Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q92565 (GFR)
 4,179 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Not all children with X-linked hypophosphatemia (XLH) have demonstrated improved linear growth with calcitriol [1,25-(OH)2D3] and inorganic phosphate (Pi) therapy. To assess which factors are associated with a favorable growth response during this treatment, we retrospectively compared demographics and biochemical parameters of bone metabolism to the linear growth patterns of 20 children with XLH who were prepubertal and had not required osteotomy. A total of 15 patients had family histories consistent with XLH; 5 appeared to be sporadic cases. During 3 years of therapy, the growth velocities of 12 patients had been at or above the mean for age (good growers) and those of 8 patients had been below the mean (poor growers). Data from the two groups were contrasted. We found no difference between the good growers and poor growers before or after the 3 year period of therapy in mean age, dietary calcium, calcitriol dose or compliance, or Pi dose or compliance. Both groups increased their mean fasting serum Pi levels with treatment. The TmP/GFR (mean +/- SEM) of the good growers improved with therapy (1.9 +/- 0.2 to 2.6 +/- 0.2 mg/dl, p = 0.01), and their posttreatment value was higher compared to that of the poor growers (2.6 +/- 0.1 versus 2.2 +/- 0.1 mg/dl, p = 0.02). However, their enhanced TmP/GFR was not associated with a reduction in serum iPTH levels (before, 693 +/- 50; after, 688 +/- 76 pg/ml; p = 0.9). The Z test for binomial proportions showed that the group that grew well contained a disproportionate number of girls (10 of 12, p = 0.04). Our findings suggest that calcitriol may exert a direct effect on the renal tubule to improve Pi reclamation in XLH. The observation that heterozygous girls appear to respond better than hemizygous boys to calcitriol and Pi therapy provides evidence for a gene dosage effect in the expression of this X-linked dominant disorder.
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PMID:X-linked hypophosphatemic rickets: a study (with literature review) of linear growth response to calcitriol and phosphate therapy. 141 77

The main features of X-linked dominant renal hypophosphatemic rickets are illustrated in this study of two patients who presented with rickets, deformities of the lower limbs, and small stature. Hypophosphatemia secondary to a reduction in renal tubular reabsorption of phosphate and a defect of vitamin D hydroxylation are the hallmarks of the disease. The best measure of renal handling of phosphate is to determine the tubular maximum of phosphate transport normalized for glomerular filtration rate (TmPO4/GFR). Determination of the calcium/creatinine ratio of a random urine sample proved to be a good additional parameter to control supplementation of phosphate and calcitriol. Diagnosis of the disease in our two patients enabled us to recognize renal hypophosphatemic rickets in both mothers and in two further ancestors of one patient. Both mothers suffered from early arthrosis.
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PMID:[Familial hypophosphatemia]. 216 80

We report on two brothers with renal hypophosphatemia, intracerebral calcifications, minor facial anomalies, and short distal phalanges. The children presented with recurrent dental abscesses; one had premature closure of the anterior fontanelle. Biochemical findings included hypophosphatemia and elevated serum alkaline phosphatase with normocalcemia. Blood levels of parathyroid hormone, 1,25(OH)2 and 25(OH) vitamin D levels were normal; TRP (the fractional tubular reabsorption of PO4) and TmP/GFR (the tubular maximum rate of PO4 reabsorption in relation to GFR) were low. Both parents had a normal serum phosphate and brain CT scan without evidence of calcifications. This apparently new syndrome of renal hypophosphatemia associated with intracerebral calcifications appears to be inherited as either an autosomal recessive or an X-linked trait.
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PMID:Familial renal hypophosphatemia, minor facial anomalies, intracerebral calcifications, and non-rachitic bone changes: apparently new syndrome? 230 90

A controlled metabolic study to examine the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment on the renal handling of phosphate was conducted in nine patients with X-linked dominant hypophosphatemic rickets, including one with autonomous secondary hyperparathyroidism. Administration of 1,25(OH)2D3 resulted in uniform reduction in serum PTH from 63.6 +/- 14.7 (SD) to 49.3 +/- 14.8 muleq/ml (P less than 0.01), elevation of the tubular threshold for phosphate (TmP/GFR) from 1.41 +/- 0.30 to 1.90 +/- 0.31 mg/dl (P less than 0.01) and increase in serum phosphate from 2.6 +/- 0.7 to 3.4 +/- 1.1 mg/dl (P less than 0.01) in eight PTH-suppressible patients. Four patients treated with phosphate before and during the study (group A) excreted significantly more phosphate than those not treated with phosphate (group B) (P less than 0.001). In the control period, group A also had depressed TmP/GFR and higher concentrations of serum phosphate and PTH. With 1,25(OH)2D3 treatment, serum phosphate in group A became remarkably higher than in group B, 4.28 +/- 0.99 vs. 2.55 +/- 0.31 mg/dl (P less than 0.02), whereas serum PTH and TmP/GFR were similar in both groups. A good inverse linear correlation was found between mean serum PTH and mean TmP/GFR of the groups before and after treatment (r = 0.947); whereas, no correlation was found between TmP/GFR and serum calcium. The patient with autonomous secondary hyperparathyroidism, who was also treated with phosphate, had the lowest TmP/GFR. Administration of 1,25(OH)2D3 had no effect on the serum PTH and phosphate concentrations or on TmP/GFR. We conclude that in patients with X-linked dominant hypophosphatemic rickets PTH modulates to some extent the tubular handling of phosphate, and that the importance of this mechanism increases with therapeutic phosphate supplementation. Simultaneous administration of 1,25(OH)2D3 suppressed PTH activity, raised serum phosphate concentrations, and elevated TmP/GFR.
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PMID:Effects of parathyroid hormone and 1,25-dihydroxyvitamin D3 on tubular handling of phosphate in hypophosphatemic rickets. 654 75

