Navigating Allosensitization in Heart Transplant Candidates and Recipients

Heart transplantation is an evolving field. Nowhere is that more evident than in the identification and management of HLA and non HLA antibodies in heart transplant candidates and recipients. With the development of new sensitive techniques which identify HLA antibodies in patient sera, there has been both a simplification of and an added complexity to patient management. Colvin et al write an extensive review of allosensitization which serves as an educational tool for all practitioners.¹ Numerous “clinical pearls” are interspersed in the statement based on scientific data and consensus. Indeed, Colvin et al are quick to emphasize that numerous gaps in evidence based medical management of the sensitized patient. Their statement is organized by three phases of patient care i.e. waitlist management, transplant surgery and post-transplant management.

Allosensitization Pre-Transplant

With the expanding use of mechanical assist devices in transplant candidates, the increasing number of patients listed for re-transplantation and greater number of adults with complex congenital heart diseases, the management of allosensitization pre-transplant is gaining importance. In 2015, close to 20% of heart transplant candidates had a panel of reactive antibodies (PRA) consistent with sensitization.^1-3 Complement dependent cytotoxicity assays had been the main method of HLA antibody detection and remains a key technique to identify clinically significant antibodies. Panel of reactive antibodies i.e. PRA has been measured using panels of 20-60 common HLA antigens using CDC assays. These antigen panels vary depending on local lab practices. It has been shown that complement fixing HLA antibodies are associated with a higher rate of hyperacute rejection and that sensitization pre-transplant increases the risk of post-transplant humoral rejection.^4-5

Over the last decade, highly sensitive solid phase assays using bead based technology, i.e. Luminex, which identifies both T and B cell antibodies has been developed and is now widely used in clinical practice. The authors explain the differences in new and old technologies, variations in Luminex findings based on dilution, addition of C1q, anti human globulin (AHG). The lack of uniformity in HLA labs for performing dilutions, adding AHG, and varying MFI levels makes generalizability of the clinical results difficult.

With this new technology, the United Network of Organ Sharing introduced for renal transplantation the calculated PRA (cPRA) which includes the most common HLA antigens and their frequency nationally. The cPRA identifies the frequency of compatible organs. The use of cPRA is not specific to heart but is being applied to cardiac transplant candidates as the cPRA may enable comparisons of patients across regions. Colvin et al explain the differences between the traditionally used PRA and new cPRA.

Sensitization pre-transplant extends waitlist time but how to best manage pre-transplant sensitization remains unclear. Reduction in antibody levels i.e. desensitization can be attempted. Questions currently debated include which candidates should undergo desensitization? What is the most effective approach for desensitization? What is optimal timing for desensitization? What is the best methodology for identifying antibodies that will be problematic following cardiac transplantation? Colvin et al provide the practitioner with guidance and management strategies but unfortunately evidence based clinical outcome studies are lacking and the answer to the questions above remain elusive. Among clinical centers, there continues to be variability in the most basic questions such as identifying candidates who should undergo desensitization with cPRA threshold ranging from 50 to 80%. Similarly, though most centers will attempt to desensitize patients to shorten the waitlist time to transplant, but the pharmacologic interventions and timing vary. Colvin et al review current approaches and provide data on small series in heart transplant candidates and review larger series drawn from the renal transplant literature. Colvin et al also provide an overview of new agents which may be effective therapies for desensitization.

Crossmatching

A critical decision point occurs at the time of identification of a potential allograft for the candidate. With the advent of broader sharing and the likelihood that donor specific areas as units of organ allocation will be replaced by geographical zones, methods by which cross- matching of organs will be done will evolve from primarily complement derived cytotoxicity tests to virtual crossmatches^.6 Colvin et al give a clear description of these processes and provide algorithms which will certainly assist practitioners in the careful selection of organs.

Post-Transplant Donor Specific Antibodies

The presence of post-transplant donor specific antibodies is a signal that can portend a poor prognosis and risk factor for the development of accelerated cardiac vasculopathy.^7-10 However, how to approach management of the patients in the absence of graft dysfunction and documented allograft rejection is presently unknown. How to identify those recipients with low levels of DSA that actually represent accommodation of the organ from those who may have a smoldering subclinical rejection is unclear. Observational studies suggest that the presence of class II DSA may be more problematic for future graft dysfunction but there are no guidelines as to how to modify immunosuppression in such patients. Clinical trials are needed to answer these unresolved questions. Colvin et al acknowledge the inadequacies of our current management in the setting of DSA. There is much work for the heart transplant physicians to do to gain an understanding of how best to optimize the immunosuppression for these patients.