Decreased Serum Phosphate Levels Research Articles

#2696 The effect of laxatives on reducing serum phosphate levels of probiotics in hemodialysis patients: a subanalysis of RCT

Abstract Background and Aims Dysbiosis of the intestinal microbiota in chronic kidney disease increases uremic toxin, which damage the epithelial tight junctions and increase the permeability of the intestinal wall via endotoxemia and systemic inflammation. Some articles reported that probiotics reduced the uremic toxin and decreased inflammation biomarkers in CKD patients. Meanwhile, we have already reported that oral administration of Bifidobacterium longum in a gastro-resistant seamless capsule decreases serum phosphate levels in patients receiving hemodialysis (Clin Kidney J, 5:373-374, 2012). In addition, in this congress, we reported that three-combination probiotics decreased serum phosphate levels. Meanwhile, some articles reported the relationship hypophosphatemia and laxative abuse. The aim of this subanalysis study is to evaluate the efficacy of laxatives on reducing serum phosphate levels of three-combination probiotic in patients receiving hemodialysis. Method A 6-month prospective, randomized, double-blind, placebo-controlled study was conducted at three hemodialysis centers. As probiotic therapy, of three-combination probiotics (Bio-Three) tablets, each containing 2 mg of lactomin (Streptococcus faecalis T-110), 10 mg of Clostridium butyricum TO-A, and 10 mg of Bacillus mesentericus TO-A, were used. The patients receiving hemodialysis were randomly assigned to the Bio-Three group (n = 37) and the placebo group (n = 36). In both the Bio-Three group and the placebo group, patients orally received 6 tablets 3 times daily. We evaluated the effect of probiotic on serum phosphate level and gut microbiome before and 6 months after the start of treatment. The gut microbiome composition was analyzed by a 16s rRNA gene-based sequencing protocol. In addition, in patients with laxative (n = 24), we evaluate the effect of probiotic on serum phosphate levels and gut microbiome. Results The serum phosphate levels in the Bio-Three group significantly decreased after 6-month treatment, while did not change in the placebo group. Furthermore, the serum phosphate level in patients with Bio-Three and laxative additionally decreased. In a 16s rRNA gene-based sequencing protocol analysis, serum phosphate levels were positively correlated with the occupancy ratio of Erysipelotrichaceae, Lachnospiraceae, Oscillospiraceae, Ruminococcaceae, and Sutterellaceae and were negatively correlated with the occupancy ratio of Leuconostocaceae and Lachnospiraceae in patients with Bio-Three and laxatives. Conclusion In this subanalysis study, the effect of reducing serum phosphate levels on three-combination probiotic might be augmented by laxatives and the specific bacteria in the gut microbiome might contribute to the decrease of serum phosphate levels.

Assessing the predictive value of serum phosphate for short-term mortality in acute-on-chronic liver failure patients: An observational study at a non-transplant tertiary care centre.

The gradual clinical worsening of acute-on-chronic liver failure (ACLF) leads to a high 28-day mortality rate. There are several prognostication scores for predicting early mortality in ACLF. Serum phosphate, which is the main component of adenosine tri-phosphate (ATP) synthesis, is utilized for liver synthetic functions, leading to subnormal or decreased serum phosphate levels. Hence more than normal levels of serum phosphate can be used as a marker of decreased liver cell reserve. Hence, we aimed to compare serum phosphate levels with available prognostic scores to assess mortality among ACLF patients. 100 consecutive ACLF patients according to the Asia Pacific Association for Study of the Liver (APASL) definition were studied. The baseline blood workups and determination of viral bio-markers, serum phosphate, and lactate levels on days 1, 3, and 7 were carried out and prospectively followed up, and the baseline serum phosphate levels were compared with the usual scores to predict the 28-day mortality. CLIF-SOFA (accuracy 76-91%) followed by CLIF-C score (accuracy 73-84%) and AARC score (accuracy 70-85%) had the statistically significantly highest accuracy as compared with CTP, MELD, and MELD-Na on all three days. Serum phosphate values (accuracy 69-86%) on all three days were not better than the CLIF-SOFA score but better than all other prognostic scores on days 3 and 7. The high serum phosphate levels on day 3 with a value of more than 6.4 mg/dl showed almost comparable accuracy with CLIF-SOFA for screening short-term mortality. Hence serum phosphate measurement can be used as a simple bedside laboratory investigation to predict mortality in ACLF patients and early interventions in low-resource settings.

SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption

The mechanistic regulation of bone mass in aged animals is poorly understood. In this study, we examined the role of SIRT6, a longevity-associated factor, in osteocytes, using mice lacking Sirt6 in Dmp-1-expressing cells (cKO mice) and the MLO-Y4 osteocyte-like cell line. cKO mice exhibited increased osteocytic expression of Sost, Fgf23 and senescence inducing gene Pai-1 and the senescence markers p16 and Il-6, decreased serum phosphate levels, and low-turnover osteopenia. The cKO phenotype was reversed in mice that were a cross of PAI-1-null mice with cKO mice. Furthermore, senescence induction in MLO-Y4 cells increased the Fgf23 and Sost mRNA expression. Sirt6 knockout and senescence induction increased HIF-1α binding to the Fgf23 enhancer sequence. Bone mass and serum phosphate levels were higher in PAI-1-null aged mice than in wild-type mice. Therefore, SIRT6 agonists or PAI-1 inhibitors may be promising therapeutic options for aging-related bone metabolism disruptions.

Short-Term Effects of a Therapeutic Diet on Biochemical Parameters in Hemodialysis Patients: A Randomized Crossover Trial

Although unhealthy diets exacerbate nutritional and metabolic derangements in patients with end-stage kidney disease (ESKD), how therapeutic diets that possess a variety of different dietary strategies acutely modify diverse biochemical parameters related to cardiovascular disease remains underexplored. Thirty-three adults with end-stage kidney disease undergoing thrice-weekly hemodialysis participated in a randomized crossover trial comparing a therapeutic diet with their usual diets for 7days, separated by a 4-week washout period. The therapeutic diet was characterized by adequate calorie and protein amounts, natural food ingredients with a low phosphorus-to-protein ratio, higher portions of plant-based food, and high fiber content. The primary outcome measure was the mean difference in the change-from-baseline intact fibroblast growth factor 23 (FGF23) level between the 2 diets. The other outcomes of interest included changes in mineral parameters, uremic toxins, and high-sensitivity C-reactive protein (hs-CRP) levels. Compared with the usual diet, the therapeutic diet lowered intact FGF23 levels (P=.001), decreased serum phosphate levels (P<.001), reduced intact parathyroid hormone (PTH) levels (P=.003), lowered C-terminal FGF23 levels (P=.03), increased serum calcium levels (P=.01), and tended to lower total indoxyl sulfate levels (P=.07) but had no significant effect on hs-CRP levels. Among these changes, reduction in serum phosphate level achieved in 2days, modifications of intact PTH and calcium levels in 5days, and reductions in intact and C-terminal FGF23 levels in 7days of therapeutic diet intervention. Within the 1-week intervention period, the dialysis-specific therapeutic diet rapidly reversed mineral abnormalities and tended to decrease total indoxyl sulfate levels in patients undergoing hemodialysis but had no effect on inflammation. Future studies to assess the long-term effects of such therapeutic diets are recommended.

Favorable Effects of Burosumab on Fibroblast Growth Factor 23-Related Osteomalacia: A Case Report