Besides rickets and osteomalacia, the X-linked hypophosphatemic male mouse (Hyp/Y) presents with low serum calcium (Ca) and increased urinary hydroxyproline (OH-Pro) excretion, suggesting a parathyroid hormone (PTH)-stimulated bone resorption despite reduced magnesium (Mg) bone content. In this study, we have investigated by histochemical methods the state of bone resorption in 50-day-old untreated Hyp/Y mice and the effects of 4 wk of Mg therapy or dietary lactose supplementation on bone formation and resorption. Mineral and skeletal changes were evaluated on serum, urinary and bone ash concentrations of Ca, phosphorus (P) and Mg, and by histomorphometric analysis of tetracycline double labeled undeclalcified caudal vertebrae. The number of acid phosphatase stained chondroclasts and osteoclasts was lower than normal in untreated Hyp/Y and was restored after Mg therapy while the osteoclastic surface was increased above normal. Accordingly, serum P and urinary Ca, P, Mg, cAMP and OH-Pro were increased while TmP/GFR was unchanged. On the other hand, dietary lactose corrected serum Ca which probably suppressed PTH secretion since the renal P conservation was improved and the osteoclast number and the osteoclastic surface were decreased. Both treatments reduced the growthplate and osteoid seam thickness and increased the bone calcification rate. The results indicate that the low skeletal Mg present in Hyp/Y partially impairs bone responsiveness to PTH since Mg therapy restored the osteoclastic bone resorption which secondarily provided new minerals for bone mineralization. The greater than normal bone resorption found in Mg treated-Hyp/Y and the decreased bone resorption observed in lactose treated animals indicate that the chronic hypocalcemia induces secondary hyperparathyroidism in Hyp/Y mice.
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PMID:Effects of magnesium and lactose supplementation on bone metabolism in the X-linked hypophosphatemic mouse. 682 87

We diagnosed non X-linked hypophosphataemic bone disease in a 38-month-old girl. Findings included: genu varum, shortened stature, fasting hypophosphataemia (2.3-2.5 mg/100 ml; 0.74-0.81 mmol/l), diminished theoretical renal threshold for phosphate (TmP/GFR), and osteomalacia without rickets. One patient (the father) had fasting hypophosphataemia (2.3-2.7 mg/100 ml; 0.74-0.87 mmol/l) and low TmP/GFR without osteomalacia or shortened stature. Treatment of the girl with 1,25-(OH)2D3 (1 microgram a day) raised the level of serum phosphorus, improved tubular reabsorption of phosphate, and healed the bone deformity; this combination of responses is not present in X-linked hypophosphataemia. There was no correction of hypophosphataemia or TmP/GFR with 1,25-(OH)2D3 treatment (1-3 micrograms a day) in the father.
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PMID:Autosomal hypophosphataemic bone disease responds to 1,25-(OH)2D3. 721 58

A 36-year-old Russian man presented with neck and low back pain in September 1990. He was of normal stature, and there were no stigmata of rickets. The family history was negative for bone disease. He was found to have hypophosphatemia (2.3 mg/dl), impaired phosphate reabsorption (TmP/GFR 2.08), hyperphosphatasemia (254 IU/l), normocalcemia, normal vitamin D metabolite levels, and secondary hyperparathyroidism. Clinically, his spinal movements were quite impaired and there was moderate proximal muscle weakness. On skeletal radiographs, there was generalized osteosclerosis and multiple ligamentous calcifications. Transiliac biopsy was diagnostic for severe osteomalacia. He was treated with oral phosphate (240 mEq daily) and calcitriol (4 micrograms daily) with resultant very slow clinical, biochemical, and histomorphologic improvement. The patient had hypophosphatemic osteomalacia with some features of X-linked hypophosphatemia, but sporadic and of relatively late onset. The osteopenia, height loss, incapacitating weakness, and glycinuria that are characteristics of sporadic adult onset nonfamilial hypophosphatemia, with or without an associated tumor, and the low serum calcitriol levels that may be an additional characteristic of tumor-induced osteomalacia were absent. Other known causes of acquired renal tubular dysfunction were ruled out. The etiology, pathogenesis, and nosology of the disorder remain obscure, but treatment based on experience with other forms of hypophosphatemic osteomalacia was ultimately effective.
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PMID:A unique case of adult hypophosphatemic osteomalacia. 826 43

