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At least 235 records · Page 13Linked to original sources
PubMed1975

Parathyroid hormone status and renal responsiveness in familial hypophosphatemic rickets.

Basal serum and urinary biochemical parameters and their response to PTH or calcium infusion were examined in 14 untreated patients with familial hypophosphatemic rickets (FHR) from 5 kindreds and 9 normal control subjects after a period of dietary equilibration. FHR subjects exhibited significantly elevated basal serum iPTH levels (FHR: 11.4 +/- 0.8, controls: 5.1 +/- 0.5 ng/ml, P less than 0.001) and urinary cAMP excretion (FHR: 7.83 +/- 0.81, controls: 3.78 +/- 0.46 nmol/mg creatinine P less than 0.001). In response to PTH infusion (6 units/kg over 4 hours) FHR subjects exhibited a mean 34% decrease in TRP and a 22-fold increase in cAMP excretion, both comparable to the control response. Calcium infusion (10 mg/kg over 1 h) rapidly suppressed serum iPTH and urinary cAMP values in FHR subjects. However, TRP remained inappropriately low for the level of serum phosphate. Basal and post-calcium infusion serum iPTH levels correlated positively with urinary cAMP in FHR subjects and controls. Pre- and post-calcium infusion iPTH levels correlated with serum calcium in FHR subjects. Mean Salivary phosphate concentration was significantly reduced in FHR subjects (FHR: 12.68 +/- 0.87, controls: 22.47 +/- 2.16 mg/100 ml, P less than 0.001). However, calculated salivary phosphate clearance rates were similar in FHR and control subjects. PTH or calcium infusion did not significantly alter salivary phosphate concentration or clearance rates in either patients or controls. We concluded that untreated FHR patients exhibit a state of mild secondary hyperparathyroidism and an at least normal renal phosphaturic response to PTH. In addition, there is no evidence for increased salivary phosphate excretion in FHR.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1998

Hereditary 1,25-dihydroxyvitamin D-resistant rickets due to an opal mutation causing premature termination of the vitamin D receptor.

Mutations in the vitamin D receptor (VDR) gene have been shown to cause hereditary vitamin D-resistant rickets (HVDRR). The patient in this study is a young French-Canadian boy with no known consanguinity in his family. The child exhibited the clinical characteristics of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated 1,25-dihydroxyvitamin D (1,25(OH)2D) levels as well as total alopecia. Fibroblasts were cultured from a skin biopsy of the patient and used to assess the VDR. Northern blot analysis showed that a normal size VDR transcript was expressed; however, [3H]1,25(OH)2D3-binding levels were very low and Western blot analysis failed to detect any VDR protein. Total resistance to 1,25(OH)2D3 was demonstrated by the failure of the cultured fibroblasts to induce the transcription of the 25-hydroxyvitamin D-24-hydroxylase gene when treated with high concentrations of 1,25(OH)2D3. Analysis of the DNA sequence revealed a unique C to T base change corresponding to nucleotide 218 of the VDR cDNA. This single base substitution changes the codon for arginine (CGA) to an opal stop codon (TGA), resulting in the truncation of the VDR at amino acid 30. The Arg30stop mutation prematurely terminates translation and deletes 398 amino acids including most of the zinc fingers as well as the entire ligand-binding domain. Restriction fragment length polymorphism analysis of a DdeI restriction site created by the mutation showed that the parents were heterozygous for the mutant allele. In conclusion, the Arg30stop mutation truncates the VDR and leads to a hormone-resistant condition which is the molecular basis of HVDRR in this patient.

Alopecia↗
PubMed2003

Hypertension in hypophosphatemic rickets--role of secondary hyperparathyroidism.

