American Journal of Transplantation 2014; XX: 1–7 C Copyright 2014 The American Society of Transplantation Wiley Periodicals Inc. and the American Society of Transplant Surgeons doi: 10.1111/ajt.12734 Center-Defined Unacceptable HLA Antigens Facilitate Transplants for Sensitized Patients in a Multi-Center Kidney Exchange Program L. A. Baxter-Lowe1, M. Cecka2, M. Kamoun3, Abbreviations: CPRA, calculated panel reactive anti- J. Sinacore4 and M. L. Melcher5 body; DSA, donor-specific antibody; KPD, kidney paired donation; MFI, mean fluorescence intensity; 1 NKR, National Kidney Registry; OPTN, Organ Procure- HLA Laboratory, Children’s Hospital Los Angeles, Los ment and Transplantation Network Angeles, CA 2 UCLA Immunogenetics Center, University of California Received 21 October 2013, revised 21 February 2014 Los Angeles, Los Angeles, CA and accepted for publication 26 February 2014 3Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 4National Kidney Registry, Babylon, NY 5Department of Surgery, Stanford University, Stanford, CA Introduction ÃCorresponding author: Lee Ann Baxter-Lowe, [email protected] Kidney paired donation (KPD) offers new transplant opportunities for patients with a living donor who is willing and medically suitable but HLA or ABO incompatible (1). The usefulness of KPD has been demonstrated by large Multi-center kidney paired donation (KPD) is an single-center KPD programs that have used this approach exciting new transplant option that has not yet for up to 35% of their living donor transplants (2–4). approached its full potential. One barrier to progress Theoretically, multi-center KPD programs with larger pools is accurate virtual crossmatching for KPD waitlists with many highly sensitized patients. Virtual crossmatch of donors and recipients should result in more transplants results from a large multi-center consortium, the than single-center programs (5–7). Several multi-center National Kidney Registry (NKR), were analyzed to consortia (including an Organ Procurement and Transplan- determine the effectiveness of flexible center-specific tation Network [OPTN] program) have been created to criteria for virtual crossmatching. Approximately two- facilitate multi-center KPD transplants, but the number of thirds of the patients on the NKR waitlist are highly transplants has fallen far short of the predicted potential sensitized (>80% CPRA). These patients have anti- (5,8,9). In 2012, a multidisciplinary consensus conference bodies against HLA-A (63%), HLA-B (66%), HLA-C on KPD identified several factors that hinder multi-center (41%), HLA-DRB1 (60%), HLA-DRB3/4/5 (18–22%), KPD (5). One of the major factors is virtual crossmatches HLA-DQB1 (54%) and HLA-DPB1 (26%). With donors that fail to predict an acceptable cell-based crossmatch. typed for these loci before activation, 91% of virtual crossmatches accurately predicted an acceptable cell- based donor crossmatch. Failed virtual crossmatches Virtual crossmatching is particularly challenging in the KPD were attributed to equivocal virtual crossmatches setting because the majority of waitlisted patients are (46%), changes in HLA antibodies (21%), antibodies highly sensitized to HLA (10,11) and the results for cell- against HLA-DQA (6%), transcription errors (6%), based crossmatches are often difficult to predict (12–14). suspected non-HLA antibodies (5%), allele-specific Strategies that have been developed to improve virtual antibodies (1%) and unknown causes (15%). Some crossmatch accuracy for this population include utilizing a failed crossmatches could be prevented by modifiable core laboratory (15), specifying thresholds for assigning factors such as more frequent assessment of HLA unacceptable HLA types (13,16) and allowing centers to antibodies, DQA1 typing of donors and auditing data enter two sets of antigens, one representing the center’s entry. Importantly, when transplant centers have flexibility to define crossmatch criteria, it is currently criteria for automatic refusal and another that includes feasible to use virtual crossmatching for highly sensi- antibodies that are not an automatic contraindication but tized patients to reliably predict acceptable cell-based could be a problem, particularly when there are several crossmatches. weak donor-specific antibodies (DSAs) (17). However, these strategies have not resulted in transplantation of Keywords: HLA antibodies, kidney paired donation large numbers of highly sensitized patients, in part because (KPD), virtual crossmatch use of conservative approaches to prevent unexpected 1 Baxter-Lowe et al positive crossmatches can exclude donors that would have unacceptable antigens listed for each candidate and the HLA types of the cell-based crossmatches that some transplant centers