Higher Serum Phosphate Concentrations Research Articles

Mineral Metabolism in Children: Interrelation between Vitamin D and FGF23

Fibroblast growth factor 23 (FGF23) was identified at the turn of the century as the long-sought circulating phosphatonin in human pathology. Since then, several clinical and experimental studies have investigated the metabolism of FGF23 and revealed its relevant pathogenic role in various diseases. Most of these studies have been performed in adult individuals. However, the mineral metabolism of the child is, to a large extent, different from that of the adult because, in addition to bone remodeling, the child undergoes a specific process of endochondral ossification responsible for adequate mineralization of long bones' metaphysis and growth in height. Vitamin D metabolism is known to be deeply involved in these processes. FGF23 might have an influence on bones' growth as well as on the high and age-dependent serum phosphate concentrations found in infancy and childhood. However, the interaction between FGF23 and vitamin D in children is largely unknown. Thus, this review focuses on the following aspects of FGF23 metabolism in the pediatric age: circulating concentrations' reference values, as well as those of other major variables involved in mineral homeostasis, and the relationship with vitamin D metabolism in the neonatal period, in vitamin D deficiency, in chronic kidney disease (CKD) and in hypophosphatemic disorders.

Cord blood effectively resists mineralization through mechanisms that stabilize calciprotein particles

Calcium and phosphate are present in serum at concentrations that would be expected to precipitate in solution, but unwanted mineral deposition outside osseous tissue in vivo is typically only observed in old age and in certain disease states (e.g., chronic kidney disease). For decades, hyperphosphatemia has been considered a prime driver of ectopic mineralization in chronic kidney disease, yet many other mammalian species have much higher serum phosphate concentrations than human adults without obvious sequelae.

Impact of sucroferric oxyhydroxide on the oral and intestinal microbiome in hemodialysis patients

Hyperphosphatemia is a consequence of chronic kidney disease associated with mineral/bone impairment, increased cardiovascular events and mortality. Therapeutically, most dialysis patients have to take phosphate binders. Here, we investigated effects of the Fe(3+)-based phosphate binder sucroferric oxyhydroxide (SFOH) on the oral and gastrointestinal microbiome of 11 hemodialysis patients. Saliva, dental plaque and stool were collected at baseline, one and four weeks of SFOH intake and subjected to 16S rRNA gene (V3-V4 region) directed Illumina MiSeq-based analysis. Total Fe, Fe(2+) and Fe(3+) were determined in stool and saliva. Overall, the microbiome did not change significantly. However, some patient-, sample- and taxon-specific differences were noted, which allowed patients to be divided into those with a shift in their microbiome (6/11) and those without a shift (5/11). Total Fe and Fe(2+) were highest after one week of SFOH, particularly in patients who exhibited a shift in microbiome composition. Eight bacterial taxa showed significant unidirectional changes during treatment. In-depth microbiome analysis revealed that taxa that significantly benefited from iron plethora had no iron-binding siderophores or alternatives, which was in contrast to taxa that significantly declined under iron plethora. Patients with microbiome-shift were significantly younger and had higher serum phosphate concentrations. In conclusion, this study sheds light on the impact of iron on the microbiome of hemodialysis patients.

Urinary Phosphate Excretion and Microvascular Function in a Population-Based Cohort

Urinary Phosphate Excretion and Microvascular Function in a Population-Based Cohort

Survival estimates and outcome predictors in dogs with newly diagnosed diabetes mellitus treated in a veterinary teaching hospital

BackgroundDiabetes mellitus (DM) is one of the most common endocrine disorders in dogs, but prognostic factors are still largely unknown. The aim of this retrospective, single-centre, case series study was...

SUN-246 24-HOUR URINARY PHOSPHATE EXCRETION (24uP) IN A MULTI-ETHNIC ASIAN POPULATION

High serum phosphate concentrations (sP) are associated with increased risks of cardiovascular disease events and death among patients with chronic kidney disease (CKD). We hypothesize that ethnic differences in dietary habits affect phosphate intake in a multi-ethnic population. Assuming that the 24uP reflects phosphate intake, we compared 24uP between healthy individuals with normal kidney function and CKD patients in a multi-ethnic Asian population.

