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Deleterious Impact of Mismatching for Human Leukocyte Antigen-C in Presensitized Recipients of Kidney Transplants

Tran, Thuong Hien; Döhler, Bernd; Heinold, Andreas; Scherer, Sabine; Ruhenstroth, Andrea; Opelz, Gerhard

doi: 10.1097/TP.0b013e318224c14e
Clinical and Translational Research
Free

Background. Allocation of deceased donor kidneys is commonly based on matching for human leukocyte antigen (HLA)-A, -B, and -DR, whereas HLA-C is currently disregarded. We investigated the influence of HLA-C compatibility on renal allograft survival. In addition, we tested an approach of matching for HLA-C epitopes.

Methods. A cohort of 2260 deceased donor kidney transplants were typed for HLA-C using polymerase chain reaction-sequence specific primer method. Samples for DNA typing, serum results on presensitization (lymphocytotoxicity), and clinical data were provided by transplant centers participating in the Collaborative Transplant Study.

Results. HLA-C mismatch was found to be associated with significantly decreased graft survival in presensitized (P<0.001) but not in non-presensitized (P=0.75) recipients. Mismatch of certain HLA-C epitopes seemed to be more influential than others, with mismatches showing a negative impact on graft survival in presensitized patients.

Conclusions. HLA-C mismatch has a substantial deleterious effect on graft survival in presensitized kidney recipients. Our study points out the need for investigations directed at identifying donor-specific HLA-C antibodies and evaluating their relevance in transplantation. In view of the fact that current assays for determining HLA-C specific antibodies are hampered by additional detection of clinically irrelevant antibodies, matching for HLA-C may provide a reasonable approach to improve transplant outcomes in presensitized kidney transplant recipients.

Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany.

The authors declare no conflicts of interest.

Address correspondence to: Thuong Hien Tran, M.D., Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.

E-mail: hien.tran@med.uni-heidelberg.de

T.H.T., and G.O. participated in research design and writing of the manuscript; T.H.T., B.D., A.H., and S.S. participated in performance of the research; and B.D., A.R., and G.O. participated in statistical analysis and data management.

Received 22 March 2011. Revision requested 12 April 2011.

Accepted 16 May 2011.

Compatibility for human leukocyte antigens (HLA) has a significant impact on kidney allograft survival (1, 2). Commonly, the HLA-A, -B, and -DR locus antigens are considered for matching in clinical kidney transplantation. The HLA-C locus is disregarded in the match algorithms of kidney allocation organizations such as Eurotransplant. Immunization experiments have characterized the HLA-C locus as “weakly immunogenic” in comparison with the HLA-A or -B loci (3), presumably due to low HLA-C expression at the cell surface (4). Similarly, donor-specific antibodies against HLA-C mismatches have been found at significantly lower frequencies than those induced by HLA-A and HLA-B mismatches in kidney transplant recipients (5). Although several studies did not show an effect of HLA-C mismatches on renal allograft survival (6–8), there were case reports which pointed out a possible association of kidney allograft rejection and humoral (9) or cellular (10) immune responses against HLA-C mismatches. A caveat of these studies concerns their methodology, as HLA-C was determined by serological techniques. In an evaluation of 650 individuals, Mytilineos et al. (11) found a discrepancy rate of more than 30% between the results of serological and molecular typing by polymerase chain reaction-sequence specific primer (PCR-SSP) for HLA-C. A more recent single-center study of 104 renal transplant pairs, in which both serological and molecular typing of HLA-C was performed, showed a significant correlation between HLA-C mismatch and the occurrence of acute rejection episodes, but the influence of HLA-C was observed only in transplants in which additional HLA-B mismatches were present (12). Our current study was based on the recognition that, in light of the considerable inaccuracy of serological HLA-C typing and the contradicting reports in the literature, the relevance of HLA-C matching in renal transplantation must be re-assessed in a large transplant cohort based on molecular typing. A further aspect to be taken into consideration is the strong linkage disequilibrium between HLA-C and HLA-B (13). As a consequence, an HLA-C mismatch is often associated with an HLA-B mismatch (14). It is therefore conceivable that a potential (presumably weak) influence of HLA-C mismatch may be masked by the (stronger) adverse effect of HLA-B mismatch on allograft survival. To account for this, we analyzed the relevance of HLA-C compatibility in a large cohort of 2260 deceased donor kidney transplants with no HLA-B mismatch.

