Calcium Handling and Secondary Hyperparathyroidism in Chronic Kidney Disease

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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.