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Management of Allosensitization in the Pediatric Heart Transplant Candidate


Matthew Zinn, DO
Washington University in St. Louis
St. Louis, MO, USA
mattdzinn@gmail.com

Brian Feingold, MD, MS
Children's Hospital of Pittsburgh
Pittsburgh, PA, USA
brian.feingold@chp.edu



Health care providers have been trying to unlock the secret to managing highly sensitized patients prior to transplantation since the significance of a donor-specific crossmatch was recognized by Patel and Terasaki in 1969.The majority of discussion and practice has focused on avoidance of sensitizing agents and desensitization therapy. Use of cryopreserved homografts in staged single ventricle palliation continues to produce highly sensitized patients. It seems like "failed Fontan physiology" and "single ventricle pump dysfunction" account for just as many transplant evaluations as end-stage cardiomyopathy. Blood product transfusions may not be as bad as was once thought. Intravenous immunoglobulin (IVIg), rituximab, plasmapheresis, and bortezomib have all shown promise as desensitizing agents, but lack consistent and lasting results, perhaps because the inciting antigens remain in place (i.e. homograft) before, and possibly after transplantation. With the growing numbers of "failed" Fontan patients coming to transplantation and our increased abilities to detect HLA and non-HLA antibodies, now seems like the right time to shift our focus to new areas of investigation.

To start, it would be imprudent to give up on current strategies that have shown promise in diminishing or eliminating antibodies. Further breakthroughs may not come in what we use, but when we use it. Proteasome inhibitors offer the most targeted therapy against antibody production by inducing apoptosis of the plasma cell. We commonly exhaust all other treatment options prior to use due to concern for potentially serious side effects like peripheral neuropathy, opportunistic infections, and cytopenias. To date the limited reports in children show only minimal and transient adverse drug effects (ADE). Critically ill children may be more at risk for ADEs given that they have a greater risk for infection and less tolerance of associated cytopenias. The key to success with proteasome inhibition may lie in the timing of administration. The potential for "true" desensitization with bortezomib as a first-line agent was recently shown in adult renal transplant recipients. Also, second generation proteasome inhibitors are currently being studied and appear to be effective with less ADEs. Pediatric studies are needed to evaluate primary desensitization using bortezomib-based protocols.

The question then arises regarding antibody-specific desensitization. Use of a ventricular assist device (VAD) is seen as a potentially sensitizing event, possibly due to blood products administered during implantation or secondary to the materials that comprise the device. Is an antibody clinically relevant if it is against a non-biologic material? Should we even bother with desensitization? How can we tell the difference? In fact, VAD-related antibodies infrequently result in a positive crossmatch and may occur less with non-pulsatile devices. Despite an increasing knowledge base on antibody generation, we still cannot predict which antibody will lead to a positive crossmatch. But do we need to be as aggressive in eliminating an uncommon antibody like A31 compared to an extremely common antibody like A2? It may not be clinically beneficial to the patient to receive prolonged immunotherapy on the off chance that a potential donor carries a rare HLA allele. Also, when a candidate shows only a few antibodies of weak to moderate mean fluorescence intensity (MFI) and a negative virtual crossmatch, how do we know which will result in a memory response and should potentially be avoided? Improved abilities to predict not only which will result in a positive crossmatch but which will result in antibody-mediated rejection in the first 2-4 weeks due to memory response will be an important area of understanding as we move forward.

This leads directly into the third point of discussion: is it better at times to avoid desensitization therapy and increased waitlist time by simply transplanting a patient across a positive crossmatch? Data exist that shows both decreased cost and resource utilization, as well as improved survival in highly sensitized patients transplanted with the first acceptable organ. We have even seen similar early survival when transplanted across a positive crossmatch, albeit with higher rates of early rejection. While a negative crossmatch remains ideal, transplanting across a positive crossmatch may actually be favorable, in the right patient.

Allosensitization will likely remain a source of frustration for years to come. There are many questions but few answers. Until bioengineered HLA-specific grafts become reality, we must continue to increase our understanding of HLA antibody production, relevance, and optimal pre-transplant desensitization strategies. ■

Disclosure Statement: The author has no conflicts of interest to disclose.




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