Calcium Handling and Secondary Hyperparathyroidism in Chronic Kidney Disease

应聘者：塔玛拉·伊萨科娃毕业于DownState College of Medicine，并在马萨诸塞州综合医院完成了内科住院医师培训。她目前是麻省理工学院肾脏病研究员，也是哈佛医学院人体生理研究硕士学位的候选人。导师：Ravi Thadhani博士是一位世界知名的临床研究员，具有丰富的导师经验。塔哈尼博士将确保伊萨科娃博士的培训、拟议的学习和职业发展取得成功。研究：继发性甲状旁腺功能亢进(SHPT)是慢性肾脏疾病(CKD)常见的早期并发症，与骨骼和心血管疾病及死亡率相关。虽然在晚期CKD中维持甲状旁腺激素(PTH)水平升高的因素已得到充分证实，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。来自我们小组的数据显示，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下降。相对的低钙血症伴随着尿钙的增加，并且与随后餐后甲状旁腺素水平的升高有关。重要的是，这些患者的空腹甲状旁腺素水平并没有显著增加；慢性肾脏病和对照组之间的甲状旁腺素生理学差异只有在餐后“应激”状态下才能被检测到。因此，我们假设餐后钙尿伴发作性相对低钙血症是先前未见报道的早期CKD SHPT发病的始动因素。在目前的提案中，我们将在一系列人类生理学研究中探索这一新的假设，并评估慢性肾功能不全队列(CRIC)在人群水平上的生理学机制的相关性，CRIC是一个大型的CKD患者队列。在目标1中，我们将研究慢性肾脏病患者的甲状旁腺素分泌模式及其与钙尿症、钙血症和膳食钙摄入量的关系，以测试每餐是否存在甲状旁腺素分泌增加的“堆积”效应。在目标2A中，我们将分别增加膳食蛋白质和钠的含量，以测试高蛋白和高钠膳食导致的更多钙尿是否与慢性肾脏病患者低血钙症恶化和甲状旁腺素升高有关。在目标2B中，我们将测试增加膳食钙摄入量或使用骨化三醇吸收是否会钝化餐后低钙血症，从而防止随后甲状旁腺素分泌的增加。在目标3中，我们将在CRIC中检查饮食中的钠、钙、磷和蛋白质以及利尿剂治疗对CKD患者甲状旁腺素水平和发生SHPT的风险的影响。我们相信，这些研究的结果将为早期CKD患者SHPT的新机制提供重要的见解，并有助于改善早期CKD患者的诊断和治疗。K23奖项将使Isakova博士在临床研究中获得新的技能，并发展成为一名独立的临床调查员。 公共卫生相关性：这项建议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症(CKD)的发生机制来改善患者的生活。我们的结果将为CKD患者激素问题的产生提供新的见解，并指导新的治疗方法来改善CKD患者的临床结果。

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.