X-linked hypophosphataemia: a homologous disorder in humans and mice.
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X-linked hypophosphatemia is an inherited disorder of phosphate (Pi) homeostasis characterized by growth retardation, rickets and osteomalacia, hypophosphataemia, and aberrant renal Pi reabsorption and vitamin D metabolism. Studies in murine Hyp and Gy homologues have identified a specific defect in Na+-Pi cotransport at the brush border membrane, abnormal regulation of 1,25-dihydroxyvitamin D3 (1,25(OH)2D) synthesis and degradation, and an intrinsic defect in bone mineralization. The mutant gene has been identified in XLH patients, by positional cloning, and in Hyp and Gy mice, and was designated PHEX/Phex to signify a PHosphate-regulating gene with homology to Endopeptidases on the X chromosome. PHEX/Phex is expressed in bones and teeth but not in kidney and efforts are under way to elucidate how loss of PHEX/Phex function elicits the mutant phenotype. Based on its homology to endopeptidases, it is postulated that PHEX/Phex is involved in the activation or inactivation of a peptide hormone(s) which plays a key role in the regulation of bone mineralization, renal Pi handling and vitamin D metabolism. (+info)
Protein-RNA interactions determine the stability of the renal NaPi-2 cotransporter mRNA and its translation in hypophosphatemic rats.
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Hypophosphatemia leads to an increase in type II Na(+)-dependent inorganic phosphate cotransporter (NaPi-2) mRNA and protein levels in the kidney and increases renal phosphate reabsorption. Nuclear transcript run-on experiments showed that the effect of a low phosphate diet was post-transcriptional. In an in vitro degradation assay, renal proteins from hypophosphatemic rats stabilized the NaPi-2 transcript 6-fold compared with control rats and this was dependent upon an intact NaPi-2 3'-untranslated region (UTR). To determine an effect of hypophosphatemia upon NaPi-2 protein synthesis, the incorporation of injected [(35)S]methionine into renal proteins was studied in vivo. Hypophosphatemia led to increased [(35)S]methionine incorporation only into NaPi-2 protein. The effect of hypophosphatemia on translation was studied in an in vitro translation assay, where hypophosphatemic renal proteins led to increased translation of NaPi-2 and other transcripts. NaPi-2 RNA interaction with cytosolic proteins was studied by UV cross-linking and Northwestern gels. Hypophosphatemic proteins led to increased binding of renal cytosolic proteins to the 5'-UTR of NaPi-2 mRNA. Therefore, hypophosphatemia increases NaPi-2 gene expression post-transcriptionally, which correlates with a more stable transcript mediated by the 3'-UTR, and an increase in NaPi-2 translation involving protein binding to the 5'-UTR. These findings show that phosphate regulates gene expression by affecting protein-RNA interactions in vivo. (+info)
PHEX gene and hypophosphatemia.
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PHEX gene and hypophosphatemia. X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO) are diseases that have in common abnormal proximal renal tubular function resulting in increased renal clearance of inorganic phosphorus and hypophosphatemia. The recent discovery of the PHEX gene has provided new insights to these disorders. In this regard, identification of the PHEX gene product as a membrane-bound endopeptidase suggests that the pathophysiologic cascade underlying XLH likely involves inactivation mutations of the gene causing a failure to clear an active hormone, phosphatonin, from the circulation. The presence of this hormone through unknown mechanisms decreases the sodium-dependent phosphate cotransporter in the kidney, resulting in impaired phosphate transport. In contrast, TIO likely evolves secondary to tumor overproduction of the putative phosphatonin, which exerts physiologic function despite efforts to counteract the resultant hypophosphatemia with overproduction of PHEX transcripts that are insufficient to accommodate the enhanced substrate load. These potential pathophysiologic mechanisms for XLH and TIO provide valuable inroads to understanding phosphate homeostasis, as well as vitamin D metabolism, bone mineralization, and calcium metabolism. (+info)
Persistent, progressive hypophosphataemia after voluntary hyperventilation.
