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PubMed1991

Abnormal renal glucose handling in X-linked hypophosphataemic mice.

1. The renal handling of glucose was determined in male X-linked hypophosphataemic (Hyp/Y) mice and in control littermates (+/Y) aged 4 months. Plasma glucose concentration and urinary glucose excretion were measured before and during stepwise increase in glycaemia induced by an acute infusion of glucose. The relationship between plasma glucose concentration and urinary glucose excretion was monitored per ml of glomerular filtrate in mice fed high and low phosphate diets. 2. Hyp/Y mice fed the high phosphate diet showed a significantly higher glucosuria compared with +/Y littermates. When glycaemia was increased, Hyp/Y mice developed frank glucosuria earlier than +/Y animals. In Hyp/Y mice we could not find a threshold below which virtually no glucose was excreted in the urine, whereas this was clearly visible in +/Y mice. These differences persisted in animals fed the low phosphate diet. 3. Using the acute response to the glucoregulatory hormones, glucagon and insulin, administered exogenously, we found that the regulation of plasma glucose concentration did not differ between Hyp/Y and +/Y mice. 4. The significantly lower plasma glucose concentration observed in Hyp/Y as compared with +/Y mice decreased further during fasting. 5. We conclude that the renal reabsorptive capacity for glucose is defective in Hyp/Y mice and their low plasma glucose concentration may be explained by the renal leak. Therefore the X-linked phosphataemic mouse appears not only to be characterized by a defect in renal phosphate and calcium reabsorption but also by an altered glucose reabsorption.

Animals↗
PubMed1997

Oncogenic osteomalacia: is there a new phosphate regulating hormone?

Oncogenic osteomalacia is a syndrome associated with rare, usually mesenchymal tumours, which is characterized by hypophosphataemia, phosphaturia and low concentrations of 1,25-dihydroxyvitamin D. The reversal of clinical and biochemical abnormalities following removal of the tumour, indicates it is the source of a humoral factor that is responsible for these abnormalities. It has been demonstrated that the humoral factor inhibits renal phosphate uptake and reduces 1,25-dihydroxyvitamin D production. Although there is evidence that it may act via parathyroid hormone/parathyroid hormone-related peptide receptors and may be a peptide, the factor has not yet been identified, nor has its relationship to factors involved in X-linked hypophosphataemic rickets been established. We propose unifying hypotheses for the pathogenesis of oncogenic osteomalacia and X-linked hypophosphataemic rickets which involve defects in the PEX gene. These hypotheses do not fully explain all the available data and it remains possible that hormone(s) with little or no role in X-linked hypophosphataemic rickets may be responsible for oncogenic osteomalacia.

Animals↗
PubMed1999

A trial of growth hormone therapy in well-controlled hypophosphataemic rickets.

OBJECTIVE: Conventional therapy of hypophosphataemic rickets (HR) with oral phosphate and calcitriol does not always result in normal linear growth. Recombinant human growth hormone (rhGH) offers theoretical advantages as an adjunctive therapy. We aimed to determine the effects of adjunctive rhGH therapy in children with well-controlled HR. PATIENTS: In this report, 5 prepubertal children (aged 3.5-10.9 years) with well-controlled HR on conventional therapy were given adjunctive standard dose rhGH therapy for one year. DESIGN AND MEASUREMENTS: Height, growth velocity, metabolic markers of calcium and phosphate metabolism, body composition, bone mineral density, wrist and knee X-rays, and renal sonography were assessed at regular intervals. Height and growth velocities were also calculated 12 months after ceasing rhGH therapy. RESULTS: After 12 months therapy with rhGH, no significant biochemical or radiological benefits were observed. A significant increase in height SD score was observed (P = 0.023), but this was not associated with any increase in the growth velocity SD score and appears to have been due to catch-up growth caused by conventional therapy alone. When rhGH therapy was ceased, no significant decreases in mean height SD or growth velocity SD scores were observed. CONCLUSIONS: In well-controlled hypophosphataemic rickets patients receiving conventional therapy, adjunctive therapy with standard dose rhGH offers no benefits in linear growth or rachitic disease markers.

