Developing personalized immunosuppression for older kidney transplant recipients

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ABSTRACT >400,000 older adults (age ≥55) suffer from end-stage renal disease (ESRD). There has been a 5-fold increase in the number of kidney transplants (KT) in this age group. Older recipients are a distinct group due to impaired homeostasis, higher comorbidity burden, and immune system attenuation. These physiologic factors influence older KT recipients’ response to immunosuppression (IS) medications, a lifelong treatment. The balance between short-term benefits and long-term adverse outcomes of IS can be challenging in older KT recipients. Excellent short-term outcomes (1-year allograft survival>95% and acute rejection [AR]<15%) are achieved in younger patients with modern IS, but our preliminary findings suggest that older KT recipients are at 1.5x increased risk of poor IS tolerance. Older KT recipients are also more susceptible to long-term adverse outcomes associated with the modern IS regimens like infections, malignancy, and new-onset diabetes after transplantation (NODAT) resulting in part from an attenuated immune response. Our preliminary findings suggest that IS regimens with calcineurin inhibitors increase an older recipient’s dementia risk. Yet, our preliminary data suggest that IS is not personalized; center practices account for 46% of IS regimen variation. While KT has been found to be cost saving for ESRD patients, the total KT cost is influenced by accumulating long-term adverse outcomes of IS in this population. IS is not chosen in a cost-blind environment; if the risks and benefits are similar, then cost-effectiveness is an important adjunct to IS regimen choice. The risks, benefits, and cost-effectiveness for an older KT recipient cannot simply be inferred from studies of younger recipients or from clinical trials that largely excluded older recipients. A comprehensive dataset with all key data elements is needed to develop personalized IS for older KT recipients. To develop a personalized approach to IS for older KT recipients, we will integrate 3 novel datasets with >78,800 older KT recipients KT recipients (2005-2019): (1) national data from the Scientific Registry of Transplant Recipients (SRTR); (2) Medicare claims to identify post-KT outcomes and costs; (3) pharmacy claims to identify not only IS agents used but also novel lab data of metabolized IS levels (for 14,000 older recipients). Using this integrated data, we will: 1) compare the effects of IS regimens on efficacy, morbidity, and mortality for older KT recipients; 2) develop Markov models and calculate cost-effectiveness for IS regimens for older KT recipients; and 3) generate individualized reports of predicted efficacy, morbidity, and mortality along with IS regimen cost for practitioners to use for the clinical counseling of older KT recipients. Our goal is to provide evidence and communication tools to help move the field of transplantation away from center-based protocols for IS to personalized IS for older KT recipients. The ability to predict trade-offs in AR and graft survival against long-term adverse outcomes for specific IS regimens in older KT recipients will allow patients and physicians to customize IS choices in a cost-effective and more informed manner. !