Nephrology Express Report

Publication date: 2006-09-01

Emerging Treatment Options for the Management of Secondary Hyperparathyroidism in Chronic Kidney Disease

This report was reviewed for medical and scientific accuracy by Mark A. Gendreau, MD, Consulting Physician, Lahey Clinic, Burlington, Massachusetts.

Expert Commentary

Provided by Daniel W. Coyne, MD, Professor of Medicine, Director of Hemodialysis, Chromalloy American Kidney Center, Washington University School of Medicine, St. Louis, Missouri

Secondary hyperparathyroidism (SHPT) is an early and major complication of chronic kidney disease (CKD) and progresses as glomerular filtration rate (GFR) decreases. ^1,2 Vitamin D deficiency, marked by reduced 25-hydroxyvitamin D levels, is a common medical condition, ³ and with decreased 1α-hydroxylase activity, patients with end-stage renal disease have a limited ability to convert 25-hydroxy-vitamin D to the active hormone 1,25 dihydroxyvitamin D (calcitriol). ⁴ The suboptimal levels of calcitriol decrease intestinal calcium absorption, leading to parathyroid hormone production and hyperproliferation of parathyroid cells ⁵ which contributes to the development of SHPT. Ultimately, the prolonged stimulation of the parathyroid glands results in increased bone remodeling and loss of bone density and structural integrity. As a result of parathyroid-induced changes, excess bone resorption leads to loss of bone mineral, increased release of calcium and phosphorus from bone, and increased risk for vascular and visceral calcification. Elevations in serum calcium, phosphorus, or both can result in an elevated serum calcium-phosphorus product, which has been associated with increased risk of cardiovascular complications and mortality in patients with CKD. ^6,7 Thus, interventions to treat and/or prevent SHPT should be initiated early in patients with CKD as SHPT contributes significantly to the morbidity and may play a role in the high mortality of patients with progressive renal failure. ^6-12

The development of treatment options that can safely and effectively suppress elevated parathyroid hormone levels in patients with SHPT continues to evolve. Oral calcitriol has been used in patients with mild to moderate CKD to suppress parathyroid hormone levels. ^13,14 Low doses of calcitriol are generally tolerated; however, the risk of hypercalcemia is increased with higher calcitriol doses or as GFR declines. ¹⁴ Premature acceleration of kidney dysfunction has been a concern with calcitriol use in CKD due to hypercalcemia, hyperphosphatemia, and/or hypercalciuria. ¹⁵ In addition, because calcitriol causes hyperphosphatemia, there are also concerns that hyperphosphatemia may have a negative effect on survival ¹⁶ or hasten the progression of kidney disease. ¹⁷ Development of these metabolic abnormalities suggest that calcitriol has a narrow therapeutic window ¹⁸ which often leads to withholding of calcitriol therapy, thus resulting in inadequate treatment of SHPT. Doxercalciferol, a prohormone that requires hydroxylation in the liver to become active, ^19,20 has also been used to suppress parathyroid hormone levels in CKD. ²¹ As with calcitriol, the use of doxercalciferol increases serum calcium and urinary calcium levels, ²¹ as well as increasing serum phosphorus despite increased use of phosphate-binders. ²¹ Intravenous administration of paricalcitol, an active vitamin D analog, has been shown to effectively and significantly suppress parathyroid hormone levels, with minimal impact on serum calcium and phosphorous levels in patients with CKD undergoing hemodialysis. ^22-25 Moreover, intravenous paricalcitol is associated with a significant survival advantage compared to calcitriol in patients undergoing hemodialysis. ²⁶ In hemodialysis patients, paricalcitol reduced parathyroid hormone levels more rapidly and with fewer episodes of hypercalcemia, hyperphosphatemia, and elevated calcium-phosphorus product than calcitriol. ^24,27 A research c