLA-A, HLA-B, and HLA-DR antigens were analyzed together: 214 second grafts with no mismatch had a survival rate of 82 +/- 3% at two years in contrast to a 49 +/- 4% rate in 149 grafts with 6 mismatches (P less than 0.0001, log rank). Patients whose first graft functioned for more than 1 year had a significantly higher second graft survival rate than patients with shorter first graft duration. Because the effect of HLA matching is particularly strong in patients with less than 1 year first graft duration, it is suggested that HLA well-matched kidneys should be allocated to them with priority.     

DNA typing: an important step forward?

In a collaborative project which was supported by 96 transplant centers, DNA typing of HLA-DR antigens was carried out on over 7,000 transplant donors and recipients at 8 participating laboratories. Approximately 25% of the individuals were found to have been typed incorrectly by serological means. An analysis of over 2,500 first cadaver kidney transplants showed a significant correlation of matching for the HLA-DR antigens in transplants where the serological typing was confirmed by DNA typing. In transplants where the serological typing was found to be incorrect, the analysis of serological HLA-DR mismatches resulted in no correlation with graft outcome whereas a significant correlation was found when the corrected DNA typed HLA-DR antigens were analyzed. Transplants which had been reported to the Collaborative Transplant Study based on serological typing as matched for HLA-A, -B, -DR or HLA-B, -DR were found to have a superior graft survival rate only if HLA-DR compatibility was confirmed by DNA typing.     

Blood transfusions and HLA compatibility in first cadaveric kidney transplants treated with cyclosporine A

One-year graft survival of 54 first cadaveric kidney transplants that received immunosuppressive treatment with CsA was analyzed with respect to the number of random pretransplant blood transfusions and the HLA class 1 and class 2 matching. Overall graft survival at 1 year was 80.7%. Patients with 3 to 20 pretransplant transfusions had a survival of 93.7% compared with 66.7% in those with less than three or more than 20 transfusions. All kidneys transplanted with two or less HLA-A + B mismatches survived at 1 year. With three mismatched antigens survival was of 88.9%. This value was reduced to 66.7% for four incompatibilities. A similar situation was found for HLA-DR matching since all kidneys with full compatibility survived at 1 year compared with 90.9% and 66.7% for one and two mismatches, respectively. HLA-B and HLA-DR exhibited an additive effect since again all grafts with two or less mismatches survived, whereas in the group with three different antigens this figure was 90% and only 1 of the three kidneys with completely different antigens survived.     

Evaluation of HLA matching for CREG antigens in Europe.

BACKGROUND: In North America, cross-reactive antigen group (CREG) matching was introduced recently for cadaver kidney allocation. This is expected to result in improved graft outcome and an increased number of transplants for patients with rare HLA antigens. METHODS: We analyzed the impact of CREG matching using the data of the Collaborative Transplant Study for 59,516 first cadaver transplants performed in Western Europe. The 10 HLA class I CREGs described by Takemoto et al. were used for a comparison with the conventional HLA-A+B mismatching scheme. RESULTS: Transplant outcome depends primarily on the number of HLA-A+B mismatches and not on the CREG match grades. In a retrospective analysis, CREG mismatches correlated with the number of HLA-A+B mismatches. However, in computer simulations, we found that prospective CREG matching is not associated with beneficial HLA-A+B matching. CONCLUSION: The positive CREG matching effect observed in retrospective analyses is caused by the underlying effects of conventional HLA-A+B matching. CREG-oriented cadaver kidney allocation in Europe would, therefore, be inferior to the current conventional HLA-A+B+DR allocation.     

Strength of HLA-A,HLA-B,and HLA-DR mismatches in relation to short- and long-term kidney graft survival

The separate influence of HLA-A, HLA-B, and HLA-DR mismatches on short- and long-term kidney graft survival was analyzed in a series of over 40,000 recipients of first cadaver kidney transplants. As expected, during the early posttransplant period, HLA-DR mismatches had a stronger influence on graft survival than HLA-B mismatches, and HLA-A mismatches had a very small influence. Surprisingly, during the period from 6 months to 5 years post transplantation, all three HLA loci had approximately the same influence. When the graft survival computation was started at 100 % at 6 months, the difference between grafts with zero or two mismatches at the end of 5 years was 6 %, regardless of whether HLA-A, HLA-B, or HLA-DR antigens were analyzed. The influence of the three loci was additive so that the survival rate difference between transplants with zero or six mismatches for HLA-A, -B, -DR was 17 % at 5 years. We concluded that, although the HLA-A locus exerts only a weak influence during the early posttransplant course, its influence on long-term survival is comparable to that of HLA-B and HLA-DR. In order to obtain optimal long-term survival, all three loci must be considered in the donor-recipient matching procedure.     