Body Composition↗
PubMed2003

Prolonged high-dose phosphate treatment: a risk factor for tertiary hyperparathyroidism in X-linked hypophosphatemic rickets.

OBJECTIVE: X-linked hypophosphatemic rickets is characterized by renal phosphate wasting, hypophosphatemia and defective bone mineralization. Treatment with oral phosphate (Pi) and calcitriol improves skeletal changes but associates with secondary hyperparathyroidism and nephrocalcinosis. Tertiary hyperparathyroidism is a rare complication of the treatment. The aim of the present study was to identify treatment-related factors that might be associated with the transition of secondary hyperparathyroidism to tertiary hyperparathyroidism in patients with X-linked hypophosphatemic rickets. DESIGN: Thirteen patients with X-linked hypophosphatemic rickets and secondary or tertiary hyperparathyroidism were included in the study. Their hospital records were reviewed and compared for onset, duration and dosage of treatment, and for age of diagnosis and degree of secondary hyperparathyroidism. RESULTS: Two patients developed tertiary hyperparathyroidism and 11 patients secondary hyperparathyroidism during the treatment. Patients with tertiary hyperparathyroidism had, on average, earlier onset and longer duration of treatment, higher dose of Pi and longer duration of treatment with very high Pi doses (> 100 mg/kg/day) compared to the 11 patients with secondary hyperparathyroidism. However, variation of all parameters was great with considerable overlap. Very high S-PTH levels > or = 42 pmol/l were observed in those who later developed tertiary hyperparathyroidism. CONCLUSIONS: Prolonged very high dose oral Pi treatment is a major risk factor for the development of tertiary hyperparathyroidism in X-linked hypophosphatemic rickets.

Administration, Oral↗
PubMed2001

Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23.

BACKGROUND: The gene for the renal phosphate wasting disorder autosomal-dominant hypophosphatemic rickets (ADHR) is FGF23, which encodes a secreted protein related to the fibroblast growth factors (FGFs). We previously detected missense mutations R176Q, R179W, and R179Q in FGF23 from ADHR kindreds. The mutations replace R residues within a subtilisin-like proprotein convertase (SPC) cleavage site 176RHTR-179 (RXXR motif). The goal of these studies was to determine if the ADHR mutations lead to protease resistance of FGF-23. METHODS: The ADHR mutations were introduced into human FGF-23 cDNA clones with or without an N-terminal FLAG tag by site-directed mutagenesis and were transiently transfected into HEK293 cells. Protein expression was determined by Western analyses. RESULTS: Antibodies directed toward the C-terminal portion of FGF-23 revealed that the native FGF-23 protein resolved as 32 kD and 12 kD species in HEK293 conditioned media; however, the three mutated proteins were detected only as the 32 kD band. An N-terminal FLAG-tagged native FGF-23 resolved as two bands of 36 kD and 26 kD when detected with a FLAG antibody, whereas the R176Q mutant resolved primarily as the 36 kD protein species. Cleavage of FGF-23 was not enhanced by extracellular incubation of FGF-23 with HEK293 cells. Native and mutant FGF-23s bound heparin. CONCLUSIONS: FGF-23 proteins containing the ADHR mutations are secreted, and produce polypeptides less sensitive to protease cleavage than wild-type FGF-23. Therefore, the ADHR mutations may protect FGF-23 from proteolysis, thereby potentially elevating circulating concentrations of FGF-23 and leading to phosphate wasting in ADHR patients.

Cell Line↗
PubMed2006

Renal phosphate-wasting disorders.

The renal regulation of phosphate is a complex process. Clinical disorders of phosphate handling have led to the identification of several genes and proteins involved in the maintenance of phosphate homeostasis. Further work is required to elucidate the precise pathways that regulate renal phosphate transport.

Animals↗
PubMed2006

Aminoglycoside-associated Fanconi syndrome.

