Initiation and severity of experimental pancreatitis are modified by phosphate.

Proper mitochondrial function and adequate cellular ATP are necessary for normal pancreatic protein synthesis and sorting, maintenance of intracellular organelles and enzyme secretion. Inorganic phosphate is required for generating ATP and its limited availability may lead to reduced ATP production causing impaired Ca2+ handling, defective autophagy, zymogen activation, and necrosis, which are all features of acute pancreatitis. We hypothesized that reduced dietary phosphate leads to hypophosphatemia and exacerbates pancreatitis severity of multiple causes. We observed that mice fed a low-phosphate diet before the induction of pancreatitis by either repeated caerulein administration or pancreatic duct injection as a model of pressure-induced pancreatitis developed hypophosphatemia and exhibited more severe pancreatitis than normophosphatemic mice. Pancreatitis severity was significantly reduced in mice treated with phosphate. In vitro modeling of secretagogue- and pressure-induced pancreatic injury was evaluated in isolated pancreatic acini using cholecystokinin and the mechanoreceptor Piezo1 agonist, Yoda1, under low and normal phosphate conditions. Isolated pancreatic acini were more sensitive to cholecystokinin- and Yoda1-induced acinar cell damage and mitochondrial dysfunction under low-phosphate conditions and improved following phosphate supplementation. Importantly, even mice on a normal phosphate diet exhibited less severe pancreatitis when treated with supplemental phosphate. Thus, hypophosphatemia sensitizes animals to pancreatitis and phosphate supplementation reduces pancreatitis severity. These appear to be direct effects of phosphate on acinar cells through restoration of mitochondrial function. We propose that phosphate administration may be useful in the treatment of acute pancreatitis.NEW & NOTEWORTHY Impaired ATP synthesis disrupts acinar cell homeostasis and is an early step in pancreatitis. We report that reduced phosphate availability impairs mitochondrial function and worsens pancreatic injury. Phosphate supplementation improves mitochondrial function and protects against experimental pancreatitis, raising the possibility that phosphate supplementation may be useful in treating pancreatitis.

The Role of Phosphate in Alcohol-Induced Experimental Pancreatitis.

BACKGROUND & AIMS: Heavy alcohol consumption is a common cause of acute pancreatitis; however, alcohol abuse does not always result in clinical pancreatitis. As a consequence, the factors responsible for alcohol-induced pancreatitis are not well understood. In experimental animals, it has been difficult to produce pancreatitis with alcohol. Clinically, alcohol use predisposes to hypophosphatemia, and hypophosphatemia has been observed in some patients with acute pancreatitis. Because of abundant protein synthesis, the pancreas has high metabolic demands, and reduced mitochondrial function leads to organelle dysfunction and pancreatitis. We proposed, therefore, that phosphate deficiency might limit adenosine triphosphate synthesis and thereby contribute to alcohol-induced pancreatitis. METHODS: Mice were fed a low-phosphate diet (LPD) before orogastric administration of ethanol. Direct effects of phosphate and ethanol were evaluated in vitro in isolated mouse pancreatic acini. RESULTS: LPD reduced serum phosphate levels. Intragastric administration of ethanol to animals maintained on an LPD caused severe pancreatitis that was ameliorated by phosphate repletion. In pancreatic acinar cells, low-phosphate conditions increased susceptibility to ethanol-induced cellular dysfunction through decreased bioenergetic stores, specifically affecting total cellular adenosine triphosphate and mitochondrial function. Phosphate supplementation prevented ethanol-associated cellular injury. CONCLUSIONS: Phosphate status plays a critical role in predisposition to and protection from alcohol-induced acinar cell dysfunction and the development of acute alcohol-induced pancreatitis. This finding may explain why pancreatitis develops in only some individuals with heavy alcohol use and suggests a potential novel therapeutic approach to pancreatitis. Finally, an LPD plus ethanol provides a new model for studying alcohol-associated pancreatic injury.

Study on the morphological and metabolic changes of femur in laying hens with hypophosphatemia.