Influence of HLA-A, B, and DR matching on the outcome of kidney transplant survival in preimmunized patients

The outcome of 893 prospectively typed (HLA-A, B, and DR) and matched cadaveric kidney transplants--all first grafts, with patients being transfused before transplantation--was studied using actuarial survival methods. The effect of HLA-A, B and DR matching was only found to be significantly beneficial to graft survival in the group of 289 presensitized recipients: 70% and 43% graft survival at two years in the case of best-matched (4-6 HLA-A, B, and DR) identities versus mismatched (0 and 1 HLA-A, B, and DR) identities, respectively (P = 0.05). Although a cumulative effect of matching for antigens belonging to the 3 HLA-A, B, and DR series was observed among the group of preimmunized recipients, a trend arose in favor of the prominent role of the HLA-B alleles. No significant difference related to HLA matching was observed in the group of nonsensitized recipients. These results confirm previous observations and support efforts to give priority for matched kidneys to preimmunized patients.     

HLA-DRB1 matched kidneys are preferentially HLA-A and -B compatible and survive longer

HLA-DR matching was analysed in 111 cadaveric donors and 156 patients who underwent kidney transplantation. We compared the results of conventional DR serology with sequence specific oligonucleotide typing performed on PCR-amplified DRB1 exon 2 DNA. We found discrepancies between serology and DNA typing in 10.1% when the broad antigen specificities DR1-10 were considered. The graft survival probability at 2.5 years between HLA-DR matched versus mismatched transplants was not different (0.87 vs 0.83) when matching was based on serology. However, a significant graft survival difference (0.95 vs 0.82) was found when matching was based on oligotyping for DRB1 (including all subtypes). Furthermore, a better matching for HLA-A and -B was found in the DRB1 matched group. Therefore, precise matching at one particular locus (as shown here for the DRB1 locus) significantly increases the chance to be matched at further MHC loci. The further development of high-resolution typing techniques for most or all HLA-A, -B, -C, -DR, -DQ, -DP antigens may in the future allow more precise definitions of clinically important mismatches helping to develop rational matching strategies.     

Cross-reactive group matching does not lead to a better allocation and survival of donor kidneys

BACKGROUND: In cadaveric renal transplantation HLA-A, -B, -DR matching of donor and recipient is beneficial for graft survival. However, allocation based on HLA matching seems to favor recipients with more frequently occurring HLA antigens. In this study we investigated whether matching on the basis of cross-reactive groups (CREGs), defined according to the United Network for Organ Sharing (UNOS), would be a good alternative for the allocation of kidneys without negatively influencing graft survival. Theoretically, this approach would provide more recipients with an immunologically well-matched donor organ. METHODS: The influence of CREG matching on graft survival was studied in univariate analyses using the Eurotransplant database. RESULTS: No beneficial effect of CREG matching was observed, whereas a significant HLA matching effect was observed in the 0 CREG mismatched donor/ recipient combinations. Only in the small subgroup with 1 MM for HLA-A, -B and 0 MM for HLA-DR, a significantly better survival was observed, when this mismatch belonged to the 0 or 1 MM CREG group versus two or more MM CREG group. However, this subgroup concerns only 8% of the transplants performed. CONCLUSIONS: In contrast to other reports, our study showed that HLA matching is by far more beneficial than CREG matching. In the homogenous Eurotransplant population, adjusting the matching criteria toward CREG matching would not lead to an improved graft survival.     

Simpler and equitable allocation of kidneys from postmortem donors primarily based on full HLA-DR compatibility

BACKGROUND: The introduction of human leukocyte antigen (HLA)-matching in nonliving kidney transplantation has resulted into a better graft outcome, but also in an increase of waiting time, especially for patients with rare HLA phenotypes. We addressed the question of the differential influence of HLA-DR-matching versus HLA-A,B in clinical kidney transplantation. METHODS: We used Kaplan-Meier product limit method to estimate survival rates, and Cox proportional hazard regression for the estimation of relative risks (Hazard-ratios) for different variables. RESULTS: A single center study (n=456 transplants, performed between 1985 and 1999) showed that full HLA-DR compatibility leads to a lower incidence of biopsy confirmed acute rejections in the first 180 posttransplantation days. These results were substantiated using the Eurotransplant database (n=39,205 transplants performed between 1985 and 2005) where graft survival in the full HLA-DR compatible group was significantly better than in the incompatible. An additional positive effect of HLA-A,B matching was only found in the full HLA-DR compatible group. In both studies, the introduction of a single HLA-DR incompatibility eliminates the HLA-A,B matching effect. CONCLUSIONS: We propose to allocate postmortem kidneys only to patients with full HLA-DR compatibility, and use HLA-A,B compatibility as an additional selection criterion. All patients, irrespective of their ethnic origin, will profit since the polymorphism of HLA-DR is by far lower than that of HLA-A,B. Excessive kidney travel and cold ischemia time will be significantly reduced.     

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.     

DRw antigen matching and B-cell antibody crossmatching: their effect on clinical outcome of renal transplants.

