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Pathophysiologic basis for X-linked hypophosphatemia (XLH)45). PHEX, Phosphate regulating gene with homologies to Endopeptidase, on the X chromosome; PTN, phosphatonin, PTNa, active PTN; PTNi, inactive phosphatonin; NPT2, type II Na+/Pi cotransporter.
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The serum phosphorus level is maintained through a complex interplay between intestinal absorption, exchange intracellular and bone storage pools, and renal tubular reabsorption. The kidney plays a major role in regulation of phosphorus homeostasis by renal tubular reabsorption. Type IIa and type IIc Na(+)/Pi transporters are important renal Na(+)-...
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Osteocytes remodel the perilacunar matrix and canaliculi. X-linked hypophosphatemia (XLH) is characterized by elevated serum levels of fibroblast growth factor 23 (FGF23), leading to decreased 1,25 dihydroxyvitamin D3 (1,25D) production and hypophosphatemia. Bones from mice with XLH (Hyp) have enlarged osteocyte lacunae, enhanced osteocyte expressi...
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by factor-induced dysregulation of phosphate and vitamin D metabolism resulting in alterations in bone formation, leading to bone pain and fractures. While the true incidence is likely underestimated, less than 500 cases of TIO have been reported since initial descript...
Vitamin D deficiency (hypovitaminosis D) causes osteomalacia and poor long bone mineralization. In apparent contrast, hypovitaminosis D has been reported in patients with primary brain calcifications (“Fahr’s disease”). We evaluated the expression of two phosphate transporters which we have found to be associated with primary brain calcification (S...
Vascular calcification (VC) is a critical complication in patients with chronic kidney disease (CKD). The effects of spironolactone (SPL), a mineralocorticoid receptor (MR) antagonist, on VC have not been fully investigated in CKD. The present in vivo study determined the protective effects of SPL on VC in CKD rats. Rats were divided into a control...
Phosphorus (usually as phosphate) is an essential nutrient used for enzyme activation and the synthesis of adenosine triphosphate and other biomolecules. Most phosphorus in the body is sequestered in mineralized bone tissue and teeth. Phosphate homeostasis is maintained by FGF23 derived from bones and the kidney-derived cofactor Klotho. FGF23 binds...
Citations
... Reduced concentration and active form of VD 3 might contribute to decreasing Ca absorption in gut and Ca reabsorption in kidney as a compensatory response to increased blood Ca concentration. PTH1R is involved in urinary excretion of phosphate in kidney [69]. The higher transcript of renal PTH1R in LB50 pigs is indicative of a greater excretion of phosphate in kidney in an effort to maintain the P homeostasis through reducing the increased plasma P levels. ...
Background
Very low-protein (VLP) diets negatively impact calcium (Ca) metabolism and absorption. The objective of this study was to investigate the effect of supplemental branched-chain amino acids (BCAA) and limiting amino acids (LAA) on Ca digestibility, absorption and reabsorption in pigs fed with VLP diets. Forty-eight piglets were assigned to six treatments: positive control (PC), negative control (NC), and NC containing LAA 25%, LAA 50%, LAA + BCAA 25% (LB25) and LAA + BCAA 50% (LB50) more than recommendations.
Results
Relative to PC or NC, LB25 and LB50 had higher digestibility of Ca and plasma Ca and phosphorus (P), but lower plasma vitamin D 3 . LB50 tended to increase vitamin D receptor transcript and protein in the gut, but decreased mRNA or protein abundance of parathyroid hormone 1 receptor (PTH1R), calbindin 1 (CALB1), cytochrome P450 family 27 subfamily B member 1 and occludin in small intestine. LB50 increased the transcript of cytochrome P450 family 24 subfamily A member 1 and PTH1R but decreased the transcript of transient receptor potential cation channel subfamily V member 5, CALB1 and solute carrier family 17 member 4 in kidney.
Conclusion
Overall, BCAA increased Ca digestibility through regulating the transcellular and paracellular Ca absorption in the gut and reabsorption in kidney during protein restriction.