Layer fatigue syndrome caused by the lack of calcium and phosphorus can cause fracture in laying hens. The effect of phosphorus deficiency on the femur of laying hens with layer fatigue syndrome has not been studied. In this study, sixty 22-week-old Roman white layers were randomly divided into control group (group C) and low phosphorus group (group P), 30 individuals in each group. The available phosphorus content of group P was 0.18%. At the age of 26, 30 and 34 weeks, the production performance, biomechanical index, protein expression, histopathological change of femur and serological index were detected. The results showed that the laying rate, egg quality and body weight of laying hens, bone density, cortical bone thickness, rigidity, flexural modulus, flexural rigidity, the maximum load of femur and expression of osteocalcin (OCN), receptor activator of nuclear factor kappa-Β (RANK) and receptor activator of nuclear factor kappa-Β ligand (RANKL) decreased of group P. The number of osteocytes was decreased, and the voids was increased. However, cell lacunae were not obvious. The levels of phosphorus, calcium and OCN were increased, and the content of estradiol (E2), OPG and calcitonin (CT) were decreased in serum. In conclusion, the low phosphorus diet can induce layer fatigue syndrome and affect the content of OPG and E2 in serum and the expression of OCN, OPG, RANK and RANKL in femur protein, which leads to the imbalance of bone homeostasis, the thinning of femur cortex bone and the decrease of bone density.

Hypophosphatemic Hypovitaminosis D Induces Osteomalacia in the Adult Female Rat.

Osteomalacia is a bone-demineralizing disease of adulthood, often caused by hypovitaminosis D. Current animal models of the disease mimic osteomalacia as a consequence of gastric bypass or toxic exposure to metals, but a relevant model of diet-induced osteomalacia is lacking. For that purpose, 7-month-old female Sprague Dawley rats were randomly assigned into 2 weight-stratified groups and maintained for 4 months on synthetic diets containing negligible or normal levels of vitamin D. The dietary regimen resulted in vitamin D deficiency as measured by 25-hydroxyvitamin D serum levels; however, hypovitaminosis D per se did not affect biomarkers of calcium metabolism and bone turnover, nor did it result in increased osteoid. Thus, vitamin D depletion through the diet was found to be insufficient to induce an osteomalacia-like phenotype in the adult rat. After 4 months, the phosphate content of the vitamin D-depleted diet had decreased to 0.16% (calcium:phosphorus ratio of 5.85), resulting in an osteomalacic-like condition (trabecular osteoid surface/bone surface constituted 33%; CI, 26-40). The diet change also affected both metabolic and bone turnover biomarkers, including significantly suppressing serum fibroblast growth factor 23. Furthermore, decreased dietary phosphate in a vitamin D-depleted diet led to microarchitectural changes of trabecular and cortical bone, lower bone mass density, lower bone mass content and decreased bone strength, all indicating reduced bone quality. Taken together, our results show that osteomalacia can be induced in the adult female rat by depleting vitamin D and lowering phosphate content in the diet.

Increased risk of refeeding syndrome-like hypophosphatemia with high initial amino acid intake in small-for-gestational-age, extremely-low-birthweight infants.

BACKGROUND: Recent nutrition guidelines for extremely-low-birth-weight infants (ELBWIs) recommend implementation of high initial amino acid (AA) supplementation in parenteral nutrition. OBJECTIVE: We sought to evaluate the influence of AA intake on refeeding syndrome-like electrolyte disturbances including hypophosphatemia in ELBWIs. STUDY DESIGN: Medical records of 142 ELBWIs were reviewed. Demographic, nutritional, outcome, and electrolyte data were compared between ELBWIs with initial low (1.5 g/kg/day) and high (3 g/kg/day) AA intake. Multivariate analysis was conducted to determine the odds ratio of hypophosphatemia with high AA intake and small-for-gestational-age (SGA) ELBWIs. RESULTS: The incidence of hypophosphatemia and severe hypophosphatemia increased from 51% and 8% in period I to 59% and 20% in period II, respectively (p = 0.36 and < 0.01). Specifically, SGA ELBWIs showed higher incidence of hypophosphatemia than appropriate-for-gestational age (AGA) ELBWIs in period II, whereas there was no difference in period I. For severe hypophosphatemia, SGA ELBWIs presented a 27% incidence versus a 2% incidence in AGA ELBWIs, even with low initial AA intake. Despite no difference in phosphate intake between infants with and without hypophosphatemia, serum phosphate level reached a nadir at the sixth postnatal day and gradually recovered over the second week in infants with hypophosphatemia. In multivariate analyses, the odds ratios for severe hypophosphatemia were 3.6 and 6.6 with high AA intake and SGA status, respectively, with the highest being 18.0 with combined high AA intake and SGA status. CONCLUSIONS: In summary, high initial AA intake significantly increased the risk of refeeding syndrome-like electrolyte dysregulations including severe hypophosphatemia in ELBWIs. In SGA ELBWIs, the risk of electrolyte disturbance was significantly higher, even with low initial AA intake. Therefore, new tailored parenteral nutrition protocols starting with lower energy intake and a gradual increase over the first week may be warranted for application in high-risk SGA ELBWIs.

Bone metabolism markers and hungry bone syndrome after parathyroidectomy in dialysis patients with secondary hyperparathyroidism.