Hypertension has been anecdotally reported in children with familial hypophosphatemic rickets (XLH). To better identify and characterize the clinical and laboratory features of hypertensive XLH children, we reviewed the medical records of 41 XLH children, all treated with phosphate and vitamin D analogues. Eight children, who were originally normotensive, developed hypertension during the 2nd decade of life. At diagnosis of hypertension all had persistent secondary/tertiary hyperparathyroidism (HPTD), defined as high serum parathyroid hormone (PTH) for 12 months or longer. Seven had nephrocalcinosis (NC). Analysis of data showed that of 11 children with HPTD, 8 developed hypertension compared with 0 among 30 without HPTD (P<0.001). Of 40 children studied, 18 had NC that was significantly associated with both HPTD (P<0.01) and hypertension (P<0.025). At diagnosis of hypertension, serum calcium was elevated in 2. Plasma renin activity was high in 3 of 4 patients in whom it was measured. Doppler ultrasonography or renal scan was normal in the 5 children studied. Early echocardiography showed left ventricular hypertrophy in only 2 of 5 children studied. In 3 patients who underwent parathyroidectomy, hypertension persisted and 1 progressed to renal failure. Serum creatinine remained normal in all others. Successful treatment of hypertension consisted of beta-adrenergic blockers, angiotensin converting enzyme inhibitors, and Ca channel blockers as monotherapy or in combination. We conclude that hypertension in treated XLH children is closely associated with HPTD. Emphasis should therefore be placed on prevention of the development of HPTD as a complication of XLH treatment, and close monitoring for hypertension in those who do develop HPTD.

Adolescent↗
PubMed1996

Acute biochemical effects of growth hormone treatment compared with conventional treatment in familial hypophosphataemic rickets.

OBJECTIVE: Conventional treatment of familial hypophosphaiaemic rickets with oral phosphate and 1 alpha-hydroxycholecalciferol (1 alpha HCC) does not satisfactorily correct the metabolic or physical defects of the disease and can have adverse effects, such as nephrocalcinosis. Hyperoxaluria from increased oral phosphate intake may contribute to nephrocalcinosis. Growth hormone enhances renal tubular phosphate reabsorption and 1,25-dihydroxy-cholecalciferol production in normal and in GH deficient individuals, and may thus be of benefit to patients with familial hypophosphataemic rickets. PATIENTS: We have assessed the acute effects of GH on phosphate and calcium metabolism in 6 children (age 4-14 years) with familial hypophosphataemic rickets. DESIGN: Each patient served as his/her own control and received the following in a sequential non-randomized design: conventional treatment with oral phosphate 1.0-3.4 mmol/kg/day in 3-6 divided doses and 1 alpha HCC 18-31 ng/kg/day-no treatment-GH 0.05 mg/kg daily-GH and 1 alpha HCC-and GH with phosphate and 1 alpha HCC. Each treatment was given for 7 days with 7 day periods of no treatment in between. MEASUREMENTS AND RESULTS: Glomerular filtration rate, tubular maximum rate of phosphate reabsorption per litre of glomerular filtrate (TmP/GFR) and serum 1,25-dihydroxycholecalciferol increased with GH. Mean 24-hour plasma phosphate concentrations did not increase with GH but were higher in the treatment phases which included phosphate and 1 alpha HCC (P = 0.002). Serum PTH was higher when GH was given in combination with phosphate and 1 alpha HCC compared to other phases. Urine oxalate excretion did not differ between the treatment phases. CONCLUSIONS: GH seemed to partially correct the defects in renal tubular phosphate transport and 1 alpha-hydroxylation of 25-hydroxycholecalciferol. We speculate that the net effect of GH treatment was an increase in body phosphate, although this was not reflected in a change in plasma phosphate. Therefore, GH in combination with 1 alpha HCC may act as a phosphate sparing agent, permitting treatment with lower and less frequent doses of oral phosphate and reducing adverse effects such as nephrocalcinosis.

Adolescent↗
PubMed1996

24R,25-dihydroxyvitamin D3 promotes bone formation without causing excessive resorption in hypophosphatemic mice.