Background: Fibroblast growth factor 23 (FGF23) decreases serum phosphate levels by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption by decreasing serum 1,25-dihydroxyvitamin D level, thereby regulating phosphate metabolism. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by FGF23 overproduction by tumor tissue. Resecting the responsible tumor is a radical treatment for TIO. When the responsible tumor is undetectable, phosphate and active vitamin D administration is recommended. However, supplementation alone is frequently insufficient to maintain phosphate levels and it is difficult to prevent the complications associated with medical therapy, including hypercalciuria and nephrocalcinosis. Recently, burosumab, a human monoclonal anti-FGF23 antibody, has been approved in Japan as a therapeutic agent for FGF23-related hypophosphatemia. Here, we present a patient with TIO effectively treated with burosumab in the absence of identification of tumour location. Clinical case: A 47-year-old female developed pain and edema of the feet; however, the cause could not be determined at local hospitals. Afterwards, she developed marked bone atrophy in the feet and was referred to our hospital. Her age at symptom onset, hypophosphatemia (serum P, 1.9 mg/dl, 2.7 mg/dl < n < 4.6 mg/dl), high serum FGF23 level (630 pg/ml, 16 pg/ml < n < 69 pg/ml), and decreased 1,25-dihydroxyvitamin D level (12.9 pg/ml, 20 pg/ml < n < 60 pg/ml) indicated FGF23-related osteomalacia. She was not having any medication at the time of diagnosis, including saccharified iron oxide or iron polymaltose. Urinary phosphate excretion increased without renal tubular defect; therefore, hypophosphatemic osteomalacia was diagnosed. MRI showed high signal intensity in the talus, sacral, and L5 vertebral regions, indicating multiple pseudofractures. Comprehensive imaging studies, including systemic CT scan and 111In-pentetreotide scintigraphy, did not reveal any tumors despite the suspicion of TIO. Next, we performed systemic venous sampling, which revealed high FGF23 level in the left external iliac vein. Second venous sampling limited to the left lower limb exhibited high FGF23 level in the posterior tibial vein. However, an additional imaging study limited to the left foot could not identify any tumors. Genetic variation was negative for potentially responsible genes, including PHEX and FGF23. We decided to administer burosumab to normalize serum phosphate level without phosphate supplementation. Within 2 months, pain was relieved and the visual analog scale scores also improved from 10 to 6. Moreover, bone MRI showed improved pseudofractures. Conclusion: Burosumab administration was effective for TIO of unknown origin, and it improved not only laboratory findings but also clinical symptoms in this case.

SO055PROBIOTIC BIO-THREE DECREASES SERUM PHOSPHATE LEVELS WITH INVOLVEMENT OF BACTERIA IN GUT MICROBIOMA IN HEMODIALYSIS PATIENTS: A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTOLLED STUDY

Abstract Background and Aims Recent studies revealed that the importance of the gut microbioma in the development and progression of CKD. Dysbiosis of the intestinal microbiota increases uremic toxin, which damage the epithelial tight junctions and increase the permeability of the intestinal wall via endotoxemia and systemic inflammation. Some articles reported that probiotics reduced the uremic toxin and decreased inflammation biomarkers in CKD patients, while others reported no remarkable changes. Meanwhile, we have already reported that oral administration of Bifidobacterium longum in a gastro-resistant seamless capsule decreases serum phosphate levels in patients receiving haemodialysis. The aim of this study is to evaluate the efficacy of probiotics by changes of serum data, including inflammation and intestinal flora in patients receiving hemodialysis. Method A 6-month prospective, randomized, double-blind, placebo-controlled study was conducted at three hemodialysis centers. As probiotic therapy, of three-combination probiotics (Bio-Three) tablets, each containing 2 mg of lactomin (Streptococcus faecalis T-110), 10 mg of Clostridium butyricum TO-A, and 10 mg of Bacillus mesentericus TO-A, were used. The patients receiving hemodialysis were randomly assigned to the Bio-Three group (n=37) and the placebo group (n=36). In both the Bio-Three group and the placebo group, patients orally received 6 tablets 3 times daily. We evaluated the effect of probiotic on the ratio of CRP to albumin as an inflammatory biomarker, other serum data and gut microbioma before and 6 month after the start of treatment. The gut microbioma composition was analyzed by a 16s rRNA gene-based sequencing protocol. Results The ratio of CRP to albumin did not change before and after treatment in both groups. The serum phosphate levels in the Bio-Three group significantly decreased after 6-month treatment, while did not change in the placebo group. In a 16s rRNA gene-based sequencing protocol analysis, the ratio of Firmicutes, Actinomycetales and Neisseriaies significantly changed after 6 month treatment in the only probiotic group. Meanwhile, serum phosphate levels were positively correlated with the number of genus Haemephilus and gunus Neisseria in the only probiotic group. Furthermore, serum phosphate levels were negatively correlated with the number of genus Bifidobacterium in the only probiotic group. Conclusion In this study, three-combination probiotics did not decrease systemic inflammation in hemodialysis patients. Meanwhile, three-combination probiotics might decrease serum phosphate levels, and the specific bacteria in the gut microbioma might contribute to the decrease of serum phosphate levels.

