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X-linked hypophosphatemia (XLH) is the most common heritable cause of hypophosphatemic rickets, and it is characterized by hypophosphatemia due to kidney phosphate wasting, deficiency of 1,25-dihydroxyvitamin D [1,25(OH)2D], rickets, and osteomalacia ([1][1]). Clinical features manifest as early as

Background and Objectives High plasma concentration of fibroblast growth factor 23 (FGF23) is a risk factor for left ventricular hypertrophy (LVH) in adults with CKD, and induces myocardial hypertrophy in experimental CKD. We hypothesized that high FGF23 levels associate with a higher prevalence of LVH in children with CKD. Design, setting, participants, & measurements We performed echocardiograms and measured plasma C-terminal FGF23 concentrations in 587 children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study. We used linear and logistic regression to analyze the association of plasma FGF23 with left ventricular mass index (LVMI) and LVH (LVMI ≥95th percentile), adjusted for demographics, body mass index, eGFR, and CKD-specific factors. We also examined the relationship between FGF23 and LVH by eGFR level. Results Median age was 12 years (interquartile range, 8–15) and eGFR was 50 ml/min per 1.73 m2 (interquartile range, 38–64). Overall prevalence of LVH was 11%. After adjustment for demographics and body mass index, the odds of having LVH was higher by 2.53 (95% confidence interval, 1.28 to 4.97; P Conclusions Plasma FGF23 concentration ≥170 RU/ml is an independent predictor of LVH in children with eGFR≥45 ml/min per 1.73 m2.

Background and objectives Plasma fibroblast growth factor 23 (FGF23) concentrations increase early in the course of CKD in children. High FGF23 levels associate with progression of CKD in adults. Whether FGF23 predicts CKD progression in children is unknown. Design, setting, participants, & measurements We tested the hypothesis that high plasma FGF23 is an independent risk factor for CKD progression in 419 children, aged 1–16 years, enrolled in the Chronic Kidney Disease in Children (CKiD) cohort study. We measured plasma FGF23 concentrations at baseline and determined GFR annually using plasma disappearance of iohexol or the CKiD study estimating equation. We analyzed the association of baseline FGF23 with risk of progression to the composite end point, defined as start of dialysis or kidney transplantation or 50% decline from baseline GFR, adjusted for demographics, baseline GFR, proteinuria, other CKD-specific factors, and other mineral metabolites. Results At enrollment, median age was 11 years [interquartile range (IQR), 8–15], GFR was 44 ml/min per 1.73 m 2 (IQR, 33–57), and FGF23 was 132 RU/ml (IQR, 88–200). During a median follow-up of 5.5 years (IQR, 3.5–6.6), 32.5% of children reached the progression end point. Higher FGF23 concentrations were independently associated with higher risk of the composite outcome (fully adjusted hazard ratio, 2.52 in the highest versus lowest FGF23 tertile; 95% confidence interval, 1.44 to 4.39, P =0.002; fully adjusted hazard ratio, 1.33 per doubling of FGF23; 95% confidence interval, 1.13 to 1.56, P =0.001). The time to progression was 40% shorter for participants in the highest compared with the lowest FGF23 tertile. In contrast, serum phosphorus, vitamin D metabolites, and parathyroid hormone did not consistently associate with progression in adjusted analyses. Conclusions High plasma FGF23 is an independent risk factor for CKD progression in children.

Summary Background and objectives In children with CKD, information is limited regarding the prevalence and determinants of fibroblast growth factor 23 excess and 1,25-dihyroxyvitamin D deficiency across the spectrum of predialysis CKD. This study characterized circulating concentrations of fibroblast growth factor 23 and 1,25-dihyroxyvitamin D, and investigated their interrelationships and associations with GFR and secondary hyperparathyroidism in children with CKD who were enrolled in the Chronic Kidney Disease in Children observational cohort study. Design, setting, participants, & measurements Plasma fibroblast growth factor 23 concentrations and determinants of mineral metabolism were measured in 464 children ages 1–16 years with predialysis CKD. GFR was measured by plasma disappearance of iohexol in 70% of participants and estimated by the Chronic Kidney Disease in Children estimating equation using serum creatinine and cystatin C concentrations in the remainder of the participants. Participants were grouped according to CKD stage and by 10-ml/min categories of GFR. Results Median GFR for the cohort was 45 ml/min per 1.73 m2 (interquartile range=33–57; range=15–109). Plasma fibroblast growth factor 23 concentration was above the normal range in 67% of participants (with higher levels observed among participants with lower GFR) before higher levels of serum parathyroid hormone and phosphorus were observed. Plasma fibroblast growth factor 23 levels were 34% higher in participants with glomerular disease than in participants with nonglomerular disease, despite similar GFR. Serum phosphorus levels, adjusted for age, were significantly lower at GFR of 60–69 ml/min per 1.73 m2 than higher GFR, but thereafter they became higher in parallel with fibroblast growth factor 23 as GFR declined. Serum 1,25-dihyroxyvitamin D concentrations were lower in those participants with low GFR values, high fibroblast growth factor 23 levels, 25-hydroxyvitamin D deficiency, and proteinuria. Secondary hyperparathyroidism was present in 55% of participants with GFR Conclusion In children with predialysis CKD, high plasma fibroblast growth factor 23 is the earliest detectable abnormality in mineral metabolism, and levels are highest in glomerular diseases.

