Alloimmune risk stratification for kidney transplantation

Alloreactivity after kidney transplantation occurs via both memory responses resulting from prior sensitization and de novo responses that develop due to donor-recipient disparity for the human leukocyte antigen (HLA) complex. HLA compatibility (absence of HLA-DSA) and the degree of HLA matching inform on the likelihood of allorecognition that can cause allograft rejection and allograft loss, and are therefore the two pillars of alloimmune risk assessment. Over the past decades, the detection of anti-HLA antibodies has become more sensitive and specific through single antigen bead testing, and advances in HLA typing from serology to DNA level have been instrumental for more detailed analysis of HLA compatibility. Nonetheless, alloimmune risk stratification using antigen-level HLA data has limited ability to accurately predict the risk of de novo anti-HLA responses and long-term graft outcome after transplantation, especially on the individual patient level. Aiming to improve long-term outcomes by improving HLA matching, HLA molecular mismatch algorithms have been developed. In this review, we discuss the advances, clinical evidence, limitations and clinical implementability of HLA molecular mismatch analysis to increase precision in alloimmune risk stratification in kidney transplantation. In addition, we provide an overview of the different molecular mismatch tools and their potential application in personalized medicine, such as organ allocation, criteria for donor acceptance and individualized immunosuppression.