OBJECTIVE: To explore the short-term variation in bone metabolic markers and the characteristics of hungry bone syndrome (HBS) after parathyroidectomy (PTX) with forearm autotransplantation in uremic patients with secondary hyperparathyroidism (SHPT) and to provide a basis for the pathogenesis, diagnosis and treatment of metabolic bone disease in SHPT. METHODS: A total of 115 patients with SHPT receiving PTX from July 2015 to December 2017, hospitalized at the First Affiliated Hospital of Nanjing Medical University, were enrolled in our study. We retrospectively analyzed the baseline clinical data, the levels of bone metabolism markers before and on the third day after PTX, and the risk factors predicting HBS. RESULTS: Preoperative baseline data showed that the levels of bone metabolic markers such as bone metabolism-regulating hormones: iPTH, calcitonin (CT); bone formation markers: phosphatase (ALP), osteocalcin (OC); bone resorption markers: type I collagen cross-linked N-telopeptides (NTX), type I collagen cross-linked C-telopeptides (CTX), tartrate-resistant acid phosphatase 5b (TRAP-5b) were all increased compared to normal levels. The levels of postoperative serum iPTH, CT, CTX and TRAP-5b decreased significantly compared to preoperative levels, while the levels of OC and ALP increased significantly. Of the 115 patients, 101 (87.8%) developed HBS after PTX. High preoperative serum ALP and low preoperative serum calcium level independently predicted the occurrence of HBS. Younger preoperative age, high preoperative serum ALP and iPTH level independently predicted the severity of HBS. CONCLUSIONS: In severe SHPT, both bone formation and resorption were active, which suggested the presence of high-turnover bone diseases characterized by up-regulation of osteoclasts-osteoblasts functionally coupling activation in the patients. PTX could promote osteoblast activity and reduce osteoclast activity. HBS was common after PTX. Preoperative higher serum ALP and lower calcium were independent predictors of the occurrence of HBS. Younger patients with higher preoperative ALP and PTH may need to closely monitor serum calcium levels and intensive calcium supplementation after PTX.

Reliability of calcium-phosphorus (Ca/P) ratio as a new, accurate and inexpensive tool in the diagnosis of some Ca-P disorders.

PURPOSE: The serum calcium/phosphorus (Ca/P) ratio is an accurate tool to differentiate patients with primary hyperparathyroidism (PHPT) from healthy subjects. However, other disorders of the Ca-P metabolism might impair the Ca/P ratio, such as hypophosphatemia (HypoP) not PHPT related. The aim of this study is to examine the diagnostic value of Ca/P ratio in the diagnosis of PHPT and HypoP not PHPT related. METHODS: Single-center, retrospective, case-control study, including 150 patients with PHPT and 306 patients with HypoP, compared with 150 controls. HypoP patients were enrolled among HIV-infected patients by selecting those with Fanconi-like syndrome due to antiretroviral treatment. Parameters which were measured were serum Ca, P, parathyroid hormone (PTH), 25-OH vitamin D, albumin and creatinine). RESULTS: The Ca/P ratio was significantly higher in PHPT and HypoP patients, compared to controls (p < 0.0001). At receiver operator characteristic (ROC) curve analysis, the cut-off of 3.56 (2.75 SI) for Ca/P ratio was able to identify patients with PHPT and HypoP (sensitivity 95%; specificity 93%). Among patients with Ca/P ratio above 3.56, the thresholds of 10.3 mg/dL (2.6 mmol/L) for serum Ca (sensitivity 93%; specificity 98%) and 80.5 pg/mL for PTH (sensitivity 91%; specificity 91%) were defined for the specific diagnosis of PHPT. CONCLUSIONS: The Ca/P ratio above 3.56 (2.75 SI) is a highly accurate tool to identify PHPT and HypoP not PHPT-related patients. Thanks to its simplicity, this index can be proposed as a screening and first-line examination in the diagnostic work-up when a disorder of Ca-P metabolism is suspected or should be ruled out.

Glucosuria without diabetes: key to the diagnosis of fragility fractures due to Fanconi syndrome.

A 64-year-old woman had fragility fractures which caused her to have gross deformities and confined her to bed. These were initially ascribed to vitamin D deficiency. However, despite correction of the deficiency, she did not improve. A review of previous records already showed glucosuria in the absence of diabetes, but this finding was overlooked. Eight years into the disease, it was realised that the glucosuria despite normal blood sugar could also mean that the patient was losing other substances needed for proper bone formation. Further investigations showed hypophosphataemia, renal phosphate wasting, hypokalaemia, mild metabolic acidosis, alkaline urine pH, hypouricaemia and aminoaciduria, all compatible with a proximal renal tubular defect (Fanconi syndrome). The fragility fractures were due to poor bone mineralisation because of hypophosphataemia induced by the inability of the kidneys to conserve phosphorus.

