A 54-year-old female with nonischemic cardiomyopathy status post axial flow left ventricular assist device, complicated by right ventricular failure status post magnetically levitated centrifugal right ventricular assist device, is referred for transplantation. She has had four pregnancies and required multiple blood transfusions after her assist devices were placed. Her calculated panel reactive antibodies (PRA) score is 93% (using a mean fluorescence intensity [MFI] threshold of 10,000), despite desensitization with intravenous immunoglobulin and rituximab. She undergoes further desensitization with plasmapheresis and bortezomib, which reduces her calculated panel reactive antibodies scores to 72%. She is listed Status 1A with a virtual crossmatch.
A suitable donor becomes available. The donor's human leucocyte antigen (HLA) is A1, B57, C35, DP2, DQ23, DR7. The patient's most recent panel reactive antibodies by single antigen bead assay listed by MFI are shown. As noted, an MFI >10,000 is considered strong-binding by the immunogenetics laboratory.
Which of the following reasons do you give the organ procurement agency for rejecting the donor?
Show Answer
The correct answer is: B. The virtual crossmatch is positive for one unacceptable antigen.
The virtual crossmatch allows one to avoid potential incompatible organs by avoiding specific recipient antibodies to major histocompatibility complex (MHC) antigens as determined by the HLA gene locus. HLAs corresponding to MHC class I (present on all cell surfaces) are A, B, and C. HLAs for MHC Class II (present on leukocytes) are DP, DQ, and DR. Single bead antigen assays such as the Luminex® assay (Luminex Corporation, Austin, TX, USA) allow one not only to identify recipient MHC antibodies, but also quantitate their binding affinity expressed as mean fluorescence intensity (MFI) or standardized fluorescence intensity (SFI). Quantification is important, as antibodies of greater intensity in vitro are considered to be potentially more cytotoxic in vivo.
The detection of anti-HLA antibodies prior to transplantation is important since one would avoid donors who have HLA corresponding to high-level anti-HLA antibodies in the potential recipient as this would be a risk for hyperacute rejection. In the past, the only way to assess for this was with a prospective crossmatch in which the potential recipient's serum was mixed with donor cells to assess for complement-dependent cytotoxicity. This, however, restricted the donor pool geographically to hospitals near where the candidate's serum was stored and where the transportation time would be short to avoid further increase in the donor organ ischemic time. Currently, the virtual crossmatch has replaced the prospective crossmatch at most centers. With the virtual crossmatch, HLA corresponding to high-level anti-HLA antibodies in the transplant candidate are considered "avoids," and potential donors with such HLA are not considered.
There is no universally agreed upon cut-off for an unacceptable MFI or SFI, and antigen "avoid" threshold depends upon a transplant program's size and experience with desensitization and treatment of antibody-mediated rejection. However, most programs will accept antigens with weak recipient antibodies (MFI <3,750), and some will accept up to one antigen with a moderate-intensity recipient antibody (MFI = 5,000). MFI >10,000 are considered cytotoxic and must be avoided.
Additive to the single antigen PRA, the C1q assay detects antibodies that bind C1q, the first factor in the complement cascade. These "complement fixing" antibodies carry a worse prognosis. Thus, "complement fixing" antigens must be avoided as unacceptable.
In this question, the patient has a potential donor-specific antibody to B57 (MFI >10,000), A1 (MFI <3,750), and DR7 (MFI <3,750). As the A1 and DR7 antibodies are weak by MFI threshold, they would not be potentially cytotoxic and would not need to be avoided. However, the B57 antibody is strong-binding and, thus, potentially cytotoxic. The potential donor should be rejected for this reason.
Answer option A is incorrect because the virtual crossmatch is positive for B57. Answer option C is incorrect because there is only one unacceptable antigen as A2 and DR7 are weakly binding. Answer option D is incorrect because there is adequate information on donor HLA and recipient anti-HLA antibodies to perform a virtual crossmatch. Answer option E is incorrect because a prospective crossmatch is generally reserved for patients with multiple moderate-binding antibodies that are present in the potential donor, which is not the case in this patient.
References
Kobashigawa J, Mehra M, West L, et al. Report from a consensus conference on the sensitized patient awaiting heart transplantation. J Heart Lung Transplant 2009;28:213-25.
Stehlik J, Islam N, Hurst D, et al. Utility of virtual crossmatch in sensitized patients awaiting heart transplantation. J Heart Lung Transplant 2009;28:1129-34.
Cecka JM. Calculated PRA (CPRA): The new measure of sensitization for transplant candidates. Am J Transplant 2010;10:26-9.
Chang D, Kobashigawa J. The use of the calculated panel-reactive antibody and virtual crossmatch in heart transplantation. Curr Opin Organ Transplant 2012;17:423-6.
Kittleson MM, Kobashigawa JA. Antibody-mediated rejection. Curr Opin Organ Transplant 2012;17:551-7.
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