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Some Aspects of Aging Are Advantageous

Elderly Organ Recipients May Get Away With Less Immunosuppression

Maenosono, Ryoichi MD1,2; Gabardi, Steven PharmD1; Tullius, Stefan G. MD, PhD, FACS1

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doi: 10.1097/TP.0000000000002805
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Aging impacts health care broadly. In organ transplantation, most patients currently waiting for an organ transplant are older than 55 years, with >20% of transplant recipients being over the age of 65.1 Demographic changes are also relevant for the deceased donor population with approximately 20% of donors being older than 50 years and approximately 5% >65 years old.2 Markedly are geographic differences with close to 50% of donors being older than 60 years in Spain.3

Although relevance and necessity of age-specific aspects of immunosuppression in the elderly have been recognized, clinical immunosuppressive trials in organ transplantation have mostly excluded older patients.

The aging immune system is characterized by reduced amounts of naïve T cells because of limited thymic outputs, an accumulation of less effective memory T cells, and a constricted T-cell receptor repertoire. Additional age specifics of T-cell metabolisms have started to be appreciated. The effects of immunosenescence on B-cell responses are less well understood. The efficacy of B cells may be influenced through compromised T cell function, with additional limitations in class switch recombinations playing a role.4

Clearly, understanding immunosuppression in the elderly is of clinical relevance. It is important to understand that an optimization of immunosuppression in aging may not be as simple as applying less of the same immunosuppression. Immunosuppressants that work effectively in young recipients may operate differently in the elderly. Tacrolimus, for example, has been more efficient at lower doses with age-specific effects based on lower calcineurin levels in older human CD-4 T cells. Moreover, mammalian target of rapamycin inhibition has been more effective in experimental models with reduced proinflammatory interferon-γ production and augmented amounts of interleukin (IL)-10 by old CD4+ T cells.5

Studying age-specific aspects of clinical immunosuppression appears, therefore, timely and relevant. While previous studies have compared the application of the polyclonal antibody Thymoglobulin (ATG) and Basiliximab (BSX) targeting the IL-2 receptor on activated T cells as induction treatments, those regimens have not been compared in the elderly.

Masset et al6 from France showed that both ATG and BSX were effective in immunological low risk older (≥65 y) recipients. Three-year graft survival was different (74% for ATG- and 68% for BSX-treated recipients), however, not reaching statistical significant difference. BSX-treated patients also had higher rates of acute T-cell–mediated rejections. As the most prominent finding of this study, the occurrence of posttransplant diabetes (PTD) had been significantly higher in BSX compared to ATG-treated recipients (23% versus 15%, P = 0.04), potentially related to higher tacrolimus trough levels in the BSX group (BSX 9.48 versus ATG 7.30 ng/mL, P = 0.023). As T-cell–mediated rejections had been significantly higher in BSX-treated recipients, those patients may have also had an additional corticosteroid burden. A few additional aspects, including center-specific approaches of protocol versus for-cause biopsies and an overall small cohort, need to be contemplated. Moreover, conclusions of this study are based on a retrospective analysis with a broad center-specific variance of immunosuppressive treatments and only a small albeit significant difference for the incidence of PTD.

Do those results confirm that less is more when it comes to immunosuppression in the elderly, or are there additional aspects to consider? We have come to understand that alloimmunity is determined by the sum of recipient’s alloimmune responses. The immunogenicity of the graft itself is playing an additional role. In aging, this constellation appears of particular relevance: older organs elicit more frequent acute rejections linked to activated intragraft dendritic cells.7-9 Remarkably, the frequency of acute rejections when transplanting older organs is blunted when older organs are transplanted into older recipients. Of additional clinical relevance, older recipients are more likely to receive an older organ that is, in turn, more likely to develop a delayed graft function,10 emphasizing the importance to postpone the initiation of calcineurin inhibitors.

Immunosuppressive protocols for the elderly will thus need to have those complexities in mind. Although more frequent rates of PTD may very well be linked to increased tacrolimus trough levels, this finding may not necessarily make an argument for a BSX induction in elderly transplant recipients. A reduced Thymoglobulin dosage in parallel to a reduced tacrolimus dosage, initiated days after transplantation, may be a preferable alternative.

Masset et al6 have helped us to focus on the elderly in transplantation with the goal to work toward an optimized immunosuppression in this growing transplant population.

Future prospective immunosuppressive studies in the aging population with an additional detailed evaluation of alloimmune responses may provide further clarification for a clinically pressing problem in organ transplantation (Figure 1).

FIGURE 1
FIGURE 1:
Future immunosuppressive trials in the elderly may address dosing of established immunosuppressants in addition to age-specific effects and alloimmune responses. ATG, antibody thymoglobulin.

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