[Hypophosphatemia in preterm infants: a bimodal disorder]. / Hipofosfemia en recién nacidos prematuros: un trastorno bimodal.

New nutritional approaches to treat extreme premature babies have demonstrated relevant eviden ce of metabolic disturbances with early hypophosphatemia, especially in patients with intrauterine growth restriction (IUGR). They have shown late hypophosphatemia, as well, which is characteristic in the metabolic bone disease. A sytematic search of literature describing metabolic disturbances of phosphorus in preterm newborns is presented, related to the use of early parenteral nutrition and also in the context of metabolic bone disease. The articles were gathered from electronic data bases, such as PubMed and Rima. We include articles in english and spanish which were selected by titles and abstracts. Several strategies for early nutrition have been proposed in order to ensure an adequate amount of nutrients to accomplish the development and growth of preterm babies. Patients with parenteral nutrition support with different doses of phosphate, or inadequate calcium phosphate relation, or an increased amino acid content, may present hypophosphatemia, hypercalcemia, hy pomagnesemia, hypokalemia and hyperglycemia, all of these are additionally noteworthy in the pre sence of intrauterine growth restriction. Furthermore, said alterations are associated with prolonged mechanical ventilation, as well as bronchopulmonary dysplasia and increase in late onset sepsis. The late hypophosphatemia, described several years ago, arises as normocalcemia and as an increment of alkaline phosphatases in the metabolic bone disease in preterm babies, and also with an inadequate mineralization in different grades, secondary to an inadequate supply due to high nutritional requi rements in these patients. When early or late hypophosphatemia appears in preterm babies, it shall require timely control of phosphemia and will need to adjust the nutritional intake in order to correct it. In case of preterm babies with early parenteral nutrition it will also need a control of calcemia in the first week of birth, especially if those belonging to the IUGR group. Adjustment must be made along with metabolic follow up, as well. In late hypophosphatemia, a weekly or every two weeks fo llow up will be a must for all preterm babies in risk and they should be given supplements to get an optimum mineral supply.

Suitability of oral administration of monosodium phosphate, disodium phosphate, and magnesium phosphate for the rapid correction of hypophosphatemia in cattle.

BACKGROUND: Hypophosphatemia is commonly associated with disease and decreased productivity in dairy cows particularly in early lactation. Oral supplementation with phosphate salts is recognized as suitable for the rapid correction of hypophosphatemia. Little information is available about the differences in efficacy between salts used for oral phosphorus supplementation. OBJECTIVES: Comparison of efficacy of oral administration of NaH2 PO4 , Na2 HPO4 , and MgHPO4 in treating hypophosphatemia in cattle. ANIMALS: 12 healthy dairy cows in the fourth week of lactation in their second to fifth lactation. METHODS: Randomized clinical study. Phosphorus deficient, hypophosphatemic cows underwent a sham treatment and were afterwards assigned to 1 of 3 treatments-NaH2 PO4 , Na2 HPO4 , or MgHPO4 (each provided the equivalent of 60 g of phosphorus). Blood samples were obtained immediately before and repeatedly after treatment. RESULTS: Treatment with NaH2 PO4 and Na2 HPO4 resulted in rapid and sustained increases of plasma phosphate concentrations ([Pi]). Significant effects were apparent within 1 hour (NaH2 PO4 : P = .0044; Na2 HPO4 : P = .0077). Peak increments of plasma [Pi] of 5.33 mg/dL [5.26-5.36] and 4.30 mg/dL [3.59-4.68] (median and interquartile range) were reached after 7 and 6 hours in animals treated with NaPH2 PO4 and Na2 HPO4 , respectively, whereas treatment with MgHPO4 led to peak increments 14 hours after treatment (3.19 mg/dL [2.11-4.04]). CONCLUSIONS AND CLINICAL IMPORTANCE: NaH2 PO4 and Na2 HPO4 are suitable to rapidly correct hypophosphatemia in cattle. Because of the protracted and weaker effect, MgHPO4 cannot be recommended for this purpose. Despite important differences in solubility of NaH2 PO4 and Na2 HPO4 only small plasma [Pi] differences were observed after treatment.