High Phosphate-Induced Calcification of Vascular Smooth Muscle Cells is Associated with the TLR4/NF-κb Signaling Pathway

Background/Aims: Hyperphosphatemia is one of the most notable features of chronic kidney disease (CKD). Numerous epidemiological and clinical studies have found that high serum phosphate concentrations are associated with calcification in the coronary arteries. However, the mechanisms underlying the vascular calcification induced by high phosphate have not been understood fully. Methods: Vascular smooth muscle cells (VSMCs) were cultured in high-phosphate media to induce vascular calcification, which was detected by Alizarin red S staining. Gene expression and protein levels of differentiation markers were determined by real-time RT-PCR and western blotting, respectively. Protein levels of phosphorylated NF-κB and TLR4 were detected by western blotting, and the role of NF-κB/TLR4 was further confirmed by using an NF-κB inhibitor or TLR4 siRNA. Results: Our results showed that high-phosphate media induced obvious calcification of VSMCs. Simultaneously, VSMC differentiation was confirmed by the increased expression of bone morphogenetic protein-2 and Runt-related transcription factor 2 and decreased expression of the VSMC-specific marker SM22α, which was accompanied by the increased expression of inflammatory cytokines. Moreover, a significant upregulation of TLR4 and phosphorylated NF-κB was also detected in VSMCs with high-phosphate media. In contrast, VSMC calcification and the increased expression of inflammatory cytokines were markedly attenuated by pretreatment with TLR4 siRNA and pyrrolidine dithiocarbamic acid, an NF-κB inhibitor. Conclusion: These data suggest that high-phosphate conditions directly induce vascular calcification via the activation of TLR4/NF-κB signaling in VSMCs. Moreover, inhibition of the TLR4/NF-κB signaling pathway might be a key intervention to prevent vascular calcification in patients with CKD.

Relationship of dietary phosphate intake with risk of end-stage renal disease and mortality in chronic kidney disease stages 3-5: The Modification of Diet in Renal Disease Study.

KDIGO guidelines recommend dietary phosphate restriction to lower serum phosphate levels in CKD stage 3-5. Recent studies suggest that dietary phosphate intake is only weakly linked to its serum concentration, and the relationship of phosphate intake with adverse outcomes is uncertain. To further evaluate this, we used Cox proportional hazards models to assess associations of baseline 24 hour urine phosphate excretion with risk of end stage renal disease (ESRD), all-cause mortality, and mortality subtypes (cardiovascular disease (CVD) and non-CVD) using the Modification of Diet in Renal Disease data. Models were adjusted for demographics, CVD risk factors, iothalamate GFR, and urine protein and nitrogen excretion. Phosphate excretion was modestly inversely correlated with serum phosphate concentrations. There was no association of 24 hour urinary phosphate excretion with risk of ESRD, CVD-, non-CVD- or all-cause mortality. For comparison, higher serum phosphate concentrations were associated with all-cause mortality (hazard ratio per 0.7 mg/dL higher, 1.15 [95% CI 1.01, 1.30]). Thus, phosphate intake is not tightly linked with serum phosphate concentrations in CKD stage 3-5, and there was no evidence that greater phosphate intake, assessed by 24 hour phosphate excretion, is associated with ESRD, CVD-, non CVD-, or all-cause mortality in CKD stage 3-5. Hence, factors other than dietary intake may be key determinants of serum phosphate concentrations and require additional investigation.

Urinary excretion of calcium and phosphate in dogs with pituitary-dependent hypercortisolism: case control study in 499 dogs

Pituitary-dependent hypercortisolism (PDH) in dogs is frequently associated with high serum phosphate and parathormone concentrations which are in turn associated with prognosis and clinical presentation. The pathogenesis of such abnormalities...

Association studies of calcium-sensing receptor (CaSR) polymorphisms with serum concentrations of glucose and phosphate, and vascular calcification in renal transplant recipients.

BackgroundCardiovascular disease is the major cause of death in renal transplant recipients (RTRs) and linked to arterial calcification. The calcium-sensing receptor (CaSR), a G-protein coupled receptor, plays a pivotal role in extracellular calcium homeostasis and is expressed in the intimal and medial layers of the arterial wall. We investigated whether common CASR gene variants are predictors for aortic and coronary artery calcification or influence risk factors such as serum calcium, phosphate and glucose concentrations in RTRs.MethodsTwo hundred and eighty four RTRs were investigated for associations between three CASR promoter region single nucleotide polymorphisms (SNPs) (rs115759455, rs7652589, rs1501899), three non-synonymous CASR coding region SNPs (A986S, R990G, Q1011E), and aortic and coronary artery calcium mass scores, cardiovascular outcomes and calcification risk factors that included serum phosphate, calcium, total cholesterol and glucose concentrations.ResultsMultivariate analysis revealed that RTRs homozygous for the minor allele (SS) of the A986S SNP, when compared to those homozygous for the major allele (AA), had raised serum glucose concentrations (8.7±5.4 vs. 5.7±2.1 mmol/L, P<0.05). In addition, RTRs who were heterozygous (CT) at the rs115759455 SNP, when compared to those homozygous for the major allele (CC), had higher serum phosphate concentrations (1.1±0.3 vs. 1.0±0.2 mmol/L, P<0.05). CASR SNPs were not significant determinants for aortic or coronary artery calcification, and were not associated with cardiovascular outcomes or mortality in this RTR cohort.ConclusionsCommon CASR SNPs may be independent predictors of serum glucose and phosphate concentrations, but are not determinants of vascular calcification or cardiovascular outcomes.