... Calcium homeostasis is regulated by parathyroid hormone (PTH), calcitonin, the active form of vitamin D (1α,25-dihydroxyvitamin D (1,25(OH)2D3)), and serum calcium and phosphate levels. Regulation of phosphate metabolism is also important as phosphate is involved in protein and enzyme function, cell signaling, and skeletal mineralization and is a component of cell membranes and nucleic acids [2,3]. The main factors that regulate phosphate homeostasis are PTH, fibroblast growth factor 23 (FGF-23), 1,25(OH)2D3, and Klotho [3]. ...
... In addition to PTH, phosphate levels are mainly regulated by FGF-23, 1,25(OH)2D3, Klotho, and dietary phosphate [3,22,26,27], while calcitonin also affects phosphate levels [4,5]. PTH, FGF-23, and Klotho decrease serum phosphate levels (by inhibiting renal phosphate reabsorption), while 1,25(OH)2D3 increases serum phosphate levels (by increasing renal phosphate reabsorption, phosphate absorption from the intestine, and phosphate release from the bones) [2,22]. It has been suggested that FGF-23 acts in a negative feedback loop with PTH [28]; PTH stimulates FGF-23 production [28], while FGF-23 has been shown to inhibit PTH secretion indirectly (by increasing urinary phosphate excretion) and directly (by acting directly on parathyroid glands) [29]. ...
Abstract: Calciotropic hormones, parathyroid hormone (PTH) and calcitonin are involved in the regulation of bone mineral metabolism and maintenance of calcium and phosphate homeostasis in the body. Therefore, an understanding of environmental and genetic factors influencing PTH and calcitonin levels is crucial. Genetic factors are estimated to account for 60% of variations in PTH levels, while the genetic background of interindividual calcitonin variations has not yet been studied. In this review, we analyzed the literature discussing the influence of environmental factors
(lifestyle factors and pollutants) on PTH and calcitonin levels. Among lifestyle factors, smoking, body mass index (BMI), diet, alcohol, and exercise were analyzed; among pollutants, heavy metals and chemicals were analyzed. Lifestyle factors that showed the clearest association with PTH levels were smoking, BMI, exercise, and micronutrients taken from the diet (vitamin D and calcium). Smoking, vitamin D, and calcium intake led to a decrease in PTH levels, while higher BMI and exercise led to an increase in PTH levels. In terms of pollutants, exposure to cadmium led to a decrease in PTH levels, while exposure to lead increased PTH levels. Several studies have
investigated the effect of chemicals on PTH levels in humans. Compared to PTH studies, a smaller number of studies analyzed the influence of environmental factors on calcitonin levels, which gives
great variability in results. Only a few studies have analyzed the influence of pollutants on calcitonin levels in humans. The lifestyle factor with the clearest relationship with calcitonin was smoking (smokers had increased calcitonin levels). Given the importance of PTH and calcitonin in maintaining calcium and phosphate homeostasis and bone mineral metabolism, additional studies
on the influence of environmental factors that could affect PTH and calcitonin levels are crucial.
... This subnormal calcitriol value may be surprising at first glance, as no difference is detected for PTH values between the two groups, and thus is likely related to high serum phosphate [4][5][6][7][8] and high FGF23 concentrations in SCD patients [8,50,51], which would exert an inhibitory effect on calcitriol synthesis by the proximal tubule [49]. Moreover, hypophosphatemia is a frequent feature in pHPT, as PTH inhibits phosphate reabsorption by proximal tubules [52][53][54][55]. In our series, only 2 out of 12 pHPT SCD patients (17%) have hypophosphatemia versus 52 out of 91 pHPT (57%) renal stone patients. ...
Primary hyperparathyroidism (pHPT) has been reported to have a higher prevalence in sickle cell disease (SCD) patients, including a high rate of recurrence following surgery. However, most patients are asymptomatic at the time of diagnosis, with surprisingly infrequent hypercalciuria, raising the issue of renal calcium handling in SCD patients. We conducted a retrospective study including (1) 64 hypercalcemic pHPT non-SCD patients; (2) 177 SCD patients, divided into two groups of 12 hypercalcemic pHPT and 165 non-pHPT; (3) eight patients with a diagnosis of familial hypocalciuric hypercalcemia (FHH). Demographic and biological parameters at the time of diagnosis were collected and compared between the different groups. Determinants of fasting fractional excretion of calcium (FeCa2+) were also analyzed in non-pHPT SCD patients. Compared to non-SCD pHPT patients, our data show a similar ionized calcium and PTH concentration, with a lower plasmatic calcitriol concentration and a lower daily urinary calcium excretion in pHPT SCD patients (p < 0.0001 in both cases). Fasting FeCa2+ is also surprisingly low in pHPT SCD patients, and thus inadequate to be considered hypercalcemia, recalling the FHH phenotype. FeCa2+ is also low in the non-pHPT SCD control group, and negatively associated with PTH and hemolytic biomarkers such as LDH and low hemoglobin. Our data suggest that the pHPT biochemical phenotype in SCD patients resembles the FHH phenotype, and the fasting FeCa2+ association with chronic hemolysis biomarkers strengthens the view of a potential pharmacological link between hemolytic by-products and calcium reabsorption, potentially through a decreased calcium-sensing receptor (CaSR) activity.