Recently, HLA class I and class II epitopes haven been defined by adsorption and elution of antibodies from single HLA antigens (15, 16). In a second phase of our project, we tested whether epitope matching for HLA-C may have an effect on kidney transplant survival.

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RESULTS

Effect of HLA-C Compatibility on Kidney Allograft Survival Depending on Recipient Presensitization Status

HLA-C mismatch had no effect on allograft survival in non-presensitized patients (Fig. 1A). In contrast, in presensitized recipients (panel-reactive antibodies [PRA] >10%), HLA-C mismatched grafts had a significantly lower survival rate than HLA-C matched grafts (70.3%±7.5% for two HLA-C mismatches and 79.6%±2.7% for one HLA-C mismatch versus 87.7%±1.7% for zero HLA-C mismatch, log rank with trend P<0.001) (Fig. 1B). For all further analysis steps, we concentrated on the reference group with zero HLA-C mismatch and combined the two groups with one or two HLA-C mismatches for comparison.

FIGURE 1.

FIGURE 1.

Because there may be a qualitative difference of the effect of sensitization between first transplants and retransplants (the cause of preformed antibodies before first transplant includes blood transfusions and pregnancies, whereas retransplanted patients have been exposed to the sensitizing effect of a rejected previous kidney graft), we separately analyzed presensitized patients who received a first transplant and those who underwent retransplantation. In presensitized first transplant patients, HLA-C mismatched grafts showed a trend toward lower graft survival in univariate analysis (P=0.071, Fig. 2A), which reached statistical significance in multivariate analysis considering multiple confounders, showing an increased hazard ratio (HR) of 1.92 for graft loss in this group (P=0.043, Table 1). In presensitized regrafted patients, both univariate (P=0.003) (Fig. 2B) and multivariate analysis demonstrated a deleterious effect of HLA-C mismatch on graft survival (HR=1.82, P=0.043, Table 1).

FIGURE 2.

FIGURE 2.

TABLE 1

TABLE 1

Remarkably, in sensitized patients, HLA-C mismatch appeared to inflict a risk of graft loss comparable with that of HLA-DR mismatch (HR=1.89, P=0.003 for HLA-C mismatch; HR=1.75, P=0.011 for HLA-DR mismatch). In nonsensitized patients, neither HLA-DR nor HLA-C mismatch was associated with a significant impact on graft survival (Table 1).

Even when transplant pairs were matched for HLA-A+B+DR, HLA-C mismatched grafts in presensitized recipients were inferior to HLA-C matched grafts (graft survival of HLA-C mismatched grafts, 80.5%±4.5%, n=77, vs. HLA-C matched grafts, 90.1%±2.1%, n=203; P=0.023). Among non-presensitized recipients, however, HLA-C mismatches had no adverse impact on graft survival (88.9%±1.9%, n=264, in HLA-C mismatched transplants, vs. 88.8%±1.5%, n=439, in HLA-C matched transplants; P=0.94).

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Effect of HLA-C Epitope Matching on Kidney Allograft Survival in Presensitized Patients

El-Awar et al. (15, 16) identified HLA epitopes by monoclonal antibodies or alloantibodies that were absorbed and eluted from HLA recombinant single antigen cell lines. To assess whether mismatching for HLA-C epitopes might have an effect on allograft survival in presensitized patients, we compared graft survival rates between transplants that were matched or mismatched for each of the HLA-C epitopes E37, E39, E40, E41, E244, E245, E246, or E421 (epitope ID numbers according to El-Awar et al.). Mismatches for the epitopes E245, E246, and E421 were found to be associated with significantly decreased graft survival in presensitized recipients, whereas no significant influence was observed for mismatches at the other HLA-C epitopes (Fig. 3).

