Outcome-Based Risk Assessment of Non-HLA Antibodies in Heart Transplantation: A Systematic Review.

Abstract

Current monitoring after heart transplantation (HT) employs repeated invasive endomyocardial biopsies (EMB). Although positive EMB confirms rejection, EMB fails to predict impending, sub-clinical, or EMB-negative rejection events. While non-HLA antibodies have emerged as important risk factors for antibody-mediated rejection (AMR) after HT, their use in clinical risk stratification has been limited. A systematic review of the role of non-HLA antibodies in rejection pathologies has potential to guide efforts to overcome deficiencies of EMB in rejection monitoring. Databases were searched to include studies on non-HLA antibodies in HT recipients. Data collected included: number of patients, type of rejection, non-HLA antigen studied, association of non-HLA antibodies with rejection, and evidence for synergistic interaction between non-HLA antibodies and HLA-DSA responses. A total of 56 studies met the inclusion criteria. Strength of evidence for each non-HLA antibody was evaluated based on the number of articles and patients in support vs. against their role in mediating rejection. Importantly, despite previous intense focus on the role of anti-MHC class I chain-related gene A (MICA) and anti-angiotensin II type I receptor (AT1R) antibodies in HT rejection, evidence for their involvement was equivocal. Conversely, strength of evidence for other non-HLA antibodies supports that differing rejection pathologies are driven by differing non-HLA antibodies. This systematic review underscores the importance of identifying peri-HT non-HLA antibodies. Current evidence supports the role of non-HLA antibodies in all forms of HT rejection. Further investigations are required to define the mechanisms of action of non-HLA antibodies in HT rejection.