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Management of Calcium and Bone Disease in Renal Patients
We have made significant advances in understanding of the pathogenesis and treatment of secondary hyperparathyroidism in chronic kidney disease (CKD). These include: (1) the discovery of the calcium-sensing receptor CaSR and the development of calcimimetics to target this receptor to suppress PTH secretion and production; (2) the recognition that metabolic derangements in calcium and phosphate have a significant impact on morbidity and mortality, possibly through effects on vascular calcification; (3) the discovery of the FGF23-bone kidney axis, where FGF23 produced by osteoblasts/osteocytes suppresses 1,25(OH) 2 D production as an early adaptive response to the loss of kidney function; (4) the finding that elevated serum FGF23 concentration is an important predictor of mortality and progression of kidney disease; (5) the development of less hypercalcemic and hyperphosphatemic vitamin D analogues with the potential of reduced toxicity; (6) the recognition of the possible importance of nutritional vitamin D deficiency on innate immune function; and (7) the availability of non-calcium containing phosphate binders. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI TM ) and more recently KDIQGO have also provided guidelines for earlier interventions and management of mineral metabolism disorders in CKD. These new pharmacological agents and treatment paradigms offers the potential to more effectively and safely manage disordered mineral metabolism in patients with CKD.
Keywords
Bone, secondary Hyperparathyroidism, parathyroid glands, calcimimetics, vitamin D, renal osteodystrophy, FGF23, PTH, phosphate binders, hyperphosphatemia
Introduction
We have made significant advances in understanding of the pathogenesis and treatment of secondary hyperparathyroidism in chronic kidney disease (CKD). These include: (1) the discovery of the calcium-sensing receptor CaSR and the development of calcimimetics to target this receptor to suppress PTH secretion and production; (2) the recognition that metabolic derangements in calcium and phosphate have a significant impact on morbidity and mortality, possibly through effects on vascular calcification; (3) the discovery of the FGF23-bone kidney axis, where FGF23 produced by osteoblasts/osteocytes suppresses 1,25(OH) 2 D production as an early adaptive response to the loss of kidney function, (4) the finding that elevated serum FGF23 concentration is an important predictor of mortality and progression of kidney disease; (5) the development of less hypercalcemic and hyperphosphatemic vitamin D analogs with the potential of reduced toxicity; (6) the recognition of the possible importance of nutritional vitamin D deficiency on innate immune function; and (7) the availability of non-calcium containing phosphate binders. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI TM ) and more recently KDIQGO have also provided guidelines for earlier interventions and management of mineral metabolism disorders in CKD. These new pharmacological agents and treatment paradigms offers the potential to more effectively and safely manage disordered mineral metabolism in patients with CKD.
Parathyroid Gland Disease versus Mineral Metabolism Disorders in CKD
Secondary hyperparathyroidism is an adaptive response to the loss of kidney function. Progressive parathyroid gland disease (i.e., hypertrophy and hyperplasia) and pathological consequences of elevated serum PTH levels have dominated the clinical focus of disordered mineral metabolism in CKD. PTH actions are mediated through PTH receptor (PTH1R) in the kidney, whose activation inhibits renal Pi reabsorption, decreases renal tubular calcium excretion and increases 1,25(OH) 2 D 3 production. Activation of PTH1R in osteoblasts in bone stimulates bone formation and osteoclastic bone resorption. Chronic elevation of PTH in SHPT leads to increased bone remodeling which plays crucial role in mineral homeostasis by providing access to the stores in bones Ca and Pi. Thus, PTH is a calcemic hormone that maintains serum calcium levels by stimulating 1,25(OH) 2 D production, renal calcium conservation and bone calcium efflux. The phosphaturic actions of PTH permit excretion of phosphate that accompanies the gastrointestinal absorption and bone efflux of calcium.
It is clinically important to prevent and treat secondary hyperparathyroidism, since increments in PTH (typically levels that exceed the 400–600 pg/ml range) are associated with increased mortality in CKD. In addition, elevated PTH is associated with progressive parathyroid disease leading to tertiary hyperparathyroidism that may require parathryoidectomy and high cortical bone remodeling leading to an increase in the risk of bone fractures.