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Hyperventilation (HV) and respiratory alkalosis are associated with hypophosphataemia, although the extent and duration of HV required to produce changes in serum phosphate levels are not known. We sought to characterize the effects of HV, with or without dextrose loading, on serum phosphate levels and other biochemical parameters. HV was monitored by controlling the end-tidal partial pressure of carbon dioxide (PETCO(2)). The effect of dextrose was studied because infusion of a glucose load is known to promote a fall in serum phosphate via stimulation of glycolysis. Eight healthy volunteers were enrolled in four study protocols: (1) HV for 20 min to a PETCO(2) of 25-30 mmHg (mild); (2) HV for 20 min to a PETCO(2) of 15-20 mmHg (severe); (3) mild HV with intravenous dextrose loading, and (4) dextrose loading alone. Periodic measurements of serum phosphate, venous pH, serum 2,3-diphosphoglycerate (2,3-DPG) and other parameters were made. Serum phosphate fell during HV and continued to decline after cessation of HV. Dextrose loading alone caused a fall in serum phosphate that continued for at least 30 min after cessation of the infusion (P<0.0002). HV combined with dextrose resulted in a greater decline in serum phosphate than either variable alone (P=0.003). The maximal decline in serum phosphate occurred in severe HV, with a mean decrease of 0.38 mmol/l at 20 min after cessation of HV (P<0.0001). Serum phosphate was still significantly lowered compared with baseline at 90 min after cessation of HV (P=0.001). Other significant changes seen with HV included a decrease in serum glucose (P<0.01), a decrease in serum potassium (P<0.05) and an increase in venous pH (P<0.007). Serum 2, 3-DPG levels did not change significantly in any study protocol. Thus relatively mild acute HV produces significant changes in serum phosphate. In both mild and severe HV this effect is progressive after cessation of HV. This phenomenon has not been shown before, and may have significant clinical implications. (+info)
Severe hypophosphatemia during hematopoietic reconstitution after allogeneic peripheral blood stem cell transplantation.
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A patient suffering from acute myeloid leukemia (FAB M5a) received a PBSC allograft from a matched, related donor. On day 13 after transplantation severe hypophosphatemia (0.21 mmol/l) was first noted which persisted irrespective of intravenous phosphate administration, and within 2 days reached concentrations below 0.13 mmol/l. After repeated phosphate substitution serum phosphate returned to 1.40 mmol/l on day 17. Phosphate in urine, and calcium in serum were recorded as unchanged throughout. Clinical signs and symptoms due to severe hypophosphatemia were not observed except for paresthesia in the lower extremities. The precipitous fall in serum phosphate coincided with hematopoietic reconstitution as reflected by a steep rise in leukocyte count from 0.08 x 109/l on day 10 to 5. 94 x 109/l on day 15 after transplantation. Thus, isolated hypophosphatemia was likely the result of excessive cellular phosphate uptake during hematopoietic reconstitution. Electrolyte monitoring after PBSCT should include serum phosphate to identify the hypophosphatemia associated with hematopoietic recovery. (+info)
Reflex sympathetic dystrophy in hypophosphataemic osteomalacia with femoral neck fracture: a case report.
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We report a male patient who presented with suspicion of skeletal metastases based upon an abnormal 99-mTc bone scan, which showed increased uptake at both femoral heads, left femoral neck, and several ribs. The images also suggested reflex sympathetic dystrophy, subcapital fracture of the left femur, and rib fractures. A diagnosis of hypophosphataemic osteomalacia was finally made. (+info)
Recognition and management of hungry bone syndrome--a case report.
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Hungry bone syndrome (HBS) following successful parathyroid surgery is a well described phenomenon. However, few studies have clearly addressed this syndrome or looked at the outcome of perioperative management. We report a case of HBS following successful parathyroid surgery. The perioperative management is discussed and literature pertaining to this interesting case is reviewed. (+info)
Impaired phosphate handling of renal allografts is aggravated under rapamycin-based immunosuppression.
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BACKGROUND: Impaired phosphate handling of the renal allograft is a common problem and of multifactorial origin. The aim of the study was to elucidate whether a rapamycin- or a mycophenolate-based immunosuppressive therapy aggravates the renal phosphate leak in kidney transplant recipients. METHODS: Renal phosphate handling was determined in thirty-eight cadaveric allograft recipients, with good renal function at 8, 12, 20 and 28 weeks after transplantation. Nineteen patients (group 1) received triple immunosuppression with rapamycin, cyclosporine and prednisolone, nineteen other transplant recipients received mycophenolate mofetil, cyclosporine and prednisolone immunosuppression (group 2), and six healthy subjects (group 3) served as controls. After 12 weeks of stable graft function, group 1 patients were divided further into two subgroups. Ten patients were kept on their immunosuppressive regimen (group 1A), whereas the remaining nine randomly chosen subjects had their cyclosporine withdrawn; they were thus maintained on a dual immunosuppression regimen with prednisolone and a higher dosage of rapamycin (group 1B). RESULTS: Renal phosphate reabsorption was significantly lower in group 1 at 8 and 12 weeks after transplantation as compared with groups 2 and 3. At 20 weeks after transplantation, patients with rapamycin-based immunosuppression (groups 1A and 1B) continued to exhibit hypophosphataemia and impaired renal phosphate handling. Group 1B had the lowest TmP/ GFR compared with all groups. At 28 weeks, renal phosphate reabsorption and plasma phosphate levels were no longer different between patient groups and controls. CONCLUSION: These data suggest that rapamycin-based immunosuppression prolongs the phosphate leak of the allografted kidney, leading to low serum phosphate levels during the first weeks after transplantation. (+info)