Proton pump inhibitors may hinder hypophosphatemic effect of lanthanum carbonate, but not of ferric citrate hydrate or sucroferric oxyhydroxide, in hemodialysis patients

Because end-stage renal disease patients undergoing hemodialysis frequently take acid suppressants for the treatment or prevention of gastrointestinal diseases, it is important to clarify the drug-interactions between acid suppressants and phosphate binders on the control of serum phosphate levels. In the present study, we examined whether the phosphate-lowering effects of three phosphate binders, lanthanum carbonate (LC), ferric citrate hydrate (FCH), and sucroferric oxyhydroxide (SFOH), were affected by proton pump inhibitors (PPIs) in maintenance hemodialysis patients. Laboratory data for 71 patients who had been newly prescribed one of the three phosphate binders were examined. LC at a dosage of 500 ± 217 mg/day significantly decreased serum phosphate levels by −18% in the absence of a PPI (n = 9), while a dosage of 700 ± 230 mg/day only decreased it by −3% in the presence of a PPI (n = 10). Thus, the efficacy of LC in reducing serum phosphate levels was significantly hindered by the presence of PPIs. FCH significantly decreased serum phosphate levels by −18% in the absence of a PPI (n = 7, FCH: 571 ± 189 mg/day) and by −17% in the presence of a PPI (n = 20, FCH: 638 ± 151 mg/day). The decrease in serum phosphate levels by SFOH (393 ± 197 mg/day) was −7% in the absence of a PPI (n = 7), and SFOH at a dosage of 556 ± 316 mg/day significantly decreased serum phosphate levels by −13% in the presence of a PPI (n = 18). These results suggest that the phosphate-lowering effect of LC, but not of FCH or SFOH, is diminished in the presence of PPIs in hemodialysis patients.

Functional diversity of fibroblast growth factors in bone formation.

The functional significance of fibroblast growth factor (FGF) signaling in bone formation has been demonstrated through genetic loss-of-function and gain-of-function approaches. FGFs, comprising 22 family members, are classified into three subfamilies: canonical, hormone-like, and intracellular. The former two subfamilies activate their signaling pathways through FGF receptors (FGFRs). Currently, intracellular FGFs appear to be primarily involved in the nervous system. Canonical FGFs such as FGF2 play significant roles in bone formation, and precise spatiotemporal control of FGFs and FGFRs at the transcriptional and posttranscriptional levels may allow for the functional diversity of FGFs during bone formation. Recently, several research groups, including ours, have shown that FGF23, a member of the hormone-like FGF subfamily, is primarily expressed in osteocytes/osteoblasts. This polypeptide decreases serum phosphate levels by inhibiting renal phosphate reabsorption and vitamin D3 activation, resulting in mineralization defects in the bone. Thus, FGFs are involved in the positive and negative regulation of bone formation. In this review, we focus on the reciprocal roles of FGFs in bone formation in relation to their local versus systemic effects.

Dose-finding study of bixalomer in patients with chronic kidney disease on hemodialysis with hyperphosphatemia: a double-blind, randomized, placebo-controlled and sevelamer hydrochloride-controlled open-label, parallel group study.

