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Methods
Study Population
Virtual crossmatches were studied for patients who were registered in the NKR and received a match offer between March 1, 2011 and December 20, 2012. Transplant centers (n = 64 on December 20, 2012) listed unacceptable donor HLA types based on their assessment of the recipient's antibody profile and history. The registry listed age, gender, ABO blood type and HLA type of each donor and recipient along with other factors that could influence a transplant center's acceptance of a donor kidney including vascular anatomy, relevant medical history and willingness of the donor to travel. Patients who were listed in the NKR on December 20, 2012 were studied to determine HLA sensitization and HLA antibody specificities. Study of data from the NKR registry is approved by the Institutional Review Board at Stanford University.
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 antibodies were resolved to higher resolution types corresponding to HLA molecules represented in commercial reagents for determining antibody specificity (e.g. HLA-DPB1*04 resolved to HLA-DPB1*04:01 and HLA-DPB1*04:02). For recipients, HLA-A, -B and -DRB1 typing were required.
Unacceptable Antigens
Transplant centers in consultation with their HLA laboratories determined criteria for unacceptable donor antigens for each patient. For this study, all centers used at least one solid-phase assay to identify anti-HLA antibodies (predominantly single antigen reagents). Centers could list unacceptable antigens for HLA-A, -B, -C, -DRB1, -DR51, -DR52, -DR53, -DQB1 and -DPB1. Each transplant center set its own threshold for unacceptable antigens; criteria for listing unacceptable antigens varied considerably among transplant centers. For example, some centers routinely used a threshold of 1000 mean fluorescence intensity (MFI) for DSAs to exclude donors while others accepted DSAs >10 000 MFI but employed desensitization protocols. Additionally, centers were allowed to use patient-specific factors to determine unacceptable antigens, including relaxed criteria for very highly sensitized patients or more stringent criteria for patients who were likely to have several compatible donors.
Panel reactive antibodies
For the NKR, calculated panel reactive antibody (CPRA) was dynamically determined for each patient at the time of match offers using the unacceptable antigens listed for each candidate and the HLA types of the current NKR donor pool. The CPRA was the percentage of donors that are excluded by virtual crossmatches that are automatically performed as part of the match run. For this study, CPRA was determined for waitlisted patients using donor HLA types and unacceptable antigens that were listed in the registry on December 20, 2012. Patients with CPRA≥80% were considered to be highly sensitized. To compare the CPRA with a national metric, an online calculator (http://optn.transplant.hrsa.gov/resources/professionalResources.asp?index=78) was used to determine CPRA using an algorithm developed by the OPTN (CPRA). The CPRA calculation predicts the percentage of incompatible donors using haplotype frequencies (HLA-A, -B, DR and -DQ) determined from HLA types of OPTN donors.
Crossmatching
Computer-generated match offers were based on virtual crossmatches as described elsewhere. The virtual crossmatch was considered negative if a potential donor had none of the HLA types that were listed as an unacceptable antigen for the patient. The program used this information to identify potential chains of KPD transplants with negative virtual crossmatches. 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 multiple weak HLA antibodies against the donor, allele-specific antibodies and recent changes in HLA antibodies. If the donor offer was accepted by the transplant center, cell-based crossmatches were planned and samples were sent to each center's HLA laboratory. The acceptance criteria for cell-based crossmatches were at the discretion of each transplant center. A virtual crossmatch was considered to be a failure if the reason for refusing the donor at this stage was the result of the cell-based crossmatch. Transplant centers self-reported the causes for failed virtual crossmatches. To identify approaches to prevent recurrent failures, unsuccessful virtual crossmatches were also periodically reviewed by a panel of experts from participating centers and laboratories. For example, HLA-DPB typing of donors became mandatory after several virtual crossmatch failures were attributed to antibodies against HLA-DPB.
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