Prognostic factors for survival in dogs with pituitary-dependent hypercortisolism treated with trilostane

Pituitary-dependent hypercortisolism (PDH) is one of the most frequent endocrinopathies in dogs, but prognostic factors are largely unknown. The aim of this retrospective case series study was to determine the...

Oral phosphate binders in CKD - is calcium the (only) answer?

All-cause mortality and cardiovascular- related mortality have both been linked to abnormal serum phosphate concentrations in chronic kidney disease (CKD). Aberrant serum phosphate concentration in patients with CKD has also been associated with adverse cardiac and renal outcomes. Early prevention or management of rising or high serum phosphate concentrations in patients with CKD is now considered to be an important intervention to prevent downstream complications resulting from the poor management of serum calcium and parathyroid hormone (PTH). It is widely considered that starting phosphate binder therapy early, with concurrent dietary management of serum phosphate, constitutes an effective course of interventions, although normalization of serum phosphate in dialysis patients remains atypical, unless specific dialytic measures are also undertaken. Calcium- based phosphate binders are often the first type of binders prescribed due to their low cost. Evidence shows that most phosphate binders are roughly equally effective in lowering serum phosphate concentrations in adults compared to placebo, with a small probability that sevelamer hydrochloride is better than calcium acetate or lanthanum carbonate. However, not all binders are created equal in regards to their safety profiles. The potential for accumulations and toxicities does exist with very long-term continuous exposure. We discuss these issues in the course of this review.

Clinical Uses of 1,25-dihydroxy-19-nor-vitamin D&lt;sub&gt;2&lt;/sub&gt; (Paricalcitol)

The activation of vitamin D receptors (VDR) - (including activation by 25-hydroxyvitamin D) - seems to have not only mineral-metabolism beneficial effects but also important extra-skeletal actions. Paricalcitol is a synthetic vitamin D2 agonist of the VDR approved for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD). As a result of its selectivity, paricalcitol provides a wider therapeutic window for PTH suppression, minimizing deleterious effects of high serum calcium and/or phosphate concentrations. Paricalcitol also shares, and sometimes improves pleiotropic vitamin-D related systemic effects. For instance, paricalcitol has been repeatedly shown to decrease calcium and phosphate deposition in vessels and to decrease the expression of osteogenic factors preventing the active transformation of smooth muscle vascular cells into osteoblast-like cells in experimental models. In patients, paricalcitol has been associated with improved survival of dialysis patients and it may improve residual albuminuria in diabetic patients. Consequently, paricalcitol may enhance the standard of care in these high-risk patients. Although it seems reasonable to use these potential advantages to guide the individual and integral management of the complex CKD-mineral and bone disorder, it is necessary to recognize that many of these observations have not been proven nor confirmed in prospective clinical trials.

Pulmonary and gastric metastatic calcification due to milk-alkali syndrome: a case report.

The incidence of metastatic calcification is influenced by high serum calcium and phosphate concentrations and local physicochemical conditions, such as pH. A high pH accelerates tissue calcification. Patients with milk-alkali syndrome typically present with renal failure, hypercalcemia, and metabolic alkalosis, which are caused by the ingestion of calcium and absorbable alkali. Among patients with impairment of renal function, milk-alkali syndrome is a major cause of hypercalcemia. Long-term use of furosemide will lead to hypokalemia, metabolic alkalosis, and eventually renal failure (i.e., pseudo-Bartter syndrome). Even if the level of calcium ingestion is relatively low, the renal failure caused by long-term furosemide use can readily lead to milk-alkali syndrome. We describe a case of a 45-year-old woman who was admitted with cough and dyspnea and presented with pulmonary and gastric metastatic calcification. She had been taking alfacalcidol and oral alkaline medications such as sodium bicarbonate and calcium carbonate as well as oral furosemide for a long time. The patient was found to have hypercalcemia, chronic renal failure, and metabolic alkalosis, so milk-alkali syndrome was diagnosed. Saline was administered and oral medications were discontinued. Serum creatinine levels subsequently decreased, but pulmonary metastatic calcification was not diminished. In this case, the milk-alkali syndrome that caused the severe metastatic calcification was exacerbated by multiple factors, including oral alkaline medications such as sodium bicarbonate and calcium carbonate. In addition, metabolic alkalosis and renal failure were affected by long-term furosemide use (i.e., pseudo-Bartter syndrome).