FIGURE 3.

FIGURE 3.

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DISCUSSION

The influence of HLA-C mismatches on kidney allograft survival is not clear. Studies addressing this topic are scarce and the majority of them were published some 30 years ago (6–8). These studies, which included up to 400 deceased donor and 150 living donor transplants, suggested no effect of HLA-C mismatches on graft survival. However, one should be aware that the results were based on serological HLA-C typing, bearing a substantial likelihood of mistyping and erroneous assignment of the HLA-C match grade (11).

Among the genetic loci of the major histocompatibility complex, HLA-B and HLA-C genes are located adjacent to each other and show strong linkage disequilibrium (13). Rees et al. (14) observed that if renal recipients and their donors were matched for HLA-B, more than 60% were also matched for HLA-C, and conversely, if there was a mismatch for HLA-B, 85% of the recipient/donor pairs were also mismatched for HLA-C. To exclude the possibility that an HLA-C mismatch effect could be masked by the consequence of an HLA-B mismatch, we based our current analysis on transplants that were matched for HLA-B, thereby increasing the likelihood of revealing a true impact of HLA-C incompatibility in kidney transplantation. Moreover, we used molecular methods for the accurate determination of HLA-C specificities in donor and recipient because serological HLA-C typing has been shown to be afflicted with a high technical error rate (11).

In the present study of 2260 HLA-B matched kidney transplants, HLA-C mismatches were associated with significantly lower graft survival in presensitized recipients. Typically, for the effect of presensitization against HLA, this effect became apparent during the first few months after transplantation. In multivariate analysis, HLA-C mismatch was found to be an independent factor for increased risk of graft loss in presensitized patients at a level comparable with HLA-DR mismatch (Table 1). Even if the HLA-A, -B, and -DR antigens were matched (zero HLA-A+B+DR mismatch), a situation which is considered as “optimal matching” in kidney transplantation, the outcome of HLA-C mismatched grafts in presensitized patients was inferior to that of HLA-C matched grafts, suggesting that HLA-C matching is beneficial in addition to matching for HLA-A, -B and -DR in presensitized kidney transplant recipients. In this context, it is noteworthy that donor-recipient HLA-C mismatch in terms of KIR ligand incompatibility (i.e., with regard to their belonging to HLA-C group 1 or group 2 alleles) was not associated with kidney transplant outcomes as previously reported by us (17) and others (18).

A negative impact of HLA-C mismatch on kidney transplant outcome was previously reported by Frohn et al. (12) who found a significant correlation between HLA-C mismatch and acute rejection episodes in a study of 104 transplants. This effect was only detected in the presence of an additional HLA-B mismatch. However, neither separate evaluation of first and retransplants was performed nor was the sensitization status of the recipients taken into consideration, presumably because the number of patients was too small for such analysis.

In the current multicenter study involving 63 centers from 17 countries, PRA testing was carried out at the participating laboratories as part of the routine transplant preparation. The HLA-C specificity of the antibodies was not determined. Testing for HLA-C antibodies is technically demanding and, in fact, currently no reliable method is available. It has been recognized for many years that serological specificity testing is problematic due to cross reactivity and the insufficient characterization of target cells (19). Recent reports on the prevalence of HLA-C antibodies among sensitized kidney transplant candidates (5, 20, 21) were all based on the Luminex method using single antigen beads (One Lambda Inc., Canoga Park, CA). The sensitive Luminex technology is able to define HLA antibodies specificities below the threshold detectable by complement-dependent lymphocytotoxicity assay and enzyme-linked immunosorbent assay (22). In this context, it is important to recognize that the Luminex technology for determination of HLA specificities is afflicted with concomitant reactions against dissociated HLA antigens (23, 24) and identifies antibodies to denatured antigens that are not relevant for kidney graft survival (25). A recent Collaborative Transplant Study (CTS) report showed that the incidence of donor-specific HLA antibodies, including antibodies against HLA-C, detected by the Luminex single-antigen assay was not higher in patients with graft loss than in patients without graft loss (26). Thus, careful interpretation of the Luminex-based test results, taking into account the patient's history and all antibody screening data (possibly including those which have been characterized by other techniques), is recommended. The accurate determination of transplant-relevant alloantibodies against HLA-C remains a challenge in the field of transplant diagnostics.