In a series of 36 cadaver transplants, we have found that matching the DR antigens had greater value in predicting good transplant outcome than did matching the A and B antigens. A much larger series of transplants utilizing DR antigen matching will be necessary to confirm these promising results; however, it would appear that performed donor-specific BLC detected at room temperature have no relationship to subsequent transplant outcome. It is, however, important to differentiate them from weak HLA-A,B,C antibodies which have been proven to lead to accelerated rejection. We recommend that the clinical crossmatch include simultaneous B-cell-depleted and B-cell-enriched tests to avoid this problem.     

A prospective randomized trial of matching for HLA-A and B versus HLA-DR in renal transplantation

A prospective randomized trial was performed comparing survival of cadaveric grafts allocated by HLA-A+B matching and HLA-DR matching. The two allocation methods resulted in very similar graft survivals. HLA-A matching had no significant effect on graft survival. HLA-B and HLA-DR matching were shown to have approximately equal, significant, independent, and additive effects on graft survival. Other factors that were demonstrated to have significant effects were blood transfusion, preformed antibodies, graft number, and recipient sex. The results indicate that neither allocation method alone is optimal, and that matching for HLA-B+DR is necessary. However a large pool size is necessary to obtain a high frequency of good matches.     

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.     

HLA matching and cadaver kidney transplant survival in North America: influence of center variation and presensitization.

In an analysis of 4,851 first cadaver kidney transplants, we found a statistically highly significant correlation between the number of HLA antigens mismatched and graft survival (P less than 0.0005 at 1 year). The difference in the survival rates of grafts with no HLA mismatch compared with grafts with four mismatches was 11 to 12%, similar to results of previous analyses. HLA-A locus antigens had a slightly stronger effect than B locus antigens. The correlation of HLA matching with graft survival was most significant at centers with poor overall transplant outcome, and there was no correlation at centers with very good overall results. Presensitization also had the strongest effect at centers with poor overall graft survival.     

Influence of mismatching of HLA cross-reactive groups on cadaveric kidney transplantation

Finding fully HLA-matched recipients for a given donor is not practical due to the allelic diversity of the loci. Cross-reactive group (CREG) matching has been considered a feasible alternative to HLA matching. However, the true efficacy of CREG matching in cadaveric kidney transplantation is controversial. Using conventional HLA and CREG classifications proposed by Rodey and McKenna, we counted the number of mismatches for 319 patients who received cadaver kidney transplants between 1992 and 2003 at Asan Medical Center in Korea. When we compared transplants with four or fewer HLA-A, -B, and -DR antigen mismatches with those with five or more, we observed a significant difference in 5-year survival rate (88.5% versus 78.6%; P = .0189). Transplants with no or one HLA-DR mismatch had a significantly better 5-year survival rate than those with two HLA-DR mismatches (87.9% versus 80.0%; P = .0469). Among transplants with one or two HLA-DR mismatches, transplants with zero or one CREG mismatch showed better 5-year graft survival rate than those with two or more CREG mismatches (89.4% versus 79.8%; P = .0415) only in McKenna's CREG classification. These results suggest that the impact of CREG mismatches on graft survival may depend on CREG classification and on the distribution of HLA-DR mismatches.     

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.     

HLA-A, B, C, DRB1, DQB1 matching heterogeneity in 'favourably matched' kidney recipients

Allocation of cadaveric donor kidneys in the UK is founded on matching for HLA-A, -B and -DR, primarily at the broad specificity level. Increasing evidence shows that matching at a higher resolution and consideration of additional loci, such as HLA-C, -DQ and -DP, improves graft outcome. The aim of this study was to clarify the typical level of split specificity HLA-A, -B, -C, -DR, -DQ and allelic -DRB1 and -DQB1 mismatching in 'favourably matched' cadaveric renal transplant pairs. Two hundred and thirty-seven cadaveric donor/recipient pairs, 'favourably matched', according to United Kingdom Transplant criteria, were typed at the split specificity level for HLA-A, -B, -C and at the allele level for HLA-DRB1 and -DQB1. The level of split specificity and allele mismatching was then assessed. Overall, 66.7% of the patients had at least one HLA-C mismatch with their donors; 36.9% of those matched for HLA-B and 85.5% of those mismatched for HLA-B (P<0.0001). A broad specificity HLA-A or -B mismatch influenced the presence of an HLA-B, or HLA-A split specificity mismatch, respectively, (P<0.05) but made no significant difference to the presence of an HLA-DR split mismatch. Overall, 4.6% of the patients were mismatched for HLA-DR split specificities but 30.4% were mismatched at HLA-DQ and 50.6% had at least one HLA-DRB1 or -DQB1 allele mismatch. Considerable HLA-A, -B, -C, -DR, -DQ matching heterogeneity exists even amongst 'well matched' renal transplant patient groups. Little is known about the effects of combinations of mismatched specificities on graft survival. Thus, further investigation is merited particularly for HLA-C and -DQ mismatching.