The X-linked Hyp mutation, a murine homologue of X-linked hypophosphatemia in humans, is characterized by renal defects in phosphate reabsorption and vitamin D metabolism. In addition, the renal adaptive response to phosphate deprivation in mutant Hyp mice differs from that of normal littermates. While Hyp mice fed a low phosphate diet retain the capacity to exhibit a significant increase in renal brush-border membrane sodium-phosphate cotransport in vitro, the mutants fail to show an adaptive increase in maximal tubular reabsorption of phosphate per volume of glomerular filtrate (TmP/GFR) in vivo. Moreover, unlike their normal counterparts, Hyp mice respond to phosphate restriction with a fall in the serum concentration of 1,25-dihydroxyvitamin D [1,25(OH)2D] that can be ascribed to increased renal 1,25(OH)2D catabolism. The dissociation between the adaptive brush-border membrane phosphate transport response and the TmP/GFR and vitamin D responses observed in Hyp mice is also apparent in X-linked Gy mice and hypophysectomized rats. Based on these findings and the notion that transport across the brush-border membrane reflects proximal tubular function, we suggest that the adaptive TmP/GFR response requires the participation of 1,25(OH)2D or a related metabolite and that a more distal segment of the nephron is the likely target for the 1,25(OH)2D-dependent increase in overall tubular phosphate conservation.
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PMID:Renal adaptation to phosphate deprivation: lessons from the X-linked Hyp mouse. 851 5

The X-linked Hyp and Gy mutations are murine homologues of X-linked hypophosphatemia (XLH), a dominant disorder of phosphate (Pi) homeostasis characterized by growth retardation, rickets, hypophosphatemia and decreased renal tubular maximum for Pi reabsorption relative to glomerular filtration rate (Tmp/GFR). In Hyp and Gy mice, the decrease in Tmp/GFR is associated with a reduction in renal brush-border membrane (BBM) Na(+)-Pi cotransport that can be ascribed to a decrease in renal-specific, Na(+)-Pi cotransporter (NPT2) mRNA and protein abundance. Although renal NPT2 gene expression is reduced in Hyp and Gy mice, the NPT2 gene does not map to the X chromosome. These findings exclude NPT2 as a candidate gene for murine and human X-linked hypophosphatemias and suggest that genes at the Hyp, Gy and XLH (HYP) loci are involved in regulation of NPT2 gene expression. Both Hyp and Gy mice respond to low Pi diet with an increase in BBM Na(+)-Pi cotransport, NPT2 mRNA and protein. The increase in NPT2 protein in Pi-depleted mice far exceeds the increase in NPT2 mRNA, suggesting that translational or post-translational mechanisms are involved in the adaptive process. NPT2 protein is localized to the apical surface of the proximal tubule, where immunostaining in both normal and Hyp mice is increased in response to low Pi diet. Pi-deprived Hyp and Gy mice fail to show an increase in Tmp/GFR, indicating that adaptation at the BBM is not sufficient for the overall increase in Tmp/GFR in response to low Pi diet.
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PMID:Renal Na(+)-phosphate cotransporter gene expression in X-linked Hyp and Gy mice. 869 20

X-linked hypophosphatemia (XLH) is characterized clinically by rickets, hypophosphatemia and hyperphosphaturia. Conventional treatment of XLH with oral phosphate and vitamin D is associated with hypercalcuria and nephrocalcinosis. Recently, intravenous and oral dipyridamole has been reported to decrease fractional excretion of phosphate in adults with idiopathic hyperphosphaturia. Our objective was to determine whether oral dipyridamole therapy reduces urinary phosphate excretion and increases serum phosphate concentration in children with XLH. A prospective study was performed in six children with XLH. The average age of the patients at the start of the study was 12.5+/-1.0 years. The effects of 12 weeks of oral dipyridamole therapy, at 4.4+/-0.4 mg/kg body weight per day, on serum phosphorous, parathyroid hormone (PTH), 1,25 (OH)2 vitamin D, osteocalcin, tubular maximum for phosphate reabsorption (TmP/GFR), urinary calcium excretion, and cyclic adenosine 3',5'-monophosphate (cAMP) excretion, were compared to baseline levels. Our results show that there was no change in serum phosphorous concentration or TmP/GFR after 12 weeks of dipyridamole therapy. Dipyridamole therapy also had no effect on serum PTH, serum 1,25 (OH)2 vitamin D, alkaline phosphatase, osteocalcin levels, urinary calcium or cAMP excretion. We therefore concluded that in children with XLH, a 12-week course of dipyridamole had no effect on serum phosphorous or its urinary excretion. Dipyridamole therapy is unlikely to improve the bone disease in children with XLH.
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PMID:Effect of dipyridamole on serum and urinary phosphate in X-linked hypophosphatemia. 1109 12


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