Hyperphosphatemia is a prognostic factor for morbidity and mortality in chronic kidney disease. Bixalomer (Kiklin® Capsules) is a non-absorbable polymer that decreases serum phosphate levels by binding phosphate in the gastrointestinal tract. This study was a multicenter, double-blind, randomized, placebo-controlled study to confirm the superiority of bixalomer to placebo for a 4-week treatment period in patients with chronic kidney disease on hemodialysis with hyperphosphatemia. Sevelamer hydrochloride (HCl), a similar non-absorbable polymer, was used as an active comparator for open-label as a reference without statistical comparison for efficacy and safety. The primary endpoint was the change in serum phosphorus level from baseline. The safety profile was also investigated. The number of subjects was 32 in the placebo group and 31 in each bixalomer group (1.5, 3.0 and 4.5 g/day), respectively. The baseline serum phosphorus level was 7.95 to 8.25 mg/dL. Bixalomer showed a significant decrease in serum phosphorus level at all doses compared with placebo, and the adjusted mean change in serum phosphorus level from the baseline to the end of treatment (at Week 4 or at the time of discontinuation) was +0.24 mg/dL in the placebo group, -0.75 mg/dL in the 1.5 g/day group, -1.32 mg/dL in the 3.0 g/day group, and -1.80 mg/dL in the 4.5 g/day group, showing a dose-dependent decrease in serum phosphorus level. The mean change in serum phosphorus level was -2.32 mg/dL in the sevelamer HCl group under the mean dose of 4.8 g/day. Major adverse events included constipation, hard feces, vomiting, etc.; however, none of the adverse events were serious or severe. Consequently, the superiority of bixalomer to placebo and its dose-dependency for treating hyperphosphatemia were confirmed (Clinical trial registration: NCT00505037).

Effects of sevelamer treatment on cardiovascular abnormalities in mice with chronic renal failure

Elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease (CVD) in patients with chronic renal failure (CRF). The phosphate-binder sevelamer has been shown to decrease both phosphate and FGF23, but limited data indicate that sevelamer improves CRF-related CVD, such as diastolic dysfunction, left ventricular hypertrophy (LVH), and aortic stiffness. To gain additional information, we measured the effects of sevelamer on CVD in a murine model of CRF. Groups of CRF and sham-operated mice received regular chow or 3% sevelamer-HCl in the chow for 14 weeks, starting 6 weeks after the initiation of CRF or sham operation. After the first 8 weeks of sevelamer treatment, CRF mice had decreased serum phosphate levels and an improved aortic systolic expansion rate, pulse-wave velocity, and diastolic function, although LVH remained unchanged. Following an additional 6-week course of sevelamer, LVH had not progressed. The FGF23 serum level was not reduced by sevelamer until after 14 weeks of treatment. In multiple regression analysis, serum phosphate, but not FGF23, was independently correlated with LV diastolic function and mass. Thus, sevelamer first improved aortic stiffness and diastolic dysfunction and secondarily prevented LVH in mice with CRF. The phosphate-lowering, rather than FGF23-lowering, effect appears to be responsible for the observed cardiovascular improvement.

Randomized Controlled Trial of Bixalomer Versus Sevelamer Hydrochloride in Hemodialysis Patients With Hyperphosphatemia

Hyperphosphatemia is a prognostic factor for morbidity and mortality in chronic kidney disease. Bixalomer is a nonabsorbable polymer that decreases serum phosphate levels by binding phosphate in the gastrointestinal tract. This study compared the efficacy and safety of bixalomer versus sevelamer hydrochloride for controlling hyperphosphatemia in hemodialysis patients. This was a multicenter, randomized open-label, non-inferiority study. The primary endpoint was serum phosphate on completion of treatment. Administration of bixalomer was started at 1.5 g/day and adjusted to a maximum of 7.5 g/day depending on the serum phosphate level. Sevelamer hydrochloride was started at 3.0 or 6.0 g/day and adjusted to a maximum of 9.0 g/day. Treatment was continued for 12 weeks. Fifty-five patients were randomized to each treatment group. After 12 weeks, the baseline adjusted mean serum phosphate level was 5.87 mg/dL in the bixalomer group and 5.55 mg/dL in the sevelamer group, with a difference of 0.31 mg/dL and 95% confidence interval (CI) of [-0.13 to 0.76]. The upper limit of the 95%CI for the difference of the mean serum phosphate level between the two groups was <1.0 mg/dL, which was the non-inferiority margin in this study. Thus, non-inferiority of bixalomer to sevelamer was confirmed. The incidence of adverse events was lower in the bixalomer group, and bixalomer did not promote acidosis. Bixalomer achieved a similar reduction of serum phosphate to sevelamer, while causing fewer adverse reactions. Consequently, the usefulness of bixalomer for treating hyperphosphatemia was confirmed.