Recently, HLA class I and class II epitopes were identified by the use of monoclonal antibodies or alloantibodies eluted from HLA recombinant single antigen cell lines tested with a panel of single antigen beads (15, 16). The hypothesis that these epitopes may be responsible for antibody-mediated rejection prompted us to test whether mismatching for HLA-C epitopes may influence graft survival. Our analysis showed a negative impact on graft survival of mismatching for the HLA-C epitopes E245, E246, and E421, but not for the epitopes E37, E39, E40, E41, and E244. The reason for the diverging effects of these HLA-C epitopes is not easily explained. We hypothesize that the epitopes E245, E246, and E421 may be more immunogenic than the other epitopes tested, leading to higher fraction of patients with HLA-C antibodies. The higher immunogenicity of E245, E246, and E421 compared with that of E37, E39, E40, and E41 might correlate to the higher number of amino acids which define their specificities: the “strongly immunogenic” epitopes E245, E246, and E421 consist of two to four amino acid residues, whereas the “weakly immunogenic” epitopes E27, E39, E40, and E41 are characterized by a single amino acid (15, 16). A correlation between the number of polymorphic amino acid differences and the immunogenicity of HLA mismatches, in terms of alloantibody response, has recently been shown (27). The relevance and clinical utility of our finding remains to be assessed in further investigations.

In summary, our data show that HLA-C antigen mismatches exert a deleterious effect in presensitized kidney transplant recipients. This study points out the importance of conducting investigations on the HLA-C specificities of preformed antibodies and their relevance in transplantation. If the specificity of HLA-C antibodies is accurately determined, it will be possible to avoid donor HLA-C mismatches against which the antibodies are reactive. The importance of HLA-C specific sensitization was acknowledged for example by the UK deceased kidney donor organ allocation scheme which includes defined HLA-C antibody specificities to delineate unacceptable donor antigens for transplant (28, 29). However, due to the current lack of specific tests for the identification of clinically relevant HLA-C antibodies, for the time being, matching of HLA-C in addition to matching for HLA-A, -B and -DR may provide a reasonable strategy for improving transplant outcomes in presensitized patients. This implies that HLA-C typing of donors and recipients should be considered as part of the routine work-up for patients awaiting kidney transplantation and as a component of the kidney allocation algorithm. To our knowledge, the present work is the largest study to date on the relevance of HLA-C matching in renal transplantation. This study was made possible by the generous and continuous support of the transplant centers participating in the CTS (see Acknowledgment).

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MATERIALS AND METHODS

Kidney Recipients and Donors

Samples (blood or spleen tissue) and clinical data were provided by 63 transplant centers from 17 countries participating in the CTS (www.ctstransplant.org). The following selection criteria were applied: transplants performed between 1988 and 2008 in Europe or North America; recipients and donors of Caucasian origin; kidney grafts from deceased donors; zero HLA-B mismatch; and DNA amount sufficient for testing. The study cohort consisted of 2260 transplants in total (1824 first transplants and 436 retransplants). Demographic and baseline characteristics are listed in Table 2.

TABLE 2

TABLE 2

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HLA Typing

DNA was extracted from peripheral blood or spleen tissue by the salting-out method (30). Molecular typing of HLA-C was performed using the HLA-C CTS-PCR-SSP Tray Kit (CTS, Heidelberg, Germany) according to the manufacturer's instruction. Molecular typing results for HLA-DRB1 were obtained by the RFLP typing method as described by Bidwell et al. (31) or by using the HLA-DRB1 CTS-PCR-SSP Tray Kit (CTS, Heidelberg, Germany). All molecular HLA typing was carried out at the study center in Heidelberg, Germany. HLA-A and -B typing and determination of PRA based on complement-dependent cytotoxicity assays were performed at the tissue typing laboratories of the participating centers. HLA-C specific antibodies were not tested and, therefore, no information was available to us.