In spite of the importance of PTH, the recognition that hyperphosphatemia, vascular calcifications and different treatment strategies may have a greater impact upon survival of patients with CKD has lead to a broadening of our conceptualization of hyperparathyroidism and “renal osteodystrophy” to include other metabolic abnormalities, termed, Chronic Kidney Disease—Mineral and Bone Disorder (CKD-MBD). CKD-MBD describes a clinical syndrome that includes multiple metabolic/endocrine abnormalities, parathyroid gland dysfunction, bone disease, and unique CKD associated cardiovascular risk factors as well as other adverse clinical outcomes, such as fractures, vascular and soft tissue calcifications.
Because of the integration and interdependence of the calcium, phosphate, vitamin D and PTH axis, it is difficult to elucidate the primary or proximate causes of secondary hyperparathyroidism in CKD. Hyperphosphatemia, 1,25(OH) 2 D 3 and hypocalemia, acting through distinct molecular mechanisms, act in concert to cause secondary hyperparathyroidism in CKD. However, elevations of FGF23 and secondary suppression of 1,25(OH) 2 D production may the initial abnormality in CKD that leads to increments in PTH, which may further stimulate FGF23 levels. Nevertheless, suppression of PTH, while minimizing hyperphosphatemia, providing adequate vitamin D replacement, and maintaining bone health, remains the major goal of therapy. Different strategies to achieve this are based on different molecular targets for the available therapies that include, phosphate binders, vitamin D analogues and calcimimetics.
Molecular Targets for Suppressing Parathyroid Gland Function in CKD
Role of Hyperphosphatemia
A decline in GFR and reduced renal phosphate excretion is associated with increased PTH secretion by the parathyroid glands in CKD. In patients on maintenance hemodialysis, increased levels of serum phosphate strongly predict the degree of serum PTH elevation. The importance of phosphate is also supported by the observation that phosphate restriction can attenuate the development of secondary hyperparathyroidism in CKD. The stimuli linking hyperphosphatemia and increments in PTH are likely to be both direct and indirect. The molecular mechanism mediating the direct effects of phosphate on the parathyroid gland, however, are poorly understood. Increments in media phosphate concentrations increases PTH synthesis in parathyroid cell cultures, regulates PTH message stability, and dietary restriction of phosphorus retards the development of hyperparathyroidism. Phosphorus also modulates parathyroid growth and hypertrophy through activation of MAPK (mitogen activated protein kinases), TGF-alpha, and cyclin dependent kinases. To date, no specific receptors, transporters or other molecular targets have been identified that mediate direct effects of phosphate on the parathyroid gland function.
Indirect effects of hyperphosphatemia on parathyroid gland function have greater experimental support, and are potentially mediated via FGF23, 1,25(OH) 2 D 3 , and calcium, acting on their respective receptors in the parathyroid gland. Phosphate loading can also decrease 1,25(OH) 2 D 3 production by the kidney, which in turn can decrease dietary absorption of calcium, thereby regulating parathyroid gland function indirectly through both the calcium sensing receptor and the vitamin D receptor.
Vitamin D Receptor and the Role of 1, 25(OH) 2 D 3 Deficiency
Decrements in both 25(OH)D and 1,25(OH) 2 D occur early in the course of CKD-MBD. Low levels of vitamin D are associated with increased mortality in CKD and treatment in vitamin D analogs are believed to have a survival benefit. (1,25(OH) 2 ) acts on the vitamin D receptor (VDR) in the parathyroid gland to suppress PTH transcription, but not PTH secretion, whereas calcitriol acts on the small intestines to increase active transport of both calcium and phosphate. Reductions in serum 1,25(OH) 2 D levels play a central role in the pathogenesis of secondary hyperparathyroidism. Cross sectional studies of patients with CKD show that serum 1, 25(OH) 2 D 3 levels decline as a function of the severity of renal impairment. Increments in PTH are inversely correlated with serum 1, 25 (OH) 2 D 3 levels below GFRs of 60 ml/min/m 2 . Low levels of 1,25(OH) 2 D stimulate PTH though both loss of direct effects of 1,25(OH) 2 D 3 on vitamin D receptors (VDR) in the parathyroid glands and due to reductions in gastrointestinal absorption of calcium, which leads inhibition of the calcium sensing receptor (CaSR) in the parathyroid gland.
Nutritional deficiency of vitamin D as measured by low circulating 25(OH)D 3 levels, is also common in patients with CKD, likely due to poor nutritional status, inadequate exposure to sunlight and chronic illness. The negative correlation between serum PTH concentrations and 25(OH) vitamin D, the precursor to 1,25(OH) 2 D 3 , is well established in the general population, and may also contribute to secondary hyperparathyroidism in stage 3 and 4 CKD.
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