Oral administration of Bifidobacterium longum in a gastro-resistant seamless capsule decreases serum phosphate levels in patients receiving haemodialysis.

Oral administration of Bifidobacterium longum in a gastro-resistant seamless capsule decreases serum phosphate levels in patients receiving haemodialysis.

Loss-of-Function ENPP1 Mutations Cause Both Generalized Arterial Calcification of Infancy and Autosomal-Recessive Hypophosphatemic Rickets

The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis; for example, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Here, we report presumable loss-of-function mutations in the ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase) in members of four families affected with hypophosphatemic rickets. We provide evidence for the conclusion that ENPP1 is the fourth gene-in addition to PHEX, FGF23, and DMP1-that, if mutated, causes hypophosphatemic rickets resulting from elevated FGF23 levels. Surprisingly, ENPP1 loss-of-function mutations have previously been described in generalized arterial calcification of infancy, suggesting an as yet elusive mechanism that balances arterial calcification with bone mineralization.

Effect of acute changes of serum phosphate on fibroblast growth factor (FGF)23 levels in humans

Fibroblast growth factor (FGF)23 was identified as a humoral factor involved in the development of several hypophosphatemic diseases. Subsequent studies indicated that FGF23 is a hormone regulating serum phosphate level. However, it is still unknown how the production and serum level of FGF23 are regulated. This study was designed to determine whether acute changes of serum phosphate modulate FGF23 levels in human. Four healthy volunteers participated in the study. In the phosphate infusion study, dibasic potassium phosphate was infused at a rate of 10 mEq/h for 4 h, and serum FGF23 levels were measured for up to 6 h after the start of the infusion. In the carbohydrate study, partially hydrolyzed starch corresponding to 150 g glucose was ingested and FGF23 levels were measured similarly for 6 h. Phosphate infusion significantly increased and carbohydrate ingestion decreased serum phosphate levels, respectively. However, FGF23 did not change by these maneuvers. It is concluded that acute changes of serum phosphate do not modify FGF23 levels in the healthy human.

Molecular bases of diseases characterized by hypophosphatemia and phosphaturia: new understanding.

Serum phosphate levels are regulated in both calcium-dependent and -independent fashions. Active vitamin D increases while PTH decreases serum phosphate levels in association with the elevation of serum calcium. On the other hand, a calcium-independent phosphaturic factor, historically called phosphatonin is believed to exert a physiological function based on findings in hereditary and tumor-induced diseases characterized by hypophosphatemia with normocalcemia. Among them, autosomal dominant hypophosphatemic rickets (ADHR) has contributed greatly to its elucidation because the gene responsible for ADHR encodes fibroblast growth factor 23 (FGF23) that has been found to have a phosphaturic effect. In addition, FGF23 has been proved to be involved in most cases of oncogenic osteomalacia and X-linked hypophosphatemic rickets that are also characterized by hypophosphatemia and normocalcemia. Moreover, familial tumoral calcinosis, which represents the metabolic mirror image of hypophosphatemic conditions, is caused by a loss-of-function mutation in the FGF23 gene in some patients. Very recently, hereditary hypophosphatemic rickets with hypercalciuria has been found to be caused by mutations in the SLC34A1 gene which encodes a type of sodium phosphate cotransporter. These findings may provide new strategies for treating patients with abnormal phosphate metabolism.