... Circulating concentrations of phosphorus are regulated through altering reabsorption by the kidneys [2][3][4]. FGF23 acts in the kidney to downregulate the sodium-dependent phosphate transporters (NPT2a and NPT2c) to reduce phosphate reabsorption [5,6]. In parallel, FGF23 reduces the expression of the anabolic vitamin-D metabolizing enzyme 25-OH vitamin D 1α-hydroxylase and upregulates the catabolic 1,25-OH vitamin D 24-hydroxylase to lower circulating 1,25(OH) 2 vitamin D (1,25D) [7]. ...
Background
During aging, there is a normal and mild loss in kidney function that leads to abnormalities of the kidney-bone metabolic axis. In the setting of increased phosphorus intake, hyperphosphatemia can occur despite increased concentrations of the phosphaturic hormone FGF23. This is likely from decreased expression of the FGF23 co-receptor Klotho (KL) with age; however, the roles of age and sex in the homeostatic responses to mild phosphate challenges remain unclear.
Methods
Male and female 16-week and 78-week mice were placed on either normal grain-based chow or casein (higher bioavailable phosphate) diets for 8 weeks. Gene expression, serum biochemistries, micro-computed tomography, and skeletal mechanics were used to assess the impact of mild phosphate challenge on multiple organ systems. Cell culture of differentiated osteoblast/osteocytes was used to test mechanisms driving key outcomes.
Results
Aging female mice responded to phosphate challenge by significantly elevating serum intact FGF23 (iFGF23) versus control diet; males did not show this response. Male mice, regardless of age, exhibited higher kidney KL mRNA with similar phosphate levels across both sexes. However, males and females had similar blood phosphate, calcium, and creatinine levels irrespective of age, suggesting that female mice upregulated FGF23 to maintain blood phosphorus, and compromised renal function could not explain the increased serum iFGF23. The 17β-estradiol levels were not different between groups, and in vivo bone steroid receptor (estrogen receptor 1 [Esr1], estrogen receptor 2 [Esr2], androgen receptor [Ar]) expression was not different by age, sex, or diet. Trabecular bone volume was higher in males but decreased with both age and phosphate challenge in both sexes. Cortical porosity increased with age in males but not females. In vitro studies demonstrated that 17β-estradiol treatment upregulated FGF23 and Esr2 mRNAs in a dose-dependent manner.
Conclusions
Our study demonstrates that aging female mice upregulate FGF23 to a greater degree during a mild phosphate challenge to maintain blood phosphorus versus young female and young/old male mice, potentially due to direct estradiol effects on osteocytes. Thus, the control of phosphate intake during aging could have modifiable outcomes for FGF23-related phenotypes.
... Besides that, phosphorylation and dephosphorylation through the activities of numerous kinases, respectively phosphatases are important in regulating protein function, as well as in carbohydrate metabolism [1]. The kidney is a major regulator of phosphate homeostasis, normally 80e90% of filtered phosphorus is reabsorbed and the rest is excreted in the urine [2,3]. ...
Background & aims
Phosphate is the main intracellular anion essential for numerous biological processes. Symptoms of hypophosphatemia are non-specific, yet potentially life-threatening. This systematic review process was initiated to gain a global insight into hypophosphatemia, associated morbidity and treatments.