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Epitope Matching

Epitopes were assigned to HLA-C antigens according to El-Awar et al. (15, 16). Because our study cohort consisted of HLA-B matched transplants, epitopes which were found exclusively on HLA-C locus (epitope numbers E37, E39, E40, and E244) or shared between HLA-B and HLA-C loci (epitope numbers E41, E245, E246, and E421) were analyzed. Epitopes which were shared between HLA-A, -B, and -C loci were not evaluated. An HLA-C epitope mismatch was considered if the epitope was present in the donor but absent in the recipient.

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Statistical Analysis

Graft survival rates were computed according to the Kaplan-Meier method and expressed as mean percentage±standard error. Graft survival was compared for patients receiving a kidney from an HLA-C matched donor with those transplanted with an HLA-C mismatched donor. Because previous case studies reported hyperacute (9) or acute (10, 12) graft rejection in HLA-C mismatched kidney transplants, we focused our study on the graft survival rate during the first year posttransplant. Multivariate Cox regression analysis was performed to determine HRs considering the following confounders: geographic origin (continent), year of transplant, transplant number, recipient and donor age, recipient and donor gender, original disease leading to transplantation, evaluation of recipient as candidate for transplantation, pretransplant PRA, cold ischemia time, number of HLA-A and -DR mismatches, and immunosuppressive treatment (intention to treat). A back step elimination algorithm was used to exclude confounders with P more than 0.2. P less than 0.05 was considered significant. The software package IBM SPSS Statistics version 18 (SPSS Inc., Chicago, IL) was used for all statistical analyses.

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ACKNOWLEDGMENTS

The authors are very grateful to the following transplant centers participating in the kidney transplant DNA typing project of the Collaborative Transplant Study (CTS) for their invaluable support: Baracaldo (Spain), Basel (Switzerland), Bergamo (Italy), Berlin (Germany), Bern (Switzerland), Bochum (Germany), Bremen (Germany), Budapest (Hungary), Cambridge (UK), Cardiff (UK), Chicago (USA), Cincinnati (USA), Cologne-Merheim (Germany), Debrecen (Hungary), Dublin (Ireland), Edmonton (Canada), Erlangen-Nuernberg (Germany), Essen (Germany), Frankfurt (Germany), Freiburg (Germany), Geneva (Switzerland), Giessen (Germany), Glasgow (UK), Halifax (Canada), Hann-Muenden (Germany), Hannover (Germany), Hartford (USA), Heidelberg (Germany), Innsbruck (Austria), Kaiserslautern (Germany), Kiel (Germany), Lausanne (Switzerland), Leicester (UK), Leuven (Belgium), Lisbon (Portugal), Louisville (USA), Luebeck (Germany), Madrid (Spain), Malaga (Spain), Malmo-Lund (Sweden), Mannheim (Germany), Marburg (Germany), Milan (Italy), Minneapolis (USA), Muenster (Germany), Nantes (France), Newcastle upon Tyne (UK), Ottawa (Canada), Pecs (Hungary), Portland (USA), Prague (Czech Republic), Quebec (Canada), Rijeka (Croatia), Rostock (Germany), San Antonio (USA), St. Etienne (France), St. Gallen (Switzerland), Szeged (Hungary), Thessaloniki (Greece), Toronto (Canada), Ulm (Germany), Zagreb (Croatia), Zurich (Switzerland). The authors thank Martina Rausch, Ulrike Obermeier, Kirsten Geppert, and Katrin Krauth for their highly professional technical assistance.

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Keywords:

HLA-C; Matching; Kidney transplantation; Graft survival; Presensitized recipients

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