Data on physical activity are limited in children with CKD. The objectives of this study were to measure the level and correlates of physical activity in children and young adults with CKD and to determine the association of physical activity with physical performance and physical functioning.Physical activity was measured for 7 days using pedometers; physical performance was measured by the 6-minute walk distance (6MWD) and physical functioning with the PedsQL 4.0.Study participants were 44 patients 7-20 years of age who had CKD stage 1-4 (n=12), had ESRD and were undergoing dialysis (n=7), or had undergone kidney transplantation (n=25). Participants were very sedentary; they walked 6218 (interquartile range, 3637, 9829) steps per day, considerably less than recommended. Physical activity did not differ among participants in the CKD stage 1-4, ESRD, and transplant groups. Females were less active than males (P0.01), and physical activity was 44% lower among young adults (18-20 years) than younger participants (P0.05). Physical activity was associated positively with maternal education and hemoglobin concentration and inversely with body mass index. Respective 6MWD in males and females was 2 and approximately 4 SDs below expected. Low levels of physical activity were associated with poor physical performance and physical functioning, after adjustment for age, sex, and body mass index.In most participants with CKD, physical activity was considerably below recommended levels. Future studies are needed to determine whether increasing physical activity can improve physical performance and physical functioning.

Dietary deficiency of vitamin D, genetic disorders of its bioactivation to 1,25-dihydroxyvitamin D [1,25(OH)2D], or disorders of vitamin D action can cause rickets. The rate-limiting, hormonally-regulated, biologically activating step in the synthesis of 1,25(OH)2D is the 1 alpha-hydroxylation of 25-hydroxyvitamin D, which occurs in kidney and other tissues and is mediated by a mitochondrial cytochrome P450 enzyme, P450c1 alpha. After many years of effort, the cDNA and gene for this enzyme were cloned in late 1997. Mutations in the P450c1 alpha gene, located on chromosome 12, cause 1 alpha-hydroxylase deficiency, also known as vitamin D-dependent rickets type I, an autosomal recessive disease characterized by rickets and impaired growth due to failure of renal synthesis of 1,25(OH)2D. X-linked hypophosphatemic rickets, a dominantly inherited disease, is caused by mutations in the PHEX gene, whose function in regulating renal phosphate and vitamin D metabolism remains to be elucidated.

Chronic renal insufficiency is associated with elevated serum parathyroid hormone (PTH) levels (2 degrees HPT), deficiency of 1,25-dihydroxyvitamin D (1,25(OH)2D), and hypocalciuria. In chronic renal insufficiency, the 2 degrees HPT may result from reduced expression of the parathyroid gland extracellular Ca(2+)-sensing receptor (CaSR). Since the CaSR was cloned from rat and human kidney, this study examined in rats whether expression of the renal CaSR is altered in experimental chronic renal insufficiency. Four weeks after chronic renal insufficiency was induced by 5/6 nephrectomy (Nx) in Sprague Dawley rats, the serum creatinine concentration was 0.96+/-0.06 mg/dl compared with 0.35+/-0.02 mg/dl in sham-operated animals (P < 0.05). The serum total Ca2+ and phosphorus concentrations were not different. In the Nx group, the serum concentration of amino-PTH was higher (65+/-8 pg/ml), and the concentration of 1,25(OH)2D was significantly lower (47+/-5 pg/ml) compared with 45+/-5 pg/ml and 61+/-4 pg/ml (P = 0.05) in the sham group, respectively. In a subset of rats studied, the Nx group was hypocalciuric (1.4+/-0.5 mg/kg per d) compared with the sham group (3.7+/-0.5 mg/kg per d) (P < 0.05). In the Nx rats, CaSR mRNA expression and CaSR protein levels were found to be reduced by 35 and 38%, respectively, than those observed in controls. These results suggest that reduced renal CaSR expression in chronic renal insufficiency may play a role in disordered mineral ion homeostasis, including hypocalciuria.

It has been contended that the metabolism of vitamin D in spontaneously hypertensive rats (SHR) is different from that in Wistar-Kyoto rats (WKY). To investigate this possibility, the plasma concentration of 1,25-dihydroxycholecalciferol (1,25[OH]2D) and several known determinants of its production rate were measured in SHR and WKY given normal and restricted amounts of dietary phosphorus. In 12-week-old male SHR given a normal amount of dietary phosphorus, the mean plasma concentration of 1,25(OH)2D (72 +/- 5 pg/ml) was significantly lower than that in age-matched WKY (129 +/- 6 pg/ml; p less than 0.001). The lower plasma concentration of 1,25(OH)2D in the SHR could not be attributed to higher circulating levels of inorganic phosphorus or ionized calcium, lower plasma concentrations of 25-hydroxycholecalciferol, or acidosis. However, in the SHR, urinary excretion of cyclic adenosine 3',5'-monophosphate (12.5 +/- 0.4 nmol/mg creatinine) was significantly lower than that in WKY (15.2 +/- 0.3 nmol/mg creatinine; p less than 0.001). In both SHR and WKY, restriction of dietary phosphorus for 1 week induced an increase in the plasma concentration of 1,25(OH)2D without affecting blood pressure. The current findings indicate that in 12-week-old male SHR, 1,25(OH)2D metabolism is different from that in age-matched WKY. The activity of 25-hydroxyvitamin D-1 alpha-hydroxylase, however, appears to be at least partially responsive to short-term restriction of dietary phosphorus. In SHR, the activity of 25-hydroxyvitamin D-1 alpha-hydroxylase may be lower than that in WKY, perhaps due in part to some impairment in the renal metabolism of, or responsiveness to, cyclic adenosine 3',5'-monophosphate.