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Context: The optimal circulating concentration of 25(OH) vitamin D is controversial., Objective: The aim was to investigate if FGF-23 and 24,25(OH)2D can guide cholecalciferol replacement., Design: Oral cholecalciferol (10,000 IU weekly) administered to subjects with 25(OH)D levels < 20 ηg/mL and eGFR > 60 mL/min/1.73 m(2) (n = 25), chronic kidney disease (CKD) (n = 27), or end stage renal disease (ESRD) (n = 14)., Setting: The study was conducted at the Veterans Affairs clinics., Main Outcome Measure: Serum FGF-23, PTH, 25(OH)D, 1,25(OH)2D, 24,25(OH)2D, calcium, and phosphorous concentrations, and urinary excretion of calcium and phosphorus at baseline and after 8 weeks of treatment., Results: Cholecalciferol treatment increased concentrations of serum 25(OH)D by (19.3 ± 8 ηg/mL, P = .001; 12.2 ± 9 ηg/mL, P = .0001) and 24,25(OH)2D (1.14 ± 0.89 ηg/mL, P = .0024; 1.0 ± 0.72 ηg/mL P = .0002), and reduced serum PTH (-11 ± 21 pg/mL, P = .0292; -42 ± 68 pg/mL, P = .0494) in normal and CKD subjects, respectively. Cholecalciferol increased serum FGF-23 levels only in normal subjects (44 ± 57 ηg/mL, P = .01). Increments in serum 25(OH)D positively correlated with serum FGF-23 and 24,25(OH)2D and negatively correlated with PTH. In ESRD, cholecalciferol administration increased 25(OH)D by (16.6 ± 6.6 ηg/mL P ≤ .05) without changing 24,25(OH)2D, FGF-23 or PTH levels., Conclusion: Modest elevations of serum 25(OH)D levels after cholecalciferol treatment are sufficient to induce compensatory degradative pathways in patients with sufficient renal reserves, suggesting that optimal circulating 25(OH)D levels are approximately 20 ηg/mL. In addition, catabolism of 25(OH)D may also contribute to the low circulating vitamin D levels in CKD, since elevations of FGF-23 in CKD are associated with increased 24,25(OH)2D after cholecalciferol administration. more...

Background: The majority of dialysis patients suffer from vitamin D deficiency, which might contribute to an adverse health outcome. We aimed to elucidate whether European dialysis patients with low 25-hydroxyvitamin D (25(OH)D) levels are at increased risk of mortality and specific fatal events., Methods: This was a prospective cohort study of incident dialysis patients in the Netherlands (the NECOSAD). We selected all patients with measured 25(OH)D at 12 months after the start of dialysis, the baseline for our study. By Cox regression analyses, we assessed the impact of 25(OH)D levels on short-term (6 months of follow-up) as well as longer-term mortality (3 years of follow-up). Associations of 25(OH)D levels with cardiovascular and non-cardiovascular mortality were also determined., Results: The data from 762 patients (39% females, age 59 ± 15 years, 25(OH)D = 18 ± 11 ng/mL) were available. Fifty-one and 213 patients died during a follow-up of 6 months and 3 years, respectively. After adjustments for possible confounders, the hazard ratio (HR) (with 95% CI) for mortality was 2.0 (1.0-3.8) for short-term and 1.5 (1.0-2.1) for longer-term mortality when comparing patients with 25(OH)D levels ≤ 10 ng/mL with those presenting with 25(OH)D levels > 10 ng/mL. Adjusted HRs for cardiovascular mortality were 2.7 (1.1-6.5) and 1.7 (1.1-2.7) for short- and longer-term mortality, respectively. For non-cardiovascular mortality, we observed no relevant association overall. The impact of 25(OH)D levels on clinical events was modified by parathyroid hormone (PTH) status, with low 25(OH)D levels meaningfully affecting outcomes only in patients with PTH levels above the median of 123 pmol/L., Conclusions: Vitamin D deficiency in dialysis patients is associated with an adverse health outcome, in particular with short-term cardiovascular mortality. Intervention studies are urgently needed to evaluate whether vitamin D supplementation improves health outcomes of dialysis patients. more...

The predominant feature of pseudohypoparathyroidism (PHP) is renal resistance to PTH. Pseudohypoparathyroidism type Ia (PHP-Ia) is caused by maternally inherited heterozygous mutations in the GNAS exons encoding the alpha-subunit of the stimulatory G protein (Gsalpha). Besides PTH resistance, PHP-Ia patients have Albright's hereditary osteodystrophy and often display resistance to additional hormones. Patients with PHP-Ib lack features of Albright's hereditary osteodystrophy, and PTH resistance is associated with loss of methylation at the maternal GNAS exon A/B. Most individuals with the autosomal dominant form of PHP-Ib have a 3-kb microdeletion within STX16 approximately 220 kb upstream of exon A/B. Here we report on the clinical and genetic aspects of a Greek PHP-Ib kindred with four affected members and three obligate carriers, who had the 3-kb deletion within STX16. Symptomatic hypocalcemia was present only in the proband, but PTH was elevated in all members who had inherited the 3-kb deletion maternally. In all affected family members, urinary phosphate excretion was normal, but 1,25-dihydroxyvitamin D levels were diminished. These findings confirm previous data regarding patient to patient variation in disease severity for autosomal dominant PHP-Ib. Furthermore, affected individuals displayed hypouricemia with increased fractional excretion of uric acid, suggesting possible involvement of PTH in the renal handling of this metabolite. more...

Unlabelled: We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism., Introduction: The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes., Materials and Methods: To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals., Results: An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1alpha-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h., Conclusions: FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis. more...

The mechanism by which GH stimulates intestinal calcium absorption was explored. In this study, seven children with idiopathic GH deficiency were studied before and during GH therapy while they were maintained on the same metabolic diet. After 5-14 months of GH administration, fractional intestinal calcium absorption increased from 0.364 +/- 0.114 to 0.449 +/- 0.159 (P less than 0.01), and serum 1,25-dihydroxyvitamin D decreased from 63.7 +/ 19.3 to 46.7 +/ 17.8 pg/ml (P less than 0.025). Serum immunoreactive parathyroid hormone, urinary cAmp, serum 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D did not change significantly. The data suggest that GH does not directly influence parathyroid hormone or vitamin D metabolism. The possibility that relative intestinal resistance to 1,25-dihydroxyvitamin D exists in patients with GH deficiency is considered. more...