Metabolic Syndrome after Pediatric Liver Transplant: Causes and Consequences

小儿肝移植后代谢综合征：原因和后果

• 批准号: 9529633
• 负责人: EMILY ROTHBAUM PERITO
• 金额: $ 19.83万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9529633
• 关键词: Adrenal Cortex Hormones; Adult; Adverse effects; Age; Atherosclerosis; Award; Calcineurin inhibitor; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Child; Childhood; Cirrhosis; Clinical; Clinical Investigator; Cross-Sectional Studies; Data; Data Analyses; Development; Diabetes Mellitus; Dose; Dyslipidemias; Endocrinologist; Enrollment; Environmental Risk Factor; Epidemic; Epidemiologist; Epidemiology; Event; Future; Gastroenterologist; Gender; Glucose Intolerance; Goals; Health; High Density Lipoproteins; Hypertension; Hypertriglyceridemia; Immunosuppression; Impairment; Individual; Insulin; Insulin Resistance; Integration Host Factors; Intervention; Intervention Studies; Investigation; Long-Term Survivors; Maintenance; Medial; Mentors; Metabolic syndrome; Modification; Morbidity - disease rate; Non obese; Obesity; Organ; Organ Transplantation; Outcome; Overweight; PPP3CA gene; Patients; Pharmaceutical Preparations; Population; Prevalence; Prospective cohort; Prospective cohort study; Protocols documentation; Research; Research Personnel; Risk; Risk Assessment; Risk Factors; Science; Severities; Solid; Structure of beta Cell of islet; Thick; Toxic effect; Training; Transplant Recipients; Transplantation; Visit; Withdrawal; cardiovascular risk factor; career development; cohort; evidence base; improved; lipid metabolism; liver transplantation; mortality; multidisciplinary; nephrotoxicity; non-alcoholic fatty liver disease; prevent; programs; prospective; public health relevance; screening; standard of care; statistics; therapy design; young adult

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：该K23将支持Emily R. Perito医学博士的职业发展，她是一名儿科肝病学家和胃肠病学家。她的目标是成为一名独立的临床研究者，专注于改善儿童肝移植受者的长期预后。移植后代谢综合征（PTMS）是成人肝移植术后长期发病和死亡的主要原因。在肝移植后的儿童中，代谢综合征的个别组成部分——包括高血压、血脂异常和葡萄糖不耐受——比预期的年龄、性别和肥胖程度更常见。但它们作为代谢综合征的聚类及其对移植物和患者健康的长期影响尚未得到研究。本研究的目的是探讨儿童肝移植受者PTMS的危险因素、后果和治疗策略。调查集中在PTMS的两个可改变的原因：肥胖和钙调磷酸酶抑制剂毒性。钙调磷酸酶抑制剂是实体器官移植后维持免疫抑制的主要药物。它们的副作用包括高血压、血脂异常和葡萄糖耐受不良，但不会导致肥胖。在K23的支持下，佩里托博士将建立两个儿科肝移植受者的前瞻性队列——移植后晚期队列，她将研究普遍的PTMS及其进展，以及移植前的试点队列，她将调查发生的PTMS。晚期队列的基线横断面研究将允许佩里托博士确定PTMS的患病率及其与早期心血管疾病和NAFLD的关系（目的1）。该队列将进行前瞻性随访，以研究钙调磷酸酶抑制剂剂量改变对PTMS、早期心血管疾病和NAFLD的影响（目的2）。佩里托博士还将对肝移植前的儿童进行小型试点队列研究，以确定新发儿科PTMS的危险因素（目的3）。该试验将侧重于肥胖和皮质类固醇暴露，以及钙调磷酸酶抑制剂的毒性。这些研究将指导未来的介入研究筛选和管理策略，以减少小儿肝移植受者经颅综合征相关的发病率。佩里托博士的指导团队和培训计划将促进她的研究和职业发展。该奖项将为佩里托博士提供以下方面的额外培训：(1)高级统计和流行病学；(2)肥胖、胰岛素抵抗和代谢综合征的科学；(3)研究队列的开发和管理；(4)介入研究的设计。儿科肝病学家和临床研究员菲利普·罗森塔尔（Philip Rosenthal）博士是主要导师。儿科内分泌学家Robert Lustig博士将提供代谢综合征方面的专业知识。生物统计学家David Glidden博士将提供纵向数据分析方面的指导。心血管流行病学家克尔斯滕·比宾斯-多明戈博士将指导年轻人进行心血管风险评估。该团队的多学科专业知识将使佩里托博士能够建立一个独特的独立研究项目，致力于改善儿童肝移植后的长期结果。

项目成果

The Impact of Increased Allocation Priority for Children Awaiting Liver Transplant: A Liver Simulated Allocation Model (LSAM) Analysis.

增加分配优先级对等待肝移植的儿童的影响：肝脏模拟分配模型（LSAM）分析。

• DOI: 10.1097/mpg.0000000000002287
• 发表时间: 2019
• 期刊: Journal of pediatric gastroenterology and nutrition
• 影响因子: 2.9
• 作者: Perito,EmilyR;Mogul,DouglasB;VanDerwerken,Douglas;Mazariegos,George;Bucuvalas,John;Book,Linda;Horslen,Simon;Kim,HeungB;Miloh,Tamir;Ng,Vicky;Reyes,Jorge;Rodriguez-Davalos,ManuelI;Valentino,PamelaL;Gentry,Sommer;Hsu,Evelyn
• 通讯作者: Hsu,Evelyn