Hipofosfemia en recién nacidos prematuros: un trastorno bimodal / Hypophosphatemia in preterm infants: a bimodal disorder

Las estrategias nutricionales para prematuros extremos con alto aporte de proteínas, han mostrado alteraciones metabólicas con hipofosfemia precoz, especialmente en el grupo de pacientes con restricción de crecimiento intrauterino (Rein). También se presenta hipofosfemia tardía, característica de la enfermedad metabólica ósea. En este artículo se revisan y actualizan conceptos en relación a la fisiopatología del metabolismo del fósforo en recién nacidos prematuros y uso de parenterales precoces en el contexto de enfermedad metabólica ósea. Los artículos fueron identificados en base de datos electrónicas como Pubmed y Rima. Fueron incluidos artículos en inglés y español. Fueron filtrados por título y resumen. La literatura actual propone diversas estrategias de nutrición precoz que permitan asegurar una adecuada cantidad de nutrientes para continuar con el crecimiento y desarrollo extrauterino. En pacientes con nutrición parenteral pero con diferentes aportes de fósforo, o relación calcio: fósforo inadecuada, a mayor contenido de aminoácidos, se presenta hipofosfemia, hipercalcemia, hipomagnesemia, hipokalemia e hiperglicemia, especialmente en casos de Rein. Estas alteraciones se asocian a prolongación de ventilación mecánica, mayor riesgo de displasia broncopulmonar y aumento de sepsis tardía. La hipofosfemia tardía, descrita ya hace muchos años, se presenta con normocalcemia y aumento de fosfatasas alcalinas, en la enfermedad metabólica ósea del prematuro, con alteración de la mineralización en distintos grados, secundaria a un inadecuado aporte de este mineral para los altos requerimientos de estos pacientes. Esta presentación de hipofosfemia precoz y tardía en el prematuro alerta sobre el control oportuno de fosfemia para ajustar el aporte nutricional. En el prematuro con nutrición parenteral precoz, el control en conjunto con la calcemia en la primera semana de vida, especialmente en Rein, permite tratar la hipofosfemia y prevenir sus complicaciones. En hipofosfemia tardía, el seguimiento semanal o quincenal desde las 4 semanas a los prematuros con riesgo, permite lograr un aporte óptimo de minerales.

New nutritional approaches to treat extreme premature babies have demonstrated relevant eviden ce of metabolic disturbances with early hypophosphatemia, especially in patients with intrauterine growth restriction (IUGR). They have shown late hypophosphatemia, as well, which is characteristic in the metabolic bone disease. A sytematic search of literature describing metabolic disturbances of phosphorus in preterm newborns is presented, related to the use of early parenteral nutrition and also in the context of metabolic bone disease. The articles were gathered from electronic data bases, such as PubMed and Rima. We include articles in english and spanish which were selected by titles and abstracts. Several strategies for early nutrition have been proposed in order to ensure an adequate amount of nutrients to accomplish the development and growth of preterm babies. Patients with parenteral nutrition support with different doses of phosphate, or inadequate calcium phosphate relation, or an increased amino acid content, may present hypophosphatemia, hypercalcemia, hy pomagnesemia, hypokalemia and hyperglycemia, all of these are additionally noteworthy in the pre sence of intrauterine growth restriction. Furthermore, said alterations are associated with prolonged mechanical ventilation, as well as bronchopulmonary dysplasia and increase in late onset sepsis. The late hypophosphatemia, described several years ago, arises as normocalcemia and as an increment of alkaline phosphatases in the metabolic bone disease in preterm babies, and also with an inadequate mineralization in different grades, secondary to an inadequate supply due to high nutritional requi rements in these patients. When early or late hypophosphatemia appears in preterm babies, it shall require timely control of phosphemia and will need to adjust the nutritional intake in order to correct it. In case of preterm babies with early parenteral nutrition it will also need a control of calcemia in the first week of birth, especially if those belonging to the IUGR group. Adjustment must be made along with metabolic follow up, as well. In late hypophosphatemia, a weekly or every two weeks fo llow up will be a must for all preterm babies in risk and they should be given supplements to get an optimum mineral supply.

Mesenchymal phosphaturic tumour: early detection of recurrence.

The case of a recurrent phosphaturic mesenchymal tumour of the maxillary sinus 10 years after the first surgical excision is reported. The neoplasm first presented with paraneoplastic osteomalacia causing a pathological femur fracture. A right maxillary sinus tumour was identified and treated thereafter. The patient had no local symptoms and serum electrolytes returned to normal after surgical removal of the tumour. However, 10 years later, the patient's urine Ca and P levels increased and an octreoscan detected a new tumour in the right maxillary sinus. Early diagnosis prevented the effects of the paraneoplastic activity of the neoplasm. This case emphasises the importance of specific, close follow-up, because the neoplasm rarely produces local signs indicating its position. To our knowledge, this is the first reported case of a late relapse presenting without relevant symptoms (local pain or swelling or pathological fractures).

