200 parathyroid glands to therapy with vitamin D sterols [72, 73]. These findings implicate a role for FGF-23 in the control of serum phosphorus and vitamin D metabolism, as well as in the pathogenesis of secondary hyperparathyroidism. A schematic representation of the interplay between PTH, FGF-23, and calcitriol is depicted in Fig. 1. Vascular or other soft tissue calcification Extra-skeletal calcification, including vascular calcification, is prevalent in adults treated with dialysis [46, 47], has its origins in childhood [48, 49], and is associated with significant cardiovascular morbidity and mortality [74, 75]. In contrast to the calcifications of atherosclerotic plaques in the vascular intima that develop with age in individuals with normal kidney function, vascular calcification in the uremic milieu develops primarily in the vascular media. Hypercalcemia, hyperphosphatemia, elevated levels of the calcium × phosphorus product, and high doses of vitamin D sterols [48–50] have all been implicated in the progression of the burden of extra-skeletal calcification. However, 40% of adult patients with stage 3 CKD, without these risk factors, show evidence of calcification [76], suggest- ing that factors in the uremic milieu itself, apart from high levels of calcium and phosphorus, contribute to cardio- vascular disease. Furthermore, increased intimal–medial thickness of the carotid artery is present in both children on dialysis and in those with early stages of CKD [77], suggesting that vascular abnormality, the leading cause of death in this population, has its origins early in childhood CKD [78]. Although the mechanisms of the development of vascular calcification remain to be fully elucidated, osteo- blasts and vascular smooth muscle cells have a common mesenchymal origin; core binding factor-1 (Cbfa1) is thought to trigger mesenchymal cell to osteoblast transfor- mation. Mice deficient in Cbfa1 fail to mineralize bone [79], and arteries obtained from patients undergoing renal transplantation show increased levels of the protein [80]. Upregulation of the sodium-dependent phosphate transport- er PIT-1 likely contributes to increased calcification [81, 82]. Furthermore, upregulation of pro-mineralization fac- tors, such as osteopontin, bone sialoprotein, osteonectin, alkaline phosphatase, type I collagen, and bone morpho- genic protein-2 (BMP-2), is potentiated by the uremic milieu [83–86], while expression of calcification inhibitors, such as fetuin A and matrix Gla protein, is suppressed [87– 89]. Levels of circulating FGF-23 may also contribute, as values are inversely correlated with peripheral vascular calcification in adult dialysis patients [90]. Treatment with high doses of calcium salts, in the form of calcium-based phosphate binders, has also been implicated in the Pediatr Nephrol (2008) 23:195–207 progression of cardiovascular calcification in adult patients treated with maintenance dialysis, and this progression is prevented with the use of non-calcium-containing phos- phate binders [46, 47]. Treatment The goal of therapy in childhood CKD-MBD is to normalize mineral metabolism with the aim of improving growth and reducing bone deformities and fragility, while minimizing the progression of extra-skeletal calcification. Biochemical markers of serum calcium, phosphorus, and PTH are primarily used to guide therapy; current therapeu- tic agents are targeted to maintain values in the normal range for the stage of CKD (Table 1). Phosphorus control As a result of phosphorus retention in CKD stages 4 and 5 [91], patients with advanced CKD and those undergoing treatment with traditional maintenance dialysis regimens— thrice-weekly hemodialysis or nightly peritoneal dialysis— often require dietary phosphate restriction as well as treatment with phosphate-binding agents. Serum phospho- rus levels should be maintained within the appropriate range for age and, due to increased rates of growth, infants and young children must maintain higher levels of serum phosphorus than older children. Calcium-containing salts have been recommended as the mainstay in phosphorus binding therapy in CKD stages 3 through 5. While several calcium salts are widely used, including calcium carbonate, calcium acetate, and calcium citrate, calcium carbonate is currently the most commonly used compound [27, 92, 93]. In recent years, however, increasing concern about the progressive vascular calcifications associated with a posi- tive calcium balance and hypercalcemia has led to the development of non-calcium-containing phosphate binders. Current recommendations suggest that total calcium intake from calcium-based phosphate binders should not exceed twice the recommended daily recommended intake (DRI) for dietary calcium. Elevated serum calcium levels (greater than 10.2 mg/dl) should be treated by the withdrawal of calcium-based phosphate binder therapy and, if persistent, by the discontinuation of active vitamin D sterols [18]. To avoid excess calcium intake, a metal-free calcium- free phosphate binder, sevelamer hydrochloride (sevelamer HCl, RenaGel) was developed. Although sevelamer is not yet approved for use in children, it has been shown in prospective trials to lower serum phosphorus levels effec- tively and control the skeletal lesions of secondary hyperparathyroidism without increasing serum calcium levels in children treated with dialysis [35, 46, 47, 94–96].