Pediatr Nephrol (2008) 23:195–207 Table 2 Native vitamin D dosing by degree of D deficiency Serum 25(OH) vitamin D (ng/ml) Ergocalciferol (vitamin D2) dose <5 (severe deficiency) 5–15 (mild deficiency) 5–30 (mild deficiency) 8,000 IU/d p.o.×4 weeks, then 4,000 IU/d×2 months 4,000 IU/d daily p.o.×12 weeks 2,000 IU/d daily p.o.×12 weeks 199 Comment Measure 25(OH)D level after 3 months Measure 25(OH)D level after 3 months treated with maintenance dialysis and receiving either low- dose oral calcitriol or no vitamin D sterol therapy. Since the 1st generation assays measure both full-length molecule and amino-terminally truncated fragments, 2nd generation PTH assays have been developed which measure, exclu- sively, the full-length molecule (“PTH(1–84)”). Although some data suggest improved ability of the newer 2nd generation assays to predict low-turnover bone disease [54], this finding has not been substantiated by others [34, 55]. Increasing skeletal resistance to the actions of PTH requires that PTH be maintained at higher levels in advanced stages of CKD [56–58] (Table 1). Downregula- tion of the PTH receptor, decreased expression of osteoblast differentiation factor, and increased levels of osteoclasto- genesis inhibitory factor occur with decreased renal function, contributing to the skeletal resistance to PTH [57, 59]. In patients with mild to moderate CKD, PTH levels that are within the normal range generally correspond to normal rates of bone formation, while mildly increased levels suggest the presence of secondary hyperparathyroid- ism [26]. In patients undergoing maintenance dialysis who are either untreated or are receiving small daily oral doses of calcitriol, PTH(7–84) levels of approximately two to five times the upper limit of normal generally correspond to normal bone formation rates [26, 33, 41, 53, 60]. Over-suppression of PTH in patients on dialysis has also been shown to result in growth failure, hypercalcemia, and adynamic bone [32]. In summary, PTH levels should be maintained in the range appropriate to the stage of CKD; levels appropriate for early stages of CKD would indicate low-turnover disease in patients treated with dialysis, while appropriate levels for stage 4 CKD represent osteitis fibrosa in mild CKD. 25(OH) vitamin D Careful attention to 25(OH) vitamin D (native vitamin D) nutrition is also fundamental to the optimal management of renal osteodystrophy [18]. Native vitamin D deficiency is prevalent in all children, including those with normal renal function [61], and the presence of renal insufficiency exacerbates this deficiency. Currently, therapeutic native vitamin D is available in two forms: vitamin D2 (ergo- calciferol) is obtained from plants and vitamin D3 (chole- calciferol) is obtained from animal sources. Repletion of vitamin D stores has been shown to increase calcitriol production, ameliorate secondary hyperparathyroidism [62, 63], and heal lesions of poor mineralization in patients with CKD stages 2 through 4 [64]. Thus, assessment and repletion of native vitamin D stores are recommended in this population [18]. Of note, current dosage recommenda- tions for native vitamin D repletion are similar to doses recommended for the treatment of nutritional rickets and far exceed recommendations for routine daily intake (Table 2). FGF-23 FGF-23 is a newly described phosphaturic hormone associated with renal phosphate wasting [65], low serum 1,25(OH)2D3 levels, and osteomalacia in animals and humans with normal kidney function [66–68]. Levels increase as kidney disease progresses and are markedly elevated in patients treated with maintenance dialysis [16]. Current data indicate that increased levels correlate with calcitriol deficiency in adults with CKD stages 2 to 4 [17], that dietary phosphorus regulates serum levels of FGF-23 [69, 70], and that the administration of vitamin D sterols increases levels [71]. Furthermore, elevated pre-treatment values of serum FGF-23 may predict resistance of the Serum calcium PTH secretion Calcitriol production P reabsorption Calcitriol production P reabsorption Ca absorption P absorption Phosphate load Fig. 1 Schematic representation of the interplay between PTH, FGF- 23, and calcitriol in mineral metabolism in vivo. Solid arrows represent the actions of PTH, while open arrows represent those of FGF-23 FGF-23 production Bone turnover Release of Ca and P