The human response to acute enteral and parenteral phosphate loads.

The human response to acute phosphate (PO4) loading is poorly characterized, and it is unknown whether an intestinal phosphate sensor mechanism exists. Here, we characterized the human mineral and endocrine response to parenteral and duodenal acute phosphate loads. Healthy human participants underwent 36 hours of intravenous (IV; 1.15 [low dose] and 2.30 [high dose] mmol of PO4/kg per 24 hours) or duodenal (1.53 mmol of PO4/kg per 24 hours) neutral sodium PO4 loading. Control experiments used equimolar NaCl loads. Maximum PO4 urinary excretory responses occurred between 12 and 24 hours and were similar for low-dose IV and duodenal infusion. Hyperphosphatemic responses were also temporally and quantitatively similar for low-dose IV and duodenal PO4 infusion. Fractional renal PO4 clearance increased approximately 6-fold (high-dose IV group) and 4-fold (low-dose IV and duodenal groups), and significant reductions in plasma PO4 concentrations relative to peak values occurred by 36 hours, despite persistent PO4 loading. After cessation of loading, frank hypophosphatemia occurred. The earliest phosphaturic response occurred after plasma PO4 and parathyroid hormone concentrations increased. Plasma fibroblast growth factor-23 concentration increased after the onset of phosphaturia, followed by a decrease in plasma 1,25(OH)2D levels; α-Klotho levels did not change. Contrary to results in rodents, we found no evidence for intestinal-specific phosphaturic control mechanisms in humans. Complete urinary phosphate recovery in the IV loading groups provides evidence against any important extrarenal response to acute PO4 loads.

Hypophosphatemia as a prognostic value in acute exacerbation of COPD.

BACKGROUND: Phosphorus (P) is an essential element in all living cells, it is extremely important in the process of production of adenosine triphosphate, main element in the structure of nucleic acids. Low levels of phosphorus in blood is very rare, however, it may be caused by unbalance between components participating in phosphorus cycle and affect performances of several systems. A low level of phosphorus in the blood increases the exacerbation and the severity of chronic obstructive pulmonary disease (COPD) and requires prolonged ventilation process. AIM: This study aims to examine the prognostic effects of hypophosphatemia in COPD patients and evaluate the correlation between phosphorus levels and severity, recurrences of attacks, ventilation duration and successful of weaning process. METHODS: Two hundred and fifty-five patients who were admitted because of worsening in COPD, from October 2010-April 2011, were examined. A comparison was made between the group with normal blood phosphorus (2.5-4.5 mg%), group of patients with low phosphorus (2-2.5 mg%) and group with very low phosphorous values (<2.0 mg%). RESULTS: Ninety-five per cent of all admissions had normal blood phosphorus levels, 3.3% had low phosphorus levels, and only 1.7% of all admissions had very low phosphorus levels. 2.4% of patients had both low levels of phosphorus and potassium. All patients (100%) with very low phosphorus needed mechanical ventilation, compared to 62.5% of patients with low phosphorus and 16.9% of patients with normal phosphorus levels. In addition, 16 ventilated patients (33% of all ventilated patients) had low potassium values. SUMMARY: Low blood phosphorus levels contribute to an increase in: COPD flare-up, need for ventilation, duration of hospitalisation, days in intensive care units and finally increased rate of mortality. Accordingly, close monitoring and careful adjustment of disorders correlated to electrolyte such as phosphorus, are crucial and may improve prognosis and also increase the survival rate of patients with COPD.

Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice.

In the present study, we evaluated the roles of type II and type III sodium-dependent P(i) cotransporters in fibroblast growth factor 23 (FGF23) activity by administering a vector encoding FGF23 with the R179Q mutation (FGF23M) to wild-type (WT) mice, Npt2a knockout (KO) mice, Npt2c KO mice, and Npt2a(-/-)Npt2c(-/-) mice (DKO mice). In Npt2a KO mice, FGF23M induced severe hypophosphatemia and markedly decreased the levels of Npt2c, type III Na-dependent P(i) transporter (PiT2) protein, and renal Na/P(i) transport activity. In contrast, in Npt2c KO mice, FGF23M decreased plasma phosphate levels comparable to those in FGF23M-injected WT mice. In DKO mice with severe hypophosphatemia, FGF23M administration did not induce an additional increase in urinary phosphate excretion. FGF23 administration significantly decreased intestinal Npt2b protein levels in WT mice but had no effect in Npt2a, Npt2c, and DKO mice, despite marked suppression of plasma 1,25(OH)(2)D(3) levels in all the mutant mice. The main findings were as follow: 1) FGF23-dependent phosphaturic activity in Npt2a KO mice is dependent on renal Npt2c and PiT-2 protein; 2) in DKO mice, renal P(i) reabsorption is not further decreased by FGF23M, but renal vitamin D synthesis is suppressed; and 3) downregulation of intestinal Npt2b may be mediated by a factor(s) other than 1,25(OH)(2)D(3). These findings suggest that Npt2a, Npt2c, and PiT-2 are necessary for the phosphaturic activity of FGF23. Thus complementary regulation of Npt2 family proteins may be involved in systemic P(i) homeostasis.