To clarify the differences in the action of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and 24,25-(OH)2D3 in hypophosphatemic (Hyp) mice, a model for familial X-linked hypophosphatemic rickets in humans, we carried out histomorphometric examinations of the effects of these agents in the lumbar vertebra of these mice. The Hyp mice received 1-1000 micrograms/kg.day 24,25-(OH)2D3, 0.01-0.1 micrograms/kg.day 1,25.(OH)2D3, or vehicle alone given daily for 28 days by ip injection. Histomorphometrically, 1,25-(OH)2D3 and 24,25-(OH)2D3 showed similar effects on bone formation. The parameters of bone formation, mineralized bone volume/bone volume, mineral apposition rate, and bone formation rate/bone surface, were improved to a similar extent in a dose-dependent manner by 1,25-(OH)2D3 and 24,25-(OH)2D3, but there were remarkable differences in the indexes of the bone resorption between these two metabolites. In 24,25-(OH)2D3-treated Hyp mice, osteoclast number/bone perimeter and osteoclast surface/bone surface, the parameters of bone resorption, increased to control levels and did not change according to the dose of 24,25-(OH)2D3. However, in 1,25-(OH)2D3-treated Hyp mice, these values increased remarkably, exceeding the control level. That is, 24,25-(OH)2D3 normalized bone resorption in the rachitic mice, whereas 1,25-(OH)2D3 caused excessive stimulation of bone resorption. This qualitative difference between the two compounds contributes to the superior effects exerted by 24,25-(OH)2D3 in improving the bone lesion in Hyp mice. At doses from 1-1000 micrograms/kg.day, 24,25-(OH)2D3 had dose-dependent effects in increasing bone formation without promoting excessive bone resorption, as shown by histomorphometric analysis.

24,25-Dihydroxyvitamin D 3↗
PubMed1983

Long-term influence of calcitriol (1,25-dihydroxyvitamin D) and supplemental phosphate in X-linked hypophosphatemic rickets.

Ten patients with hypophosphatemic rickets (eight with X-linked familial form) were treated with vitamin D2 (10,000 to 75,000 units per day) and oral phosphate (1.5 to 3.6 gm) for a total of 438 treatment months. Therapy was then changed to calcitriol (17 to 34 ng/kg/day) and the same phosphate dose. Patients served as their own controls, and significant biochemical changes noted were an increase in immunoreactive parathyroid hormone from 29 +/- 9 (SD) microliters Eq/ml (pre-phosphate) to 62 +/- 34 on vitamin D2 plus PO4, then decreasing to 40 +/- 20 on a regimen of 1,25-dihydroxyvitamin D (1,25(OH)2D) plus PO4; serum PO4 rose from 2.44 +/- 0.45 (SD) mg/100 ml to 3.06 +/- 0.79 and then to 3.43 +/- 0.76; alkaline phosphatase activity decreased from 677 +/- 298 (SD) IU/liter to 457 +/- 183 to 290 +/- 176. Serum calcium and creatinine levels were unchanged. Both urinary calcium excretion and calcium-creatinine ratio decreased after therapy with 1,25(OH)2D. Urinary phosphate excretion was higher after calcitriol administration. Serum 1,25(OH)2D levels were low in these vitamin D2-treated patients, and an inverse relationship between serum 25(OH)D and 1,25(OH)2D was found. Improved bone mineralization was evident from serial assessment by photon absorptiometry, and radial bone mineral content rose from 75.3% +/- 2.2% of expected to 82.2% +/- 1.4% (P less than .005). Stature was improved when assessed by standard deviation for chronologic age but did not reach statistical significance. Long-term 1,25(OH)2D plus phosphate therapy appears to be more efficacious than vitamin D2 in this form of rickets, particularly in improving phosphate homeostasis.

Adolescent↗
PubMed1983

Impaired phosphorus conservation and 1,25 dihydroxyvitamin D generation during phosphorus deprivation in familial hypophosphatemic rickets.

The pathogenesis of familial hypophosphatemic rickets (FHR) is incompletely understood. We therefore examined the effects of acute dietary phosphorus deprivation to see whether renal phosphate conservation and increased 1,25 dihydroxyvitamin D [1,25(OH)2D] plasma levels, which normally follow restriction of phosphorus intake, could be induced in patients with FHR. Six healthy male volunteers (age 26 +/- 3 yr) and seven male patients with FHR (age 24 +/- 3 yr) were placed on a low phosphorus diet supplemented with aluminum hydroxide and studied over a 4-d period. The patients with FHR excreted more than five times as much phosphorus per day at the conclusion of the study than did the controls (176 +/- 61 mg/24 h vs. 33 +/- 11 mg/h). In the normal subjects, maximum tubular reabsorptive capacity for phosphorus/glomerular filtration rate (TmP/GFR) rose progressively during phosphorus deprivation, and the rise from base line was more than two times greater than that seen in patients with FHR. Immunoreactive parathyroid hormone levels and nephrogenous cyclic AMP were initially normal in both groups and no change was seen in either group with phosphorus deprivation. In the normal subjects, 1,25(OH)2D levels rose progressively over the 96 h of the study (49 +/- 3 to 63 +/- 6 pg/ml, P less than 0.05), while mean circulating 1,25(OH)2D in the patients with FHR did not change (34 +/- 3 to 29 +/- 3 pg/ml). The changes in individual plasma 1,25(OH)2D levels correlated strongly with the change in individual nephrogenous cyclic AMP measurements in the patients with FHR (r = +0.93), while no such correlation was observed in the normal subjects. These data demonstrate a defective renal response to phosphorus deprivation in patients with FHR including a qualitatively abnormal response in 1,25(OH)2D generation.

