This K23 will support the career development of Emily R. Perito, MD, a pediatric hepatologist and gastroenterologist. Her goal is to be an independent clinical investigator focused on improving long-term outcomes in pediatric liver transplant recipients. Post-transplant metabolic syndrome (PTMS) is a major contributor to long-term morbidity and mortality after liver transplant in adults. In children after liver transplant, individual components of metabolic syndrome-including hypertension, dyslipidemia, and glucose intolerance-are more common than expected for age, gender, and degree of obesity. But their clustering as metabolic syndrome and their impact on long-term graft and patient health has not been studied. The goal of this research is to investigate risk factors for, consequences of, and strategies to treat PTMS in pediatric liver transplant recipients. The investigation focuses on two modifiable causes of PTMS: obesity and calcineurin- inhibitor toxicity. Calcineurin-inhibitors are the mainstay of maintenance immunosuppression after solid-organ transplant. Their side effects include hypertension, dyslipidemia, and glucose intolerance-but not obesity. With the support of this K23, Dr. Perito will establish two prospective cohorts of pediatric liver transplant recipient-a late post-transplant cohort in which she will study prevalent PTMS and its progression, and a pilot cohort followed from pre-transplant in which she will investigate incident PTMS. A baseline cross-sectional study of the late cohort will allow Dr. Perito to define the prevalence of PTMS and its association with early cardiovascular disease and NAFLD (Aim 1). This cohort will be followed prospectively to investigate the impact of calcineurin-inhibitor dose modifications on PTMS, early cardiovascular disease, and NAFLD (Aim 2). Dr. Perito will also follow a small pilot cohort of children from prior to liver transplant, to identify risk factors for new- onset pediatri PTMS (Aim 3). This pilot will focus on obesity and corticosteroid exposure, as well as calcineurin-inhibitor toxicity. These studies will guide future interventional research on screenin and management strategies to reduce PTMS-related morbidity in pediatric liver transplant recipients. Dr. Perito's mentoring team and training plan will facilitate this research and her career development. This award will provide Dr. Perito with additional training in: (1) advanced statistics and epidemiology;(2) the science of obesity, insulin resistance, and metabolic syndrome;(3) development and management of research cohorts;and (4) design of interventional studies. Dr. Philip Rosenthal, a pediatric hepatologist and clinical researcher, is the primary mentor. Dr. Robert Lustig, a pediatric endocrinologist, will provide expertise on metabolic syndrome. Dr. David Glidden, a biostatistician, will provide mentoring on longitudinal data analysis. Dr. Kirsten Bibbins-Domingo, a cardiovascular epidemiologist, will mentor on cardiovascular risk assessment in young adults. The multi-disciplinary expertise of this team will allow Dr. Perito to build a unique independent research program dedicated to improving long-term outcomes after pediatric liver transplant.
In pediatric liver transplant recipients, little is known about post-transplant metabolic syndrome, non-alcoholic fatty liver disease, or cardiovascular disease, all key contributors to morbidity and mortality in adult post liver transplant patients. This research is a prospective cohort study that investigates the causes and consequences of post-transplant metabolic syndrome in children and young adults after liver transplant-with a focus on two modifiable factors that appear to drive the condition: obesity and adverse effects of immunosuppressive medications (calcineurin-inhibitors, corticosteroids). Results will allow development of evidence-based screening and management strategies for post-transplant metabolic syndrome that aim to reduce morbidity and mortality in the growing population of long-term survivors of pediatric liver transplant.