Virtual crossmatching: Principles, practices, and the path forward—An American Society for Histocompatibility and Immunogenetics/College of American Pathologists collaborative

Donor-specific anti-human leukocyte antigen (HLA) antibodies are a significant barrier to solid organ transplant and can lead to poor outcomes in the posttransplant setting. Physical crossmatch (PXM), including complement-dependent cytotoxicity crossmatch and flow cytometric crossmatch, has substantially reduced the incidence of hyperacute rejection and, for years, has been the gold standard for compatibility assessment before transplant. However, the advent of solid-phase anti-HLA antibody testing and molecular HLA typing has allowed the introduction and rise of virtual crossmatch (VXM). With a high negative predictive value, VXM has proven to be more sensitive than PXM in detecting donor-specific anti-HLA antibodies. Recent regulations by the Centers for Medicare & Medicaid Services now recognize VXM as a suitable alternative to PXM in pretransplant compatibility assessment. As VXM gains acceptance, it is imperative that we understand its complexities, such as its definition, application, advantages, and disadvantages. In this review, we examine the principles underlying VXM, including both generally accepted concepts and areas under debate. Furthermore, we highlight current applications and discuss opportunities for future improvement.