Challenges and Opportunities in Pediatric Heart Failure and Transplantation

2313 The first cardiac transplant in the United States, and the second worldwide, was performed on a pediatric patient by Dr Adrian Kantrowitz in the late 1960s. Acute cellular rejection and other factors led to poor outcomes, limiting the growth of pediatric and adult cardiac transplantation programs. Cyclosporine-based immunosuppression was introduced in the 1980s, and survival dramatically improved. A significant rise in annual cardiac transplantation volume ensued in the late 1980s but plateaued primarily because of a lack of donors. Use of long-term mechanical circulatory support devices (ventricular assist devices) in adults allowed the bridging of candidates to transplantation, combating long wait times resulting from a limited donor pool. These devices were often not suitable for smaller pediatric patients. Extracorporeal membrane oxygenation provides short-term pediatric support, but significant complications often develop, precluding transplantation. The Berlin Heart EXCOR Pediatric Ventricular Assist Device was developed for infants and small children in the early 1990s, gained approval for use in Europe in 1996, and was approved by the US Food and Drug Administration for use in the United States in 2011. Ventricular assist device use can lead to sensitization, another barrier to transplantation. Sensitization, the development of circulating antibodies directed against human leukocyte antigen (HLA) proteins, poses a significant challenge. Risk factors for sensitization include exposure to blood products, infections, pregnancy, and use of ventricular assist devices. Surgery for congenital heart disease, especially with the use of human homograft tissue, is an additional risk factor for sensitization, affecting primarily pediatric patients. Although homografts are processed and preserved, they remain immunologically reactive and can lead to HLA antibody formation. These antibodies can be harmful to the transplanted graft. HLA antibody–mediated cardiac rejection (AMR), first described by Hammond and colleagues in the late 1980s, is a considerable risk factor for poor outcomes after pediatric transplantation. Listing or avoiding donor antigens before transplantation is but one strategy to mitigate early graft injury and loss resulting from HLA antibodies. Specifically, a transplantation program may decline an organ on the basis of the presence of antibodies that could recognize the donor antigens. This strategy, however, further constricts the donor pool and potentially prolongs the wait time. The presence of HLA antibodies is thus a challenging problem before and after transplantation. This review addresses the following: (1) the role and classification of HLA antibodies, (2) detection methods to assess for antibodies and clinical implications, (3) therapeutic options, (4) clinical strategies toward the highly sensitized pretransplantation candidate, and (5) clinical strategies to combat AMR in the posttransplantation patient. Antibodies against major blood group (ABO) antigens represent another form of sensitization. This selected topic is addressed in a separate review as part of the series on Current Challenges in Pediatric Heart Failure and Transplantation.