Calcium Handling and Secondary Hyperparathyroidism in Chronic Kidney Disease

慢性肾脏病中的钙处理和继发性甲状旁腺功能亢进症

• 批准号: 8129659
• 负责人: Tamara Isakova
• 金额: $ 16.98万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-16 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8129659
• 关键词: Attenuated; Bone Diseases; Calcitriol; Calcium; Cardiovascular Diseases; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Cohort Effect; Collaborations; Complication; Data; Development; Diagnosis; Diet; Diet Modification; Dietary Calcium; Dietary Proteins; Dietary Sodium; Disease; Diuretics; Early treatment; Ensure; Fasting; Fracture; Future; General Hospitals; General Population; Goals; Health; Hormones; Hour; Human; Hypocalcemia result; Intake; Internal Medicine; Intestines; Investigation; Kidney Failure; Lead; Macronutrients Nutrition; Massachusetts; Master' s Degree; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolism; Minerals; Nephrology; Outcome; Parathyroid gland; Pathogenesis; Patients; Pattern; Phosphorus; Physiological; Physiology; Population; Positioning Attribute; Postprandial Period; Prevalence; Protein-Restricted Diet; Proteins; Relative (related person); Reporting; Research; Research Personnel; Residencies; Risk; Role; Secondary Hyperparathyroidism; Series; Serum Calcium Level; Severities; Sodium; Staging; Stress; Supplementation; Testing; Thiazide Diuretics; Training; Work; absorption; attenuation; bone loss; calcium absorption; calcium intake; career development; cohort; college; disorder control; experience; follow-up; healthy volunteer; hormone metabolism; improved; insight; medical schools; mortality; novel; prevent; public health relevance; response; skills; success; thiazide; urinary

DESCRIPTION (provided by applicant): Candidate: Tamara Isakova received her MD from Downstate College of Medicine, and completed her Internal Medicine Residency at Massachusetts General Hospital. She is currently a research fellow in nephrology at MGH, and a candidate for a Master's degree in human physiological investigation from Harvard Medical School. Mentor: Dr. Ravi Thadhani is a world-renowned clinical investigator with extensive mentorship experience. Dr. Thadhani will ensure the success of Dr. Isakova's training, proposed studies and career development. Research: Secondary hyperparathyroidism (sHPT) is a common and early complication of chronic kidney disease (CKD) that is associated with bone and cardiovascular disease and mortality. While the factors that maintain increased levels of parathyroid hormone (PTH) in advanced CKD are well established, the pathophysiological triggers that initiate increased PTH secretion in early CKD are less clear. Data from our group demonstrated that normocalcemic patients with early CKD developed subtle but significant reductions in serum calcium levels in the postprandial state. The relative hypocalcemia followed an increase in calciuria and was associated with a subsequent increase in postprandial PTH levels. Importantly, fasting PTH levels were not significantly increased in these patients; differences in PTH physiology between CKD and controls were detectable only in the postprandial "stressed" state. Thus, we hypothesize that postprandial calciuria with episodic, relative hypocalcemia is a previously unreported initiating factor in the pathogenesis of sHPT in early CKD. In the current proposal we will explore this novel hypothesis in a series of human physiological studies and assess the relevance of the physiologic mechanisms at the population level in the Chronic Renal Insufficiency Cohort (CRIC), a large established cohort of CKD patients. In Aim 1, we will examine the PTH secretory pattern in CKD and its relationship with calciuria, calcemia and dietary calcium intake in response to 3 separate meals over the course of 24-hours to test whether there is a "stacking" effect from meal to meal on increased PTH secretion. In Aim 2A, we will increase separately the meal protein and sodium contents in order to test whether greater calciuria following high protein and sodium meals is associated with worsening hypocalcemia and greater PTH elevation in CKD. In Aim 2B, we will test whether augmenting dietary calcium intake or its absorption using calcitriol will blunt the postprandial hypocalcemia and thus prevent subsequent increases in PTH secretion. In Aim 3, we will examine in CRIC the effects of dietary sodium, calcium, phosphorus and protein, and therapy with diuretics on PTH levels and the risk of developing sHPT in CKD. We believe the results of these studies will provide important insights into novel mechanisms of sHPT in early CKD and lead to improved diagnosis and management of early-stage CKD patients. A K23 award will allow Dr. Isakova to attain new skills in clinical investigation and develop into an independent clinical investigator. PUBLIC HEALTH RELEVANCE: The long term goal of this proposal is to improve the lives of patients with chronic kidney disease (CKD) by studying the mechanisms for development of secondary hyperparathyroidism in CKD. Our results will provide new insights into the initiation of this hormone problem in CKD and guide new treatments to improve clinical outcomes for patients with CKD.

描述（由申请人提供）：候选人：塔玛拉Isakova收到她的医学博士从州医学院，并完成了她的内科住院医师在马萨诸塞州总医院。她目前是MGH的肾脏病学研究员，也是哈佛医学院人类生理学研究硕士学位的候选人。导师：Ravi Thadhani博士是世界知名的临床研究者，拥有丰富的导师经验。Thadhani博士将确保Isakova博士的培训，拟议的研究和职业发展的成功。调研：继发性甲状旁腺功能亢进（sHPT）是慢性肾脏病（CKD）的常见早期并发症，与骨骼和心血管疾病以及死亡率相关。虽然在晚期CKD中维持甲状旁腺激素（PTH）水平升高的因素已经很好地建立，但在早期CKD中启动PTH分泌增加的病理生理触发因素尚不清楚。我们组的数据表明，早期CKD的正常血钙患者在餐后状态下出现轻微但显著的血钙水平降低。相对低钙血症发生在尿钙增加之后，并与随后的餐后PTH水平升高相关。重要的是，这些患者的空腹PTH水平没有显著增加; CKD和对照组之间PTH生理学的差异仅在餐后“应激”状态下可检测到。因此，我们假设餐后钙尿伴发作性相对低钙血症是早期CKD患者sHPT发病机制中以前未报道的起始因素。在当前的提案中，我们将在一系列人体生理学研究中探索这一新的假设，并在慢性肾功能不全队列（CRIC）（一个大型CKD患者队列）中评估人群水平上生理机制的相关性。在目标1中，我们将研究CKD患者的PTH分泌模式及其与钙尿、钙血症和膳食钙摄入的关系，以测试在24小时内3次单独进餐是否存在PTH分泌增加的“堆叠”效应。在目标2A中，我们将分别增加膳食蛋白质和钠含量，以测试高蛋白和钠膳食后更大的钙尿是否与慢性肾病低钙血症恶化和甲状旁腺激素升高相关。在目标2B中，我们将测试增加膳食钙摄入或使用骨化三醇吸收钙是否会减弱餐后低钙血症，从而防止随后的PTH分泌增加。在目标3中，我们将在CRIC中检查膳食钠、钙、磷和蛋白质以及利尿剂治疗对PTH水平和CKD患者发生sHPT的风险的影响。我们相信这些研究的结果将为早期CKD中sHPT的新机制提供重要见解，并改善早期CKD患者的诊断和管理。K23奖将使Isakova博士获得临床研究的新技能，并发展成为一名独立的临床研究者。 公共卫生关系：该提案的长期目标是通过研究慢性肾脏病（CKD）继发性甲状旁腺功能亢进的发生机制来改善CKD患者的生活。我们的研究结果将为CKD中这种激素问题的发生提供新的见解，并指导新的治疗方法，以改善CKD患者的临床结局。