New developments in hyperphosphatemia management.

Patients with chronic renal failure have many associated medical problems, including a high propensity for cardiovascular disease (CVD). CVD and stroke are the leading causes of mortality in patients with ESRD (chronic kidney disease stage 5), with a 10- to 20-fold greater risk than in the general population (1,2). These data have generated greater awareness of cardiovascular risk in the chronic renal failure patient, and the most recent National Kidney Foundation guidelines for chronic kidney disease (CKD) state that patients with CKD and kidney transplant recipients should be considered in the highest risk group for CVD (3). Indeed, the significance of CVD in this patient population is such that a separate guideline to address the issue of CVD in patients with CKD is in development. Hyperphosphatemia and Hyperparathyroidism of Renal Failure: A Vicious Cycle with Cardiovascular Consequences It seems logical that an understanding of the basic pathologic mechanisms underlying the increased cardiovascular risk in CKD could lead to the development of improved treatment paradigms and better outcomes in patients with chronic renal failure. The consequences of progressive renal failure include an imbalance of calcium and phosphorus, which are normally under the tight homeostatic control of the kidneys. The loss of metabolic control of calcium and phosphorus parallels the loss of renal function (4). In early renal failure, a reduction in serum calcitriol and moderate decreases in ionized calcium contribute to an increased synthesis and secretion of parathyroid hormone (PTH). In later stages of renal failure, reduced expression of vitamin D and calcium receptors contributes to glandular resistance to the already decreased calcitriol and calcium, perpetuating the synthesis and secretion of PTH. Independent of these effects, renal failure–mediated phosphate retention and dietary phosphorus lead to increased serum phosphorus levels. Hyperphosphatemia promotes uremia-induced parathyroid gland hyperplasia and PTH synthesis and secretion. In the past decade, some of the molecular mechanisms of the effects of phosphorus on the parathyroid gland have been determined. Data indicate that high levels of phosphorus can increase parathyroid glandular expression of transforming growth factor- and promote growth in the gland via activation of mitogen-activated protein kinase cascades (5,6). Conversely, low phosphorus induces the cyclin-dependent kinase inhibitor p21, which inactivates cyclin or cyclin-dependent kinase complexes to specifically induce arrest of growth in the parathyroid gland (6). In sum, hyperphosphatemia associated with progressive renal failure can lead to secondary hyperparathyroidism and accompanying elevated phosphorus and calcium-phosphate product (Ca P). Hyperphosphatemia and secondary hyperparathyroidism are common complications of ESRD (4,7). Importantly, a growing body of evidence suggests that the clinical consequences of altered phosphorus and calcium metabolism and hyperphosphatemia include an increased risk of mortality, CVD, cardiovascular mortality, bone disease, and extraskeletal calcification of soft tissues, including blood vessels, lungs, kidneys, and joints (8 –12). Cardiac and vascular calcification is believed to be the underlying common mechanism that mediates such increased risk of morbidity and mortality. Management of hyperphosphatemia thus is a critical issue in the care of patients with renal failure and has the potential to decrease risk for CVD, particularly when instituted with appropriate measures to control other “traditional” cardiovascular risk factors.