Methods
A systematic review was conducted (PROSPERO CRD42020163191). Nine clinically relevant questions were generated, seven for adult and two for pediatric critically ill patients, and prevalence of hypophosphatemia was assessed in both groups. We identified trials through systematic searches of Medline, EMBASE, Scopus, Cochrane Central Register of Controlled Trials, CINAHL, and Web of Science. Quality assessment was performed using the Cochrane risk of bias tool for randomized controlled trials and the Newcastle–Ottawa Scale for observational studies.
Results
For all research questions, we identified 2727 titles in total, assessed 399 full texts, and retained 82 full texts for evidence synthesis, with 20 of them identified for several research questions. Only 3 randomized controlled trials were identified with two of them published only in abstract form, as well as 28 prospective and 31 retrospective studies, and 20 case reports. Relevant risk of bias regarding selection and comparability was identified for most of the studies. No meta-analysis could be performed. The prevalence of hypophosphatemia varied substantially in critically ill adults and children, but no study assessed consecutive admissions to intensive care.
In both critically ill adults and children, several studies report that hypophosphatemia is associated with worse outcome (prolonged length of stay and the need for respiratory support, and higher mortality). However, there was insufficient evidence regarding the optimal threshold upon which hypophosphatemia becomes critical and requires treatment. We found no studies regarding the optimal frequency of phosphate measurements, and regarding the time window to correct hypophosphatemia. In adults, nutrient restriction on top of phosphate repletion in patients with refeeding syndrome may improve survival, although evidence is weak.
Conclusions
Evidence on the definition, outcome and treatment of clinically relevant hypophosphatemia in critically ill adults and children is scarce and does not allow answering clinically relevant questions. High quality clinical research is crucial for the development of respective guidelines.
... So far, the relation between dietary Ca absorption and serum Ca and FGF23 levels is poorly understood [90]. Before, serum FGF23 has been positively associated with dietary P availability [92,93], which was not the case in our study. Results from human hemodialysis patients, however, support a strong positive association between serum Ca and FGF23 [94], which needs further investigation in order to complete our current understanding with respect to the underlying physiological signaling. ...
High intestinal availability of dietary phosphorus (P) may impair calcium (Ca)homeostasis and bone integrity. In the present study, we investigated the effect of phytasesupplementation in comparison to the soaking of cereal grains in 2.5% lactic acid (LA) on intestinalCa and P absorption; intestinal, renal, and bone gene expression regarding Ca and P homeostasis;bone parameters; and serum levels of regulatory hormones in growing pigs. Thirty-two pigs wererandomly assigned to one of four diets in a 2 × 2 factorial design in four replicate batches for 19days. The diets comprised either untreated or LA-treated wheat and maize without and withphytase supplementation (500 phytase units/kg). Although both treatments improved the Pbalance, phytase and LA-treated cereals differently modulated gene expression related to intestinalabsorption, and renal and bone metabolism of Ca and P, thereby altering homeostatic regulatorymechanisms as indicated by serum Ca, P, vitamin D, and fibroblast growth factor 23 levels.Moreover, phytase increased the gene expression related to reabsorption of Ca in the kidney,whereas LA-treated cereals decreased the expression of genes for osteoclastogenesis in bones,indicating an unbalanced systemic availability of minerals. In conclusion, high intestinalavailability of dietary P may impair Ca homeostasis and bone integrity
... Несмотря на то что у большинства пациентов эти изменения не проявляются клинически, следует избегать применения данных препаратов у пациентов групп риска [56,[21][22][23]. В целом все гиперосмотически активные препараты следует с большой осторожностью использовать у пациентов с нарушением функции почек и почечной недостаточностью [52][53][54][55][56][57][58][59][60]. Сульфат магнезии ввиду его известного желчегонного действия нельзя использовать у больных с желчнокаменной болезнью [9]. ...
... ПТГ ингибирует активность натрийзависимых котранспортеров фосфатов NPt2a и NPt2c на апикальной поверхности клетки проксимального канальца почки [59]. Через этот механизм повышенные сывороточные уровни ПТГ снижают реабсорбцию фосфата в проксимальных канальцах почек [60]. ...
... The main cause of TIO is the overproduction of phosphaturic FGF-23, an important humoral hormone in the regulation of phosphate metabolism, by the tumor. [5][6][7] Locating these tumors is challenging because most of them are small and present in an insidious fashion. TIO is difficult to diagnose and is easily missed even after the initial onset of symptoms. ...