Calcium metabolism in health and disease.

This brief review focuses on calcium balance and homeostasis and their relationship to dietary calcium intake and calcium supplementation in healthy subjects and patients with chronic kidney disease and mineral bone disorders (CKD-MBD). Calcium balance refers to the state of the calcium body stores, primarily in bone, which are largely a function of dietary intake, intestinal absorption, renal excretion, and bone remodeling. Bone calcium balance can be positive, neutral, or negative, depending on a number of factors, including growth, aging, and acquired or inherited disorders. Calcium homeostasis refers to the hormonal regulation of serum ionized calcium by parathyroid hormone, 1,25-dihydroxyvitamin D, and serum ionized calcium itself, which together regulate calcium transport at the gut, kidney, and bone. Hypercalcemia and hypocalcemia indicate serious disruption of calcium homeostasis but do not reflect calcium balance on their own. Calcium balance studies have determined the dietary and supplemental calcium requirements needed to optimize bone mass in healthy subjects. However, similar studies are needed in CKD-MBD, which disrupts both calcium balance and homeostasis, because these data in healthy subjects may not be generalizable to this patient group. Importantly, increasing evidence suggests that calcium supplementation may enhance soft tissue calcification and cardiovascular disease in CKD-MBD. Further research is needed to elucidate the risks and mechanisms of soft tissue calcification with calcium supplementation in both healthy subjects and CKD-MBD patients.

Presence of a deletion mutation (c.716delA) in the ligand binding domain of the vitamin D receptor in an Indian patient with vitamin D-dependent rickets type II.

Vitamin D-dependent rickets type II (VDDR-type II) is a rare disorder caused by mutations in the vitamin D receptor (VDR) gene. Here, we describe a patient with VDDR-type II with severe alopecia and rickets. She had hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and elevated serum alkaline phosphatase and 1,25-dihydroxyvitamin D(3). Sequence analysis of the lymphocyte VDR cDNA revealed deletion mutation c.716delA. Sequence analysis of her genomic DNA fragment amplified from exon 6 of the VDR gene incorporating this mutation confirmed the presence of the mutation in homozygous form. This frameshift mutation in the ligand binding domain (LBD) resulted in premature termination (p.Lys240Argfs) of the VDR protein. The mutant protein contained 246 amino acids, with 239 normal amino acids at the N terminus, followed by seven changed amino acids resulting in complete loss of its LBD. The mutant VDR protein showed evidence of 50% reduced binding with VDR response elements on electrophoretic mobility assay in comparison to the wild-type VDR protein. She was treated with high-dose calcium infusion and oral phosphate. After 18 months of treatment, she gained 6 cm of height, serum calcium and phosphorus improved, alkaline phosphatase levels decreased, and intact PTH normalized. Radiologically, there were signs of healing of rickets. Her parents and one of her siblings had the same c.716delA mutation in heterozygous form. Despite the complete absence of LBD, the rickets showed signs of healing with intravenous calcium.

Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/NaPi-IIc can be masked by vitamin D deficiency and can be associated with renal calcifications.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by mutations in SLC34A3, the gene encoding the renal sodium-phosphate co-transporter NaPi-IIc. Despite increased urinary calcium excretion, HHRH is typically not associated with kidney stones prior to treatment. However, here we describe two sisters, who displayed nephrolithiasis or nephrocalcinosis upon presentation. The index patient, II-4, presented with short stature, bone pain, and knee X-rays suggestive of mild rickets at age 8.5 years. Laboratory evaluation showed hypophosphatemia, elevated 1,25(OH) (2) vitamin D levels, and hypercalciuria, later also developing vitamin D deficiency. Her sister, II-6, had a low normal serum phosphorous level, biochemically vitamin D deficiency and no evidence for osteomalacia, but had undergone left nephro-ureterectomy at age 17 because of ureteral stricture secondary to renal calculi. Nucleotide sequence analysis of DNA from II-4 and II-6 revealed a homozygous missense mutation c.586G>A (p.G196R) in SLC34A3/NaPi-IIc. Ultrasonographic examinations prior to treatment showed grade I nephrocalcinosis for II-4, while II-6 had grade I-II nephrocalcinosis in her remaining kidney. Four siblings and the mother were heterozygous carriers of the mutation, but showed no biochemical abnormalities. With oral phosphate supplements, hypophosphatemia and hypercalciuria improved in both homozygous individuals. Renal calcifications that are presumably due to increased urinary calcium excretion can be the presenting finding in homozygous carriers of G196R in SLC34A3/NaPi-IIc, and some or all laboratory features of HHRH may be masked by vitamin D deficiency.