Parathyroid hormone increases the expression level of matrix metalloproteinase-13 in vivo.

Parathyroid hormone (PTH) increases serum calcium (Ca) by enhancing bone resorption and renal Ca reabsorption. However, detailed mechanisms of enhanced bone resorption by PTH remain to be elucidated. Although PTH has been shown to increase the expression level of osteoblastic matrix metalloproteinase (MMP)-13 in vitro, only limited results are available regarding the in vivo regulation of MMP expression. In the present study, we have examined expression levels of MMPs in PTH-infused rats. Infusion of 1.5 or 2.0 nmol/kg/day rat PTH(1-34) for 3 days resulted in a dose-dependent increase in serum Ca. PTH infusion also decreased serum phosphate levels and increased urinary excretion of Ca and phosphate. Infusion of PTH for 7 days resulted in less severe hypercalcemia and hypophosphatemia. Urinary Ca and phosphate excretion in rats infused for 7 days was less than that in rats infused for 3 days. Northern blot analysis showed that PTH infusion increased the expression level of MMP-13 in calvaria, although it did not affect MMP-2 expression. Furthermore, the time-course and severity of hypercalcemia and hypercalciuria correlated with the expression level of MMP-13. In situ hybridization also showed that PTH infusion increased the expression level of MMP-13 in femora. These results indicate that PTH enhances MMP-13 expression in vivo and suggest that PTH stimulates bone resorption at least partly by enhancing MMP-13 expression.

Loss of regulation of circulating 1,25-dihydroxyvitamin D with paradoxically decreased serum phosphate levels in individuals with recurrent kidney stones.

A low serum phosphate concentration is characteristic in individuals in whom kidney stones form, this being related to serum 1,25-dihydroxyvitamin D, parathyroid hormone and urinary phosphate excretion. In order to determine whether these parameters are related to recurrence of stone formation, they were analyzed in single and recurrent stone formers as well as controls. An inverse correlation between serum levels of phosphate and 1,25-dihydroxyvitamin D was observed in control subjects, indicating that a drop in serum phosphate results in upregulated circulating 1,25-dihydroxyvitamin D level in controls. While the circulating low phosphate level upregulated the 1,25-dihydroxyvitamin D level in single stone formers, the elevation was less than expected from the drop in serum phosphate in recurrent stone formers. The results thus suggest that loss of upregulation of 1,25-dihydroxyvitamin D by serum levels of phosphate might be important for stone formation. The possibility of deregulation of 1,25-dihydroxyvitamin D to maintain physiological requirements in stone formers and prevent further nephrolithiasis therefore warrants attention.

Niceritrol decreases serum phosphate levels in chronic hemodialysis patients

Since phosphorus retention in hemodialysis (HD) patients is known to be an important factor in the development of secondary hyperparathyroidism and renal osteodystrophy, phosphate binders have been needed for the control of serum phosphate levels (P). However, the calcium-containing phosphate binders that have been used widely can cause a rise in serum calcium levels and cause secondary hypoparathyroidism. We have recently experienced decreases in P after the administration of niceritrol (NT), a prodrug of nicotinic acid, for the treatment of low HDL-cholesteremia (HDL-C) in HD patients. The aim of the present study was to assess the mechanism of the P-lowering effect of NT in comparison with nicomol (NC), another prodrug of nicotinic acid. NT (750 mg/day) or NC (600 mg/day) was given orally to 10 or 14HD patients respectively. Blood samples were collected before the first dialysis of each week for the determination of serum urea nitrogen (UN), Cr, Ca, P, total cholesterol (TC), triglyceride (TG) and HDL-C. Serum nicotinic acid concentration (NAC) by gas chromatograph mass-spectrometry method was determined before, 4 weeks and 8 weeks after the administration of these drugs. After NT administration, P was decreased from 6.2 +/- 0.4 mg/dl to 5.1 +/- 0.4 mg/dl (1st week, p < 0.001, Mean +/- SE) and 4.5 +/- 0.3 mg/dl (2nd weeks, p < 0.001) with no change in UN, Cr or Ca levels; these significant decreases in P lasted for 8 weeks. NAC increased significantly after NT administration from 25.5 +/- 1.3 ng/ml to 549.8 +/- 102.2 ng/ml (4 weeks, p < 0.01) and 431.7 +/- 51.4 ng/ml (8 weeks, p < 0.01). HDL-C also increased (33.6 +/- 4.0 mg/dl vs 42.7 +/- 4.6 mg/dl, p < 0.05), but TC and TG did not change. In contrast, no significant changes were observed in P, NAC and HDL-C after NC administration. These discrepancies could be ascribed to the differences in serum NAC levels. These data suggest that NT could be useful for the control of P in HD patients. However further studies are needed to confirm the mechanism of the P-lowering effect of NT.

