A Pilot Feasibility Trial of Thyroid Hormone Replacement in Dialysis Patients

透析患者甲状腺激素替代的试点可行性试验

• 批准号: 9375962
• 负责人: Connie Meeyoung Rhee
• 金额: $ 7.73万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9375962
• 关键词: Affect; Atherosclerosis; Atrial Fibrillation; Award; Biological Markers; Body Composition; Cardiovascular Diseases; Cardiovascular system; Catabolism; Cessation of life; Chronic Kidney Failure; Complication; Data; Dialysis patients; Dialysis procedure; Diet; Disease; Double-Blind Method; End stage renal failure; Endocrine; Exposure to; Fatigue; Fatty acid glycerol esters; Feasibility Studies; Functional disorder; Future; GDF15 gene; General Population; Health Benefit; Heart failure; Hemodialysis; High Prevalence; Hypothyroidism; Impaired health; Impairment; Inflammation; Information Systems; Interdisciplinary Study; Kidney; Kidney Diseases; Laboratories; Link; Malnutrition; Measurable; Measures; Mentored Patient-Oriented Research Career Development Award; Morbidity - disease rate; Multi-Institutional Clinical Trial; National Institute of Diabetes and Digestive and Kidney Diseases; Normal Range; Observational Study; Outcome; Outpatients; P-Selectin; PLAB Protein; Parents; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Physical Function; Placebo Control; Placebos; Platelet Activation; Population; Prevalence; Prospective cohort; Proteins; Publishing; Quality of life; Randomized; Randomized Controlled Trials; Recruitment Activity; Reference Values; Reporting; Research; Risk; Safety; Seminal; Serum; Serum Albumin; TNFRSF5 gene; Testing; Therapeutic; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Treatment Efficacy; United States; United States National Institutes of Health; Work; arm; cohort; endothelial dysfunction; experience; health related quality of life; improved; indexing; insight; modifiable risk; mortality; muscle form; novel; prognostic; racial disparity; study population; therapeutic target; translational medicine; wasting

PROJECT SUMMARY/ABSTRACT Three decades of research have shown a disproportionate prevalence of hypothyroidism (~25%) in chronic kidney disease (CKD) patients, including those receiving dialysis. While hypothyroidism has been associated with heightened cardiovascular (CV) morbidity and mortality in the general population, there had previously been a paucity of data on its prognostic implications in CKD. During the first 2¼ years of the parent K23 award, Dr. Connie Rhee (PI) has published pioneering studies showing that elevated thyrotropin (TSH) levels even within the normal range (>3.0mIU/L) are associated with higher mortality across multiple dialysis cohorts. Her seminal work showing a link between high-normal TSH levels and worse health-related quality of life (HRQOL) Short Form 36 (SF36) scores in dialysis patients also suggest that impaired HRQOL may be an under-recognized pathway to death. However, there remains considerable controversy as to 1) whether thyroid dysfunction is causally associated with adverse CV and patient-centered outcomes, 2) if elevated TSH levels represent hypothyroidism vs. non-thyroidal illness in CKD patients, and 3) the optimal TSH range associated with the greatest health benefit in dialysis patients. Furthermore, while United States Renal Data System data show that levothyroxine (L-T4) is one of the most commonly prescribed medications in pre-dialysis CKD and end-stage renal disease patients, little is known about its efficacy and safety in this population. These discoveries have motivated the present R03 application in which Dr. Rhee aims to conduct a double-blind, placebo-controlled pilot feasibility randomized controlled trial (RCT) of L-T4 administration over 12 weeks among 96 hemodialysis patients with high-normal or subclinical hypothyroid TSH levels who will be recruited from her parent NIH/NIDDK K23 study and the K24-sponsored “Malnutrition, Diet, and Racial Disparities in CKD” cohort. Aim 1 will determine L-T4’s efficacy in achieving a target TSH range of 0.5- 3.0mIU/L (primary objective). Aim 2 will examine whether L-T4 treatment results in improvement of 1) HRQOL SF36 scores and 2) novel CV biomarkers of heart failure, endothelial function, and platelet activation, 3) without leading to increased protein catabolism ascertained by indices of protein-energy wasting (secondary objective). Findings from this pilot feasibility study will provide the framework for a future, large-scale multi- center RCT that 1) may uncover thyroid dysfunction as a novel, modifiable risk factor for CV disease and impaired HRQOL, and 2) will inform the management of the vast number of CKD patients affected by this prevalent endocrine-renal disorder. Moreover, support of the R03 award will allow Dr. Rhee to accelerate her progress towards independence by providing her with 1) practical experience in the implementation of a pilot feasibility RCT, 2) hands-on exposure to translational medicine and laboratory platforms through CV biomarker testing, and 3) extension of the rich multi-disciplinary collaborations she has developed during the parent K23 award period.

项目摘要/摘要 三十年的研究表明，甲状腺功能减退症的患病率不成比例（约25％） 慢性肾脏疾病（CKD）患者，包括接受透析的患者。甲状腺功能减退症 与普通人群中心血管（CV）的发病率和死亡率升高有关， 以前是关于其在CKD中其预后含义的数据。在父母的前2¼年 K23 Award，Connie Rhee博士（PI）发表了开拓性研究，表明甲状腺激素升高（TSH） 即使在正常范围内（> 3.0miu/L）的水平与多个透析的较高死亡率有关 同伙。她的第二件作品显示了高正常TSH水平与健康相关质量差的联系 透析患者的生命（HRQOL）短表36（SF36）得分也表明HRQOL受损可能是一种 未被认可的死亡途径。但是，关于1）甲状腺是否存在很大的争议 功能障碍有时与不良CV和以患者为中心的结果有关，2）如果TSH水平升高 代表甲状腺功能减退症与CKD患者的非甲状腺疾病，3）最佳TSH范围相关的TSH范围 透析患者的健康益处最大。此外，尽管美国肾脏数据系统数据 证明左甲状腺素（L-T4）是透析前CKD中最常见的药物之一，并且 末期肾脏疾病患者对该人群的有效性和安全知之甚少。 这些发现激发了当前的R03应用，Rhee博士旨在进行一次 L-T4给药的双盲，安慰剂控制的飞行员可行性随机对照试验（RCT） 在96例高正常或亚甲基甲状腺功能低下TSH水平的血液透析患者中​​12周 从她的父母NIH/NIDDK K23研究中招募和K24赞助的“营养不良，饮食和种族 CKD”队列的差异。AIM1将确定L-T4在达到0.5-的目标TSH范围方面的效率 3.0MIU/L（主要目标）。 AIM 2将检查L-T4治疗是否会改善1）HRQOL SF36分数和2）心力衰竭，内皮功能和血小板激活的新型CV生物标志物，3） 没有导致蛋白质分解代谢增加而通过蛋白质浪费的指标确定（次级 客观的）。这项试验可行性研究的发现将为未来的大规模多尺度提供框架 中心RCT 1）可能会发现甲状腺功能障碍是CV疾病和可修改的新型风险因素 HRQOL受损，2）将为管理层提供大量受此影响的CKD患者 普遍的内分泌肾脏疾病。此外，R03奖的支持将使Rhee博士能够加速她 通过为她提供1）实施飞行员的实践经验而朝着独立的进步 可行性RCT，2）通过简历生物标志物动手接触翻译的医学和实验室平台 测试和3）她在父母K23期间开发了丰富的多学科合作的扩展 奖励期。