The objective is to describe a case of probable aminoglycoside-induced Fanconi syndrome and make clinicians aware of the existence of this underrecognized and underdiagnosed complication in patients treated with a prolonged course of high-dose aminoglycosides. A 53-year-old man admitted for recurrent infective exacerbations of chronic bronchiectasis already colonized with Pseudomonas aeruginosa was treated intermittently with intravenous gentamicin (320 to 560 mg/d) for a total of 4 months to a total cumulative dose of 9.4 g. The patient developed profound hypophosphatemia, hypocalcemia, hyperphosphaturia, and aminoaciduria. Electrolyte disturbances persisted until gentamicin therapy was stopped, recurred with rechallenge, and did not correct with calcium and phosphate supplementation. This case shows that prolonged exposure to high-dose aminoglycoside therapy can be associated with Fanconi syndrome, which is a manifestation of proximal tubular dysfunction. There are only a few case reports to date of Fanconi syndrome as a probable complication of high-dose aminoglycoside therapy. The Naranjo Adverse Drug Reaction probability scale score indicated that this was a probable adverse reaction associated with administration of high-dose aminoglycosides. The differential diagnosis of electrolyte disturbances as a manifestation of proximal tubule dysfunction and type 2 renal tubular acidosis is vast; however, Fanconi syndrome needs to be considered in patients treated with high doses of aminoglycosides for longer than 6 days, after more common causes of hypophosphatemia are excluded.

Anti-Bacterial Agents↗
PubMed1998

High-dose phosphate treatment leads to hypokalemia in hypophosphatemic osteomalacia.

The mechanism of the decrease in plasma potassium induced by phosphate treatment was investigated in a 24-year-old hypertensive patient with hypophosphatemic osteomalacia, who was the youngest of four patients, belonging to a 23 number kindred of five generations. Parameters of potassium, sodium, calcium, and phosphate metabolism as well as specific renal functions have been studied in the basal state and during administration of graded doses of phosphate (500-6000 mg). Progressive hypokalemia developed during phosphate treatment. An inverse correlation was found between plasma potassium and doses of phosphate (plasma potassium = -0.2 g phosphate + 3.9 r = -0.49; p < 0.05; N = 21). A renal route of potassium loss was suspected, but could not be confirmed as potassium excretion did not increase although sodium excretion was augmented [basal sodium output: 56.7 mmol/24 h; phosphate treatment: 153 mmol/24 h (p < 0.05)]. Transtubular potassium gradient (TTKG) also decreased and an inverse correlation was found between TTKG and doses of phosphate (r = -0.37; p < 0.02; N = 38). Decrease of TTKG was possibly the result of suppressed K+ secretion. It was concluded that potassium loss occurred by a non-renal (intestinal) route in phosphate-induced hypokalemia. Although major hazards of treatment of hypophosphatemic osteomalacia with phosphate and calcitriol are secondary hyperparathyroidism and vitamin D intoxication, potassium loss also should be kept in mind.

Adult↗
PubMed2002

Up-regulation of liver glucose-6-phosphatase in x-linked hypophosphatemic mice.

We previously showed that a phosphate-deficient diet resulting in hypophosphatemia upregulated the catalytic subunit p36 of rat liver glucose-6-phosphatase, which is responsible for hepatic glucose production. A possible association between phosphate and glucose homeostasis was now further evaluated in the Hyp mouse, a murine homologue of human X-linked hypophosphatemia. We found that in the Hyp mouse as in the dietary Pi deficiency model, serum insulin was reduced while glycemia was increased, and that liver glucose-6-phosphatase activity was enhanced as a consequence of increased mRNA and protein levels of p36. In contrast, the Hyp model had decreased mRNA and protein levels of the putative glucose-6-phosphate translocase p46 and liver cyclic AMP was not increased as in the phosphate-deficient diet rats. It is concluded that in genetic as in dietary hypophosphatemia, elevated glucose-6-phosphatase activity could be partially responsible for the impaired glucose metabolism albeit through distinct mechanisms.

5'-Nucleotidase↗
PubMed2002

Rickets in childhood.

