Management of children undergoing cardiac transplantation with high Panel Reactive Antibodies

Abstract

Highly sensitised children in need of cardiac transplantation have overall poor outcomes because of increased risk for dysfunction of the cardiac allograft, acute cellular and antibody-mediated rejection, and vasculopathy of the cardiac allograft. Cardiopulmonary bypass and the frequent use of blood products in the operating room and cardiac intensive care unit, as well as the frequent use of homografts, have predisposed potential recipients of transplants to allosensitisation. The expansion in the use of ventricular assist devices and extracorporeal membrane oxygenation has also contributed to increasing rates of allosensitisation in candidates for cardiac transplantation. Antibodies to Human Leukocyte Antigen can be detected before transplantation using several different techniques, the most common being the "complement-dependent lymphocytotoxicity assays". "Solid-phase assays", particularly the "Luminex® single antigen bead method", offer improved specificity and more detailed information regarding specificities of antibodies, leading to improved matching of donors with recipients. Allosensitisation prolongs the time on the waiting list for potential recipients of transplantation and increases the risk of complications and death after transplantation. Aggressive reduction of antibodies to Human Leukocyte Antigen in these high-risk patients is therefore of vital importance for long-term survival of the patient and cardiac allograft. Strategies to decrease Panel Reactive Antibody or percent reactive antibody before transplantation include plasmapheresis, intravenous administration of immunoglobulin, and specific treatment to reduce B-cells, particularly Rituximab. These strategies have resulted in varying degrees of success. Antibody-mediated rejection and cardiac allograft vasculopathy are two of the most important complications of transplantation in patients with high Panel Reactive Antibody. The treatment of antibody-mediated rejection in recipients of cardiac transplants is largely empirical and includes the use of high-dose corticosteroids, plasmapheresis, intravenous administration of immunoglobulins, anti-thymocyte globulin, and Rituximab. Cardiac allograft vasculopathy is believed to be secondary to chronic complement-mediated endothelial injury and chronic vascular rejection. The use of proliferation signal inhibitors, such as sirolimus and everolimus, has been shown to delay the progression of cardiac allograft vasculopathy. In some non-sensitised recipients of cardiac transplants, the de novo formation of antibodies to Human Leukocyte Antigen after transplantation may increase the likelihood of adverse clinical outcomes. The use of serial testing for donor-specific antibodies after cardiac transplantation may be advisable in patients with frequent episodes of rejection and patients with history of sensitisation. Allosensitisation before transplantation can negatively influence outcomes after transplantation. A high incidence of antibody-mediated rejection and graft vasculopathy can result in graft fai...

Outcomes in highly sensitized pediatric heart transplant patients using current management strategies

“…With the help of our immunology team and the Lifelink Histocompatibility Lab, we devised a protocol of pre-transplant weekly plasmapheresis, weekly IVIg treatment, pulse cyclophosphamide and selective use of rituximab therapy. 7 We now utilize the Luminex single-antigen bead method of anti-HLA antibody testing, as this offers improved specificity and more detailed information concerning antibody specificities, leading to better donor-recipient matching. Individual antibody levels are semi-quantified as MFI.…”

Long-term outcomes of children after solid organ transplantation

“…This is often expressed as the percentage of panel-reactive antibodies (PRA), which is tested against a set HLA panel, or the calculated reaction frequency (cRF), which uses the value for the specific HLA antibody calculated against the known population frequency (8). A high PRA or cRF value limits the availability of donors because patients with persistently positive HLA are excluded from the donor pool.…”

“…These patients also exhibit lower allograft and patient survival rates and higher rates of allograft rejection after transplantation (9,10). Antibody-depleting strategies using plasma exchange, double filtration plasmapheresis, intravenous immunoglobulin (IVIg), rituximab and, more recently, the plasma cell-depleting agent bortezomib have produced variable results in children (8,11). However, this sensitized group is growing because of the increase in patients requiring re-transplantation who are sensitized to their failed allografts.…”

Human Leukocyte Antigen Sensitization in Solid Organ Transplantation: A Primer on Terminology, Testing, and Clinical Significance for the Apheresis Practitioner

“…The Panel Reactive Antibody (PRA) score is a broad parameter for determining the degree of HLA sensitization in an individual. The PRA score is calculated using a panel of HLA antigens representative of the HLA distribution in the donor population . Depending on the technique used, a PRA score will typically correspond to the percentage of antibodies reacting to a panel of microtiter plate‐ or latex bead‐coated lymphocyte antigens.…”