The Virtual Crossmatch: What's in a Name?

The recent article by Locke et al1 reviewed the results of the University of California, Los Angeles Virtual Crossmatch (VXM) Exchanges from 2014–2019. We commend the authors for their analysis of the vast amount of data. Although a physical crossmatch (PXM) was once the definitive pretransplant test, in current practice, the presence of donor-specific antibody (DSA) and even a positive flow cytometric crossmatch are not absolute contraindications for transplantation. Therefore, we disagree with the authors’ statement that correlating a VXM to a PXM result is critical. Because more transplant centers have adopted the VXM as their only pretransplant antibody assessment, the term VXM must be more clearly defined. Specifically, what are the reasonable expectations of a VXM? As put forward by the Clinical Laboratory Improvement Advisory Committee (CLIAC) VXM Working Group,2 the VXM is “An assessment of immunologic compatibility based on the patient’s alloantibody profile compared to the donor’s histocompatibility antigens.” However, the authors state that laboratories perform VXMs to both “…determine the presence/absence of preformed DSA and to predict the result of the flow cytometry crossmatch….” Although the VXM has been used to predict a PXM, we disagree with the notion that a PXM result should be used to define the VXM. Furthermore, the CLIAC definition did not stipulate that “…the correlation of T- and B-FXM results with DSA detected by SAB testing is critical for VXM prediction,” as asserted by the authors. Although correlating SAB median fluorescence intensity (MFI) data with crossmatch results does provide meaningful information, this point was not the intent of the VXM definition. Indeed, the term “immunologic compatibility” was deliberately chosen to allow transplant centers to be flexible in their interpretation of complex immunological data, not simply correlating with the PXM. Rather, the VXM is the process of combining HLA data with other center-specific, patient-specific, and organ-specific parameters to provide a metric of donor:recipient immunologic compatibility. The term “compatibility” should be determined according to each center’s philosophy of practice reflecting their risk tolerance, patient makeup, and therapeutic aggressiveness. For example, a candidate may possess a true DSA with an MFI value just below the threshold for calling the antigen unacceptable. However, depending upon the specifics of the DSA (eg, locus, MFI, and target epitope), a PXM with a given MFI could be positive or negative and the program may choose to transplant an organ independent of the PXM result. Such center-specific characteristics should be identified and incorporated into the HLA laboratory’s program agreement with their transplant center. Furthermore, the authors assert, “…the accuracy of the VXM prediction in the presence of DSA can be complicated…” but do not define a metric to determine accuracy. Is the assumed metric a PXM? The authors acknowledge that many variables can affect the correlation between MFI and a PXM result but nonetheless suggest, “…standardization…will be needed to improve the VXM accuracy…” How would standardization be achieved given that “accuracy” has not been defined? Striving for better agreement between MFI values and PXMs via surveys is laudable but not the primary intent of the VXM. It is also important to recognize that proficiency surveys do not always reflect reality. For example, the authors mentioned that the integrity of cellular material used to perform a PXM can vary. Badders et al3 demonstrated that peripheral blood B lymphocytes from deceased donors have significantly lower expression of class I and II than spleen or peripheral blood. The University of California, Los Angeles crossmatch survey used only peripheral blood from healthy donors. Thus, although their findings may be applicable to living donor scenarios, they may not be applicable to most deceased donor crossmatches. For these reasons and more, the VXM was classified as a consultation by Center for Medicare and Medicaid Services during the CLIAC VXM Working Group’s meeting.2 Equating the VXM with a laboratory test diminishes the efforts that underpin the process and undervalues the contributions of the laboratory director/clinical consultant. The distinctions are clear; a laboratory test versus a consultation. Proficiency testing surveys should focus on evaluating test results and not conflate laboratory testing with clinical practice.