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome. We herein report a rare case of TIO in a 58-year-old Chinese man who presented with a large lump in the right palm. Clinical, biochemical, and radiological assessments were performed. Laboratory examination showed severe hypophosphatemia, phosphaturia, an elevated serum alkaline phosphatase level, and an elevated serum fibroblast growth factor 23 (FGF-23) level. Dual-energy X-ray absorptiometry showed low bone mineral density. Magnetic resonance imaging revealed an irregular mass located in the right palm and abnormal findings in several metacarpal bones. During the operation, the surgeons found that the tumor had penetrated the surrounding muscles. The tumor had unique characteristics of local tissue invasion. The patient’s symptoms fully resolved and his serum phosphorus level normalized, although his serum FGF-23 level remained slightly high in the postoperative phase. Our findings suggest that in some patients with TIO, the serum phosphorus level might return to the normal range despite a relatively high postoperative serum FGF-23 level. These patients should be kept under close observation and regularly surveyed for any evidence of a residual tumor.
... Tip IIa ve tip IIc Na taşıyıcıları, proksimal tübüler hücrelerin fırça sınır membranında ifade edilen önemli renal Na bağımlı inorganik fosfat taşıyıcılardır. Her ikisi de diyet ile inorganik fosfat alımı, D vitamini, fibroblast büyüme faktörü 23 (FGF23) ve paratiroid hormonu (PTH) tarafından düzenlenir (2) . ...
... Type IIa and type IIc Na transporters are important renal Na dependent inorganic phosphate transporters, which are expressed in the brush border membrane of proximal tubular cells. Both are regulated by dietary inorganic phosphate intake, vitamin D, fibroblast growth factor 23 (FGF23) and parathyroid hormone (2) . ...
... By binding to its receptors on renal epithelial which interact with the Na + /H + Exchanger Regulatory Factor (NHERF1,) [32] PTH inhibits activity of the NPt2a and the NPt2c sodiumphosphate cotransporters on the brush border of the apical side of the proximal tubular cell in the kidney [12]. Through this mechanism, elevated serum levels of PTH reduce reabsorption of phosphate in the proximal tubule (▶ Fig. 1) [33]. Finally, these effects are amplified by the high serum phosphate concentrations on the basolateral side of the tubular epithelium, which decreases the trans-epithelial phosphate gradient that drives transporter activity [34]. ...
Background and study aims Colonoscopy is a widely used diagnostic procedure which requires prior cleansing of the bowel. Many different bowel cleansing preparations have been developed, all of which have specific advantages and disadvantages. This review compares two low-volume high-osmolarity bowel cleansing preparations, oral phosphate salts and oral sulphate salts, with a particular focus on risk of nephrotoxicity.
Patients and methods An electronic search of the Medline database was performed using the search terms “(phosphates OR sulfates) AND cathartics [MeSH Term] AND kidney” restricted to humans with a cut-off date of December 31, 2016.
Results Introduction of oral phosphate salts offered the advantage of low intake volume and low risk of bowel irritation compared to previous options. However, phosphate salts have been associated with renal toxicity (acute phosphate nephropathy [APN]), thought to arise due to perturbations of calcium and phosphate homeostasis as a consequence of increases in serum phosphate. This results in high concentrations of calcium phosphate in the distal tubule and collecting ducts of the kidney, where it may precipitate. Although APN is rare, it may lead to permanent kidney damage. For this reason, phosphate salts are contraindicated in vulnerable patient groups. As an alternative to phosphate salts, oral sulphate salts have recently been introduced. Because sulphate absorption from the intestinal tract is saturable, serum sulphate concentrations increase only minimally after ingestion. Furthermore, excretion of sulphate in the kidney is not accompanied by calcium excretion and urine calcium levels are unchanged. For these theoretical reasons, use of sulphate salts as bowel cleansing solutions is not expected to lead to calcium precipitation in the nephron.
Conclusions Oral phosphate salts are no longer recommended for routine use as bowel cleansing preparations as they carry significant risk of kidney damage and a safer alternative is available in the form of oral sulphate solutions. To date, use of sulphate salts has not been associated with elevations in serum creatinine or other markers of renal impairment, nor with clinical manifestations of kidney injury. Nonetheless, experience with sulphate salts in everyday practice is limited and physicians should be vigilant in detecting potential safety issues.