Intestinal phosphate transport in spontaneously hypertensive rats and genetically matched controls

Hypophosphatemia has been documented in patients with hypertension and in spontaneously hypertensive rats compared with genetically matched control Wistar-Kyoto rats. However, renal tubular reabsorption is increased in spontaneously hypertensive rats. Therefore, it was hypothesized that decreased serum phosphate levels in spontaneously hypertensive rats may be related to a decrease in the intestinal transport of phosphate. To test this hypothesis, sodium-dependent phosphate uptake by jejunal brush-border membrane vesicles of spontaneously hypertensive rats and genetically matched Wistar-Kyoto rats was determined. Phosphate uptake consisted of two components: sodium-independent passive diffusion across the brush border and sodium-dependent, carrier-mediated uptake. The initial rate of uptake in spontaneously hypertensive and Wistar-Kyoto rats was linear up to 20 seconds. The initial rate and time course of jejunal sodium-dependent phosphate uptake was decreased in adult spontaneously hypertensive rats compared with corresponding mean values in Wistar-Kyoto rats. This decrease was secondary to a decrease in Vmax rather than Km, suggesting that the number and/or the activity of the sodium-phosphate transporters is decreased. Sodium-dependent phosphate uptake was pH dependent, with greater uptake at pH 6.0 than at pH 7.4. However, uptake values were lower in spontaneously hypertensive rats than in Wistar-Kyoto rats at all pH levels tested. In contrast, sodium-dependent phosphate uptake in weanling rats (prehypertensive state) was not significantly different between spontaneously hypertensive and Wistar-Kyoto rats. Vitamin D deficiency in both spontaneously hypertensive and Wistar-Kyoto rats decreased Vmax and Km of sodium-dependent phosphate uptake, whereas 1,25(OH)2 vitamin D3 administration increased Vmax and Km in both spontaneously hypertensive and Wistar-Kyoto rats. These results suggest that the hypophosphatemia seen in adult spontaneously hypertensive rats is secondary to a decrease in sodium-dependent phosphate uptake compared with controls. The sodium-phosphate transporter in spontaneously hypertensive rats is responsive to vitamin D administration.

Decreased Serum Phosphate Levels after High-Dose Estrogens in Metastatic Prostate Cancer. Possible Implications

Hypophosphatemia and osteomalacia have been described in patients with metastatic prostate cancer. The mechanism of hypophosphatemia in prostate cancer is not known. A decrease in serum phosphate levels was observed in 16 of 18 patients with metastatic prostate cancer treated with high-dose diethylstilbestrol diphosphate. To determine if the fall in serum phosphate was indeed due to diethylstilbestrol diphosphate, the data from several similar groups of patients treated with chemotherapy and combined chemohormonal therapy that included diethylstilbestrol diphosphate were re-examined. Fifty-eight patients were treated with doxorubicin, doxorubicin plus cis-platinum, doxorubicin plus diethylstilbestrol diphosphate, or diethylstilbestrol diphosphate alone. A significant decrease in serum phosphate levels was seen only in patients treated with diethylstilbestrol diphosphate. Hypophosphatemia and possibly osteomalacia in metastatic prostate cancer may be related to estrogen therapy.