Absorption↗
PubMed1976

Exaggerated phosphaturic response to circulating parathyroid hormone in patients with familial X-linked hypophosphatemic rickets.

To determine whether the phosphaturic response to circulating parathyroid hormone (PTH) is exaggerated in patients with familial x-linked hypophosphatemic vitamin D-resistant rickets (FHR), we examined the phosphaturic response to parathyroid extract (PTE) (administered intravenously in the posthypercalcemic state) in two unrelated adult hemizygotes with FHR. In these two patients whose plasma concentration of PTH was normal (determined by radioimmunoassay). neither vitamin D nor phosphate therapy had been given during the past 10 yr. Two normal men and a hypophosphatemic man with intestinal malabsorption, hypocalcemia, and osteomalacia served as control subjects. In all subjects, calcium gluconate was adminstered intravenously from 6 p.m. to 12 midnight at a rate that maintained the concentration of serum calcium at 13-15 mg/100 ml during the administration of calcium. When normocalcemia had recurred the next morning, and the plasma PTH concentration and urinary excretion of cyclic 3', 5'-AMP were reduced. PTE was administered intravenously at successively increasing rates of 0.1, 0.4, and 0.8 U/kg per h, each rate lasting 90 min. Minutes after the initiation of PTE in the affected hemizygotes, fractional excretion of filtered phosphate increased from negligible values to values strikingly greater than those of similarly studied control subjects and plateaued at strikingly greater values throughout further administration of PTE. This phenomenon of exaggerated phosphaturia could not be attributed to volume expansion, decreases in serum concentration of calcium during the study, differences in percent of administered calcium retained, or hemodynamic changes. Only the phosphaturic response to PTE appeared to be exaggerated. At any cumulative dose of PTE, urinary excretion of cyclic 3', 5'-AMP in the hemizogytes was indistinguishable from that of control subjects. The findings in this study suggest that in patients with FHR, circulating PTH is required for the genetically transmitted abnormality to be physiologically expressed as a reduction in net renal reabsorption of phosphate, and that this physiological expression of the genetic abnormality is expressed fully at normal or nearly normal circulating levels of PTH.

Absorption↗
PubMed1989

Abnormal binding of vitamin D receptors to deoxyribonucleic acid in a kindred with vitamin D-dependent rickets, type II.

Vitamin D-dependent rickets, type II, is a hereditary disease that results from target organ resistance to the action of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. We describe here a family (designated G) with a defect in the DNA-binding domain of the 1,25-(OH)2D receptor (VDR) manifested by normal steroid binding and decreased VDR affinity for DNA. The phenotypically normal parents are heterozygous, expressing both normal and defective forms of VDR. The affected children in this family had early-onset rickets, alopecia, hypocalcemia, and elevated serum 1,25-(OH)2D3 levels. The VDR of cultured skin fibroblasts of the affected children (G1 and G2) as well as the parents (G3 and G4) bound [3H]1,25-(OH)2D3 normally (Kd = 2-3 X 10(-11) mol/L; maximal number of binding sites = 20-40 fmol/mg protein). The cells from G1 and G2 were resistant to 1,25-(OH)2D3 action, as measured by induction of 24-hydroxylase activity, while the cells from G3 and G4 responded normally. Western blot analysis using the anti-VDR monoclonal antibody 9A7 showed that hypertonic extracts of fibroblasts from both affected children (G1 and G2) and their parents (G3 and G4) had immunoreactive bands of 48K, identical to the size of the VDR in normal cells. The VDR from G1 and G2 eluted as a single peak from DNA-cellulose columns at a lower salt concentration (0.1 mol/L) than that from normal subjects (0.2 mol/L), indicating an apparent decreased affinity for DNA. Fibroblast VDR from G3 and G4 each eluted from DNA-cellulose columns as two peaks, the normal peak (0.2 mol/L) and the abnormal peak (0.1 mol/L), which was found in G1 and G2. Western blot analysis of the 0.1 and 0.2 mol/L KCl peak fractions also confirmed that VDR was present in only the 0.1 mol/L fraction and not the 0.2 mol/L fraction from G1. However, VDR was present in both fractions from G3. In summary, this vitamin D-dependent rickets, type II, kindred has a defect in the DNA-binding domain of VDR. The parents are phenotypically normal and express both the normal and defective VDR alleles, as demonstrated by both DNA-cellulose chromatography and Western blot analysis. The affected children are resistant to 1,25-(OH)2D3 action and are homozygous for the defective VDR.