Recovery of hyperphosphatoninism and renal phosphorus wasting one year after successful renal transplantation.

BACKGROUND AND OBJECTIVES: In the first months after successful kidney transplantation, hypophosphatemia and renal phosphorus wasting are common and related to inappropriately high parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) levels. Little is known about the long-term natural history of renal phosphorus homeostasis in renal transplant recipients. DESIGN, SETTING, PARTICIPANTS: We prospectively followed parameters of mineral metabolism (including full-length PTH and FGF-23) in 50 renal transplant recipients at the time of transplantation (Tx), at month 3 (M3) and at month 12 (M12). Transplant recipients were (1:1) matched for estimated GFR with chronic kidney disease (CKD) patients. RESULTS: FGF-23 levels (Tx: 2816 [641 to 10665] versus M3: 73 [43 to 111] versus M12: 56 [34 to 78] ng/L, median [interquartile range]) and fractional phosphorus excretion (FE(phos); M3: 45 +/- 19% versus M12: 37 +/- 13%) significantly declined over time after renal transplantation. Levels 1 yr after transplantation were similar to those in CKD patients (FGF-23: 47 [34 to 77] ng/L; FE(phos) 35 +/- 16%). Calcium (9.1 +/- 0.5 versus 8.9 +/- 0.3 mg/dl) and PTH (27.2 [17.0 to 46.0] versus 17.5 [11.7 to 24.4] ng/L) levels were significantly higher, whereas phosphorus (3.0 +/- 0.6 versus 3.3 +/- 0.6 mg/dl) levels were significantly lower 1 yr after renal transplantation as compared with CKD patients. CONCLUSIONS: Data indicate that hyperphosphatoninism and renal phosphorus wasting regress by 1 yr after successful renal transplantation.

El eje hueso-riñón en el control del fósforo sérico y la mineralización ósea / Bone-Kidney axis in the control of serum phosphorus and bone mineralization

El eje hueso-riñón ha sido pensado como un mecanismo por el cual el esqueleto se comunica con el riñón para coordinar la mineralización de la matriz extracelular ósea con el manejo renal del fosfato. Osteoblastos /osteocitos están bien preparados para coordinar las homeostasis sistémica de fósforo y la mineralización ósea, ya que ellos expresan todos los componentes implicados en un posible eje hueso-riñón, incluyendo al PHEX, FGF-23, MEPE, y DMP1. Los efectos autocrinos de proteínas de la familia SIBLING como MEPE y DMP1 sobre los osteoblastos podrían regular la producción de proteínas de matriz extracelular que intervienen en la mineralización. El riñón provee uno de los efectores de este eje que regula el balance de fosfato a través de la expresión apical de los cotransportadores sodio/fosfato NaPi-IIa y NaPi-IIc en el túbulo proximal. Central en este eje es el FGF-23, producido por los osteoblastos que tiene acciones fosfatúricas sobre el riñón. Cuando se descubrió que el FGF23, la primera fosfatonina era de origen osteoblástico/osteocitico, quedó establecido el eje hueso-riñón. Probar definitivamente la existencia de este eje hueso-riñón y definir exactamente su rol fisiológico requerirá de investigaciones adicionales

The bone-kidney axis has been thought as a mechanism for the skeleton to communicate with the kidney to coordinate the mineralization of extracelular matrix with the renal handling of phosphate. Osteoblasts / osteocytes are well suited for coordinating systemic phosphate homeostasis and mineralization, since they express all of the implicated components of a possible bone-kidney axis, including PHEX, FGF-23, MEPE, and DMP1. In addition, autocrine effects of SIBLING proteins as MEPE and DMP1 on osteoblasts could regulate the production of ECM proteins that regulate mineralization. The kidney provides one of the effectors of the axis that regulates phosphate balance through the apical expression of NaPi-IIa and NaPi-IIc in proximal tubules. Central in this axis is FGF-23, produced by osteoblasts that has phosphaturic actions on the kidney. When FGF23, the first phosphatonin, was discovered to be of osteoblastic/osteocyte origin, the bone kidney axis was established. Proving the existence of this bone-kidney axis and defining its physiological role will require additional investigations