Bone accretion is a two-stage process, with the osteoblasts laying down osteoid, which is then mineralized. Mineralization of osteoid requires vitamin D to be available in its active form (1,25(OH) 2 D); in addition, mineralization also requires normal levels of serum calcium, phosphorus, and alkaline phosphate. Deficiencies of any of these will result in defective mineralization of bone, in which the mineral-osteoid ratio is reduced (a qualitative abnormality). In the juvenile skeleton deficiencies particularly affect enchondral ossification at the growth plates, giving the characteristic clinical and radiological features of rickets. The bone may be soft, leading to deformity. In this article the causes of rickets in childhood are reviewed, together with the clinical and radiological features and strategies for prevention and treatment.

Child↗
PubMed1982

In vivo Response of X-linked hypophosphatemic mice to calcitonin.

Other investigations, using the Hyp mouse as an animal model for the human disease X-linked hypophosphatemia (XLH), have demonstrated renal hypersensitivity to calcitonin (CT) using in vitro single renal tubule adenylate cyclase microassays. Renal hypersensitivity to CT may explain the elevated fractional excretion of phosphate (FE-P) and urinary 3'-5'-cyclic AMP (UcAMP) present in Hyp mice. This current study was designed as the in vivo counterpart to the in vitro experiments. CT dose-dependent hypocalcemia when data were constructed in normal and Hyp mice 18 hours after thyroparathyroidectomy (TPTX). Exogenous CT administered to TPTX normal mice resulted in dose-dependent hypocalcemia when data were expressed as the percent change from pretreatment. However, CT did not elicit a hypocalcemic response in TPTX Hyp mice at any dose. Only TPTX normal mice responded to CT with significant hypophosphatemia. FE-P and UcAMP were not significantly changed by CT in either genotype. In a different experiment, a large pharmacologic dose of CT was given to TPTX mice. This dose resulted in a significant but similar elevation of FE-P 1 hour after injection in both Hyp and normal TPTX mice. While UcAMP also rose significantly in both genotypes, the percent increase compared to controls was greater in Hyp mice. In summary, results from these in vivo experiments indicate that Hyp mice are not hypersensitive to physiologic doses of CT, and in fact they seem to be resistant to the hypocalcemic effect of the hormone. The greater increase in UcAMP in TPTX Hyp mice after a pharmacologic dose of CT may be the basis for the earlier in vitro results reported by others. We conclude that renal hypersensitivity to CT does not play a role in the etiology of XLH in the Hyp mouse.

Animals↗
PubMed1994

[2 successful pregnancies in a woman with type I osteogenesis imperfecta].

The chance of a woman with osteogenesis imperfecta to succeed in a pregnancy with a healthy baby and without any harm to herself, is poor. A case of a 37-year old patient is presented, who consciously became pregnant twice, despite her severe illness. Both pregnancies finally resulted in Caesarean section, but without any complications to the patient. While the first child, a boy, is healthy, the second, a girl, is expected to suffer from phosphate diabetes since the father suffered from this illness.

Adult↗
PubMedDate not supplied

[Early diagnosis and early treatment of hypophosphatemic vitamin D-resistant rickets].

This is a report on two children with hypophosphatemic vitamin D-resistant rickets born to affected mothers diagnosed at the age of one and three months, respectively. The most important diagnostic criterium is the reduced value of the transport maximum of phosphorus in relation to glomerular filtration rate. At the age of one and six months, respectively, therapy with 1.25 (OH)2D3 and phosphate was started with the result of normal growth of length, radiological healing of rickets and normalisation of alkaline serum-phosphatase, but persistently low fasting values of serum-phosphorus during the time of observation up to twelve and twenty-four months of age, respectively in both children. The therapy with 1.25 (OH)2D3 and phosphate has a positive effect on intestinal absorption of phosphorus, because the serum-phosphorus is significantly elevated to the age corrected normal range two hours after oral administration of phosphate. There were no negative effects during therapy. It seems, therefore, that early diagnosis and therapy with 1.25 (OH)2D3 and phosphate is successful in healing this rare form of rickets.

Calcitriol↗