Improving frailty and long-term outcomes after kidney transplantation

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PROJECT SUMMARY/ABSTRACT Improving the long-term survival of kidney transplants (KT) is a national priority in the US. The prevalence of end-stage renal disease is increasing, and the organ shortage is growing. Unfortunately, long-term graft and patient survival has not improved since the 1990s. The half-life of a deceased donor kidney is currently only fifteen years. The most common cause of kidney transplant failure is patient death. In order to address this health crisis, the transplant community needs to focus on modifiable risk factors for patient death and other adverse long-term outcomes after kidney transplantation, such as frailty. Frailty is a clinical syndrome characterized by decreased physiologic reserve and is common in patients with chronic kidney disease (CKD). Frailty prior to KT has been associated with increased post-transplant mortality and has been shown to be modifiable in non-transplant patients. However, there is a significant knowledge gap regarding frailty after KT, including risk factors for its development, biomarkers with which to identify it, and interventions with which to improve it. Cellular senescence is an exciting new area of frailty research that directly applies to these deficits. During the process of senescence, metabolic stressors cause cells to enter a state of permanent growth arrest. Senescent cells accumulate throughout the body and secrete factors collectively called the senescence- associated secretory phenotype (SASP) which induce formation of other senescent cells and cause surrounding tissue damage. Cellular senescence is a mechanism of aging and age-related diseases such as frailty. Components of the SASP serve as biomarkers of frailty in non-transplant populations and may help us identify KT recipients at high risk of functional decline and premature death. In addition, frailty biomarkers could ultimately serve as surrogate endpoints in clinical trials designed to improve frailty. The overall objective of this application is to 1) identify frailty trajectories after kidney transplantation, 2) identify biomarkers of frailty after kidney transplantation, and 3) conduct a phase II clinical trial examining the preliminary efficacy, feasibility and acceptability of an exercise intervention on post-transplant frailty. The proposed K23 application involves the use of innovative biomarkers and behavioral interventions to improve frailty and long-term outcomes after KT, a priority for the NIDDK which focuses on bridging translational research gaps to improve the health and quality of life of patients with CKD. The candidate has exceptional resources available to her: a multidisciplinary team of expert mentors; access to a large volume of transplant patients; and excellent career development activities, i.e., formal courses and workshops in statistical methods, biomarker development, and behavioral clinical trials. Together, these resources will allow the candidate to achieve her long-term goal of becoming an independent investigator and nationally recognized expert on the use of biomarker technology and behavioral interventions to improve frailty and long-term outcomes after KT.