Prevention of Secondary Hyperparathyroidism With Vitamin D in Stage II/III Chronic Kidney Disease

Vitamin D is important to maintain normal calcium homeostasis and optimal bone health (1, 2). The synthesis of vitamin D and its metabolism to 1,25(OH)2D is regulated by parathyroid hormone (PTH), serum calcium, and phosphorus levels. In response to low serum calcium level, serum PTH activates alpha-1-hydroxylase for increased 1,25(OH)2D production in the kidney and also enhances tubular reabsorption of calcium (3). The higher levels of 1, 25(OH)2D results in increased intestinal calcium absorption (4). Increased serum phosphorus levels which occurs in the early stages of chronic kidney disease (CKD) results in inhibition of the 1-alpha-hydroxylase, which results in decreased 1, 25(OH)2 D production, decreased intestinal calcium absorption leading to secondary hyperparathyroidism with increased PTH levels. Circulating 1,25(OH)2D levels begin to fall when the glomerular filtration rate is less than 40 mL/min occasionally even less than 80 mL/min (11) and almost always significantly reduced in subjects with end-stage renal failure (12). Furthermore, in CKD, decreased renal mass also results in decreased expression of 1-alpha-hydroxlase and less production of 1,25(OH)2D which also exacerbates secondary hyperparathyroidism (5-7). Therefore, in CKD there are three processes that lead to secondary hyperparathyroidism. 1) decreased renal mass leading to decreased production of 1,25(OH)2D leading to a compensatory rise in PTH to further enhance production of 1,25(OH)2D 2) inhibition of the renal 1-alpha-hydroxylase by accumulating phosphorus levels leading to decreased 1,25(OH)2D which also leads to secondary hyperparathyroidism. 3) increased phosphorus leads to lower ionized calcium leading to increased parathyroid hormone secretion. Untreated secondary hyperparathyroidism can lead to renal osteodystrophy (9) and increased mortality due to cardiovascular disease (10). Prolonged secondary hyperparathyroidism can lead to bone resorption and eventually autonomous parathyroid hormone secretion termed tertiary hyperparathyroidism. Vitamin D status is one of the major factors that may prevent progression of secondary hyperparathyroidism in patients with CKD. Insufficient levels of 25-hydroxyvitamin D further exacerbate secondary hyperparathyroidism by not providing adequate substrate for the renal 1-alpha-hydroxylase for conversion to the active form of vitamin D, 1,25(OH)2D. A recent cross-sectional study on patients with moderate to severe CKD not yet on dialysis therapy from 12 geographically diverse regions of the United States has shown that only 29% and 17% of them had sufficient level, respectively (13). Vitamin D status is easily corrected. In our previous study we concluded that weekly cholecalciferol supplementation was an effective treatment to correct vitamin D status in patients with CKD stages III and IV (14). However, PTH levels did not return to normal. Therefore, it is likely that earlier intervention with vitamin D is necessary to prevent rather than to treat secondary hyperparathyroidism. This is the major question that is being evaluated in this study. Can intervening with vitamin D at an earlier stage of chronic kidney disease result in decreased incidence of secondary hyperparathyroidism? 2.0 Objectives 2.1 Overall Objective The primary objective of this study is to assess that if improving and maintaining an optimal 25(OH) D level ( by National Kidney Foundation should be greater than 30ng/ml) (15) in people with stage II/III Chronic Kidney disease would delay the progression of secondary hyperparathyroidism and translate into improved markers of bone turnover 2.2 Specific Aims Primary: 1) To determine in a double blind, randomized study whether supplementation with 50,000 IU of cholecalciferol (vitamin D3) given weekly for 12 weeks followed by maintenance cholecalciferol 50,000 IU every other week would improve and maintain vitamin D status in CKD patients stage 2/3 compared to placebo at 12 months. 2\) To determine whether early intervention with vitamin D therapy further decreases PTH levels after 12 weeks of therapy and 12 months of therapy. Secondary: 1) To determine whether early treatment with vitamin D results in improving levels of bone turnover markers- tartrate-resistant acid phosphatase isoform 5b(TRAP5b), procollagen Type 1 N-Terminal propeptide (PINP), serum C-Telopeptide and Alkaline phosphatase.