Blotting, Western↗
PubMedDate not supplied

[Growth and renal function].

Some genetic conditions, as cystinosis, familial hypophosphataemic rickets, type-I vitamin D-resistant rickets and renal tubular acidosis have an impact on growth and growth failure is one of the major problem in children with chronic renal failure (CRF). In early childhood, anorexia and malnutrition, electrolyte disturbances and metabolic acidosis are the main contributing factors for reduced growth, whereas renal osteodystrophy, anemia and hormonal disturbances are responsible for growth impairment later and during puberty. During infancy, loss of growth potential can be prevented by adequate nutrition. Later in life, catch-up growth cannot be induced by nutritional intervention or dialysis and renal transplantation allows catch-up growth in only a small percentage of patients. There is evidence for a state of resistance to growth hormone (GH) and insulin-like growth factor-I (IGF-I) in CRF. GH secretion is normal, but GH half-life is prolonged and the binding activity of the GH-binding protein is reduced, which points to a low receptor expression. IGF-I production may be diminished and the serum concentration of IGF-binding proteins (IGFBP-1 and 3) is increased. The imbalance between normal IGF-I and excessive IGFBP serum levels results in decreased IGF bioactivity that plays a pathogenic role in the growth failure. This insensitivity seems to be overcome by supraphysiological doses of recombinant human GH (rhGH). Many clinical studies have confirmed that rhGH increases growth velocity in children with CRF with and without dialysis and after renal transplant, without significant side-effects. The improvement of growth is more marked in prepubertal patients and during the first year of rhGH treatment. Long-term rhGH treatment in children with CRF improves the growth potential of children, achieving target adult height. The Authors discuss the recent studies employing rhGH in renal diseases and attempt to give some guide lines to rhGH treatment in these illnesses.

Acidosis, Renal Tubular↗
PubMed1980

Supranormal 25-hydroxyvitamin D and subnormal 1,25-dihydroxyvitamin D: their role in X-linked hypophosphatemic rickets.

Serum 25-hydroxyvitamin D (25-OH-D) and 1,25-dihydroxyvitamin D (1,25-(OH)2D) and bone mineral content by the photon-absorption technique were determined in eight patients with X-linked hypophosphatemic rickets treated for at least 24 months with oral sodium phosphate and high-dosage ergocalciferol (vitamin D2). Mean 25-OH-D2 level was 129.5 +/- 67.5 ng/mL (mean +/- SD); the level of 25-OH-D3 was 10.5 +/- 5.8 ng/mL. These values were significantly higher than in normal subjects (total 25-OH-D mean of 27 +/- 10 ng/mL). Serum 1,25-(OH)2D was 16.9 +/- 8.5 pg/mL (mean +/- SD) in the eight patients, significantly lower than 47 +/- 16 pg/mL in 27 age-matched controls. Values indicative of significant demineralization were found in seven of the eight phsophate-treated patients, who had no radiologic evidence of rickets. These results suggest that any theory of the pathogenesis of this disorder must account for inappropriate renal vitamin D metabolism and for renal hyperphosphaturia. The failure of high-dosage oral phosphate and ergocalciferol to fully correct demineralization may suggest a role for calcitriol (1,25-(OH)2D3) as a therapeutic agent.

Absorption↗