current NKR donor pool. The CPRANKR was the percentage of donors that are would consider acceptable for proceeding to transplant excluded by virtual crossmatches that are automatically performed as part of NKR (16). Although accurate virtual crossmatches are critical for the match run. For this study, CPRA was determined for waitlisted efficient KPD, the optimal approach for virtual cross- patients using donor HLA types and unacceptable antigens that were listed in the registry on December 20, 2012. Patients with CPRANKR80% were matching remains controversial. considered to be highly sensitized. To compare the CPRANKR with a national metric, an online calculator (http://optn.transplant.hrsa.gov/resources/pro- The National Kidney Registry (NKR) has allowed centers to fessionalResources.asp?index¼78) was used to determine CPRA using an develop center-specific criteria for virtual crossmatches; algorithm developed by the OPTN (CPRAOPTN). The CPRAOPTN calculation conservative centers can avoid all higher-risk transplants predicts the percentage of incompatible donors using haplotype frequencies while other centers can take advantage of innovative (HLA-A, -B, DR and -DQ) determined from HLA types of OPTN donors (20). approaches for patients who are unlikely to be transplanted using traditional criteria (18,19). In this report, we charac- Crossmatching terize the results of virtual crossmatching in this large KPD Computer-generated match offers were based on virtual crossmatches as registry where HLA compatibility criteria are at the described elsewhere (21). The virtual crossmatch was considered negative if discretion of each center and are sometimes tailored for a potential donor had none of the HLA types that were listed as an individual patients. unacceptable antigen for the patient. The program used this information to identify potential chains of KPD transplants with negative virtual cross- Methods matches. Transplant centers with patients in the selected chain had an opportunity to review the potential donor’s medical record and HLA typing to consider factors which might preclude transplant including Study population multiple weak HLA antibodies against the donor, allele-specific antibodies Virtual crossmatches were studied for patients who were registered in the and recent changes in HLA antibodies. If the donor offer was accepted by NKR and received a match offer between March 1, 2011 and December 20, the transplant center, cell-based crossmatches were planned and samples 2012. Transplant centers (n ¼ 64 on December 20, 2012) listed unacceptable were sent to each center’s HLA laboratory. The acceptance criteria for cell- donor HLA types based on their assessment of the recipient’s antibody profile based crossmatches were at the discretion of each transplant center. A and history. The registry listed age, gender, ABO blood type and HLA type of virtual crossmatch was considered to be a failure if the reason for refusing each donor and recipient along with other factors that could influence a the donor at this stage was the result of the cell-based crossmatch. transplant center’s acceptance of a donor kidney including vascular anatomy, Transplant centers self-reported the causes for failed virtual crossmatches. relevant medical history and willingness of the donor to travel. Patients who To identify approaches to prevent recurrent failures, unsuccessful virtual were listed in the NKR on December 20, 2012 were studied to determine HLA crossmatches were also periodically reviewed by a panel of experts from sensitization and HLA antibody specificities. Study of data from the NKR participating centers and laboratories. For example, HLA-DPB typing of registry is approved by the Institutional Review Board at Stanford University. donors became mandatory after several virtual crossmatch failures were attributed to antibodies against HLA-DPB. HLA typing For donors, HLA-A, -B, -Bw4/6, -C, -DRB1, -DRB3/4/5, -DQB1 and -DPB1 types were required before the donor-recipient pair could be activated. Certain HLA types that are associated with a high frequency of allele-specific Results antibodies were resolved to higher resolution types corresponding to HLA molecules represented in commercial reagents for determining antibody CPRA specificity (e.g. HLA-DPB1Ã04 resolved to HLA-DPB1Ã04:01 and HLA- Since the number and source of donor HLA types used for NKR DPB1Ã04:02). For recipients, HLA-A, -B and -DRB1 typing were required. determining CPRA could influence the result, CPRA that is based upon HLA types of a relatively small donor pool Unacceptable antigens was compared with CPRAOPTN that is calculated using a Transplant centers in consultation with their HLA laboratories determined large population of deceased donors