Hypophosphatemia Also Increases the Risk

In addition to hyperphosphatemia, hypophosphatemia also increases the cardiovascular risk (1). Low serum concentrations reduce the eNOS activity and lead to insulin resistance, ATP deficiency, and—via lowered 2,3-diphosphoglycerate—to chronic tissue hypoxia causing endothelial damage. Risk factors such as diabetes or obesity are often associated with hypophosphatemia (1, 2). The causes of clinically relevant phosphate deficiency are not only hypophosphatemic osteomalacia, malnutrition, and sepsis—as mentioned in the section entitled “The risks of hypophosphatemia” – but, in addition to poorly controlled diabetes, also chronic alcohol misuse, major surgery, infections (for example, legionellosis, malaria), COPD, long-term hemodialysis, and treatment with antacids, diuretics, catecholamines, imatinib, and others. Since serum phosphate accounts for less than 1% of the total phosphate in the body, substantial intracellular phosphate deficiency may exist even in the presence of a normal or even raised serum concentration. Phosphate homeostasis is subject to very complex regulation, whose mechanics have been understood only rudimentarily, which is affected not only by FGF-23, parathormone, and vitamin D, but also by pH, insulin, growth hormone, estrogens, stress hormones, calcium, and magnesium. The cardiovascular risk is probably determined more by an impaired phosphate metabolism than by the very low amount of extracellular phosphate alone. Children, for example, often have much higher serum phosphate concentrations than adults but none the less do not have an increased risk, and in a recent osteoporosis study (3), hypercalcemia was confirmed as a cardiovascular risk factor whereas hyperphosphatemia was not. The serum concentrations of people with healthy kidneys correlate only minimally with the phosphate content of the ingested food (2); besides, because of their circadian rhythm they fluctuate widely over the course of the day in the individual, and consequently serum phosphate readings, which are usually taken only once a day, are not always representative for the average serum concentration over 24 hours. It is possible that for a healthy diet, the absolute phosphate content of foodstuffs is less important than, for example, the ratio of calcium to phosphate in the interaction with magnesium and vitamin D.

Nephrogenic systemic fibrosis is found only among gadolinium‐exposed patients with renal insufficiency: a case–control study from Denmark

Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disease associated with exposure to gadolinium-based contrast agents (GBCA) in patients with renal insufficiency. To report the prevalence of NSF in a well-defined cohort of patients with renal insufficiency exposed to GBCA, to investigate if GBCA-unexposed controls showed signs of NSF and to evaluate selected risk factors among NSF cases and GBCA-exposed controls. A study among GBCA-exposed patients with renal insufficiency (n=565) was conducted to identify cases of NSF. The NSF cases found were age and sex matched and clinically compared with GBCA-exposed and unexposed patients with renal insufficiency in a case-control study. We identified 17 NSF cases. No signs of NSF were observed among the controls. The prevalence of NSF was 4·7%, highest among patients with chronic kidney disease (CKD) stage 5 exposed to GBCA and undergoing haemodialysis or peritoneal dialysis. Three NSF cases were identified among patients with CKD stage 3 and 4. Three patients developed NSF after macrocyclic GBCA exposure. NSF cases had a tendency to have higher serum phosphate concentrations than GBCA-exposed controls. Our study supports the view that GBCA is a major risk factor for NSF. Importantly, we found that patients with CKD stage 3 and 4 can be at risk of NSF. NSF may also be triggered by macrocyclic GBCA. Further, we observed a trend for higher phosphate levels in NSF cases compared with controls. The important findings drawn from this case-control study indicate that NSF is not an overlooked condition among patients with renal insufficiency not exposed to GBCA.

Association of Serum Phosphate Levels With Aortic Valve Sclerosis and Annular Calcification: The Cardiovascular Health Study

This study was conducted to evaluate mineral metabolism markers as potential risk factors for calcific aortic valve disease. Mineral metabolism disturbances are common among older people and may contribute to cardiac valvular calcification. Associations of serum mineral metabolism markers with cardiac valvular calcification have not been evaluated in a well-characterized general population of older adults. We measured serum levels of phosphate, calcium, parathyroid hormone, and 25-hydroxyvitamin D in 1,938 Cardiovascular Health Study participants who were free of clinical cardiovascular disease and who underwent echocardiographic measurements of aortic valve sclerosis (AVS), mitral annular calcification (MAC), and aortic annular calcification (AAC). We used logistic regression models to estimate associations of mineral metabolism markers with AVS, MAC, and AAC after adjustment for relevant confounding variables, including kidney function. The respective prevalences of AVS, MAC, and AAC were 54%, 39%, and 44%. Each 0.5 mg/dl higher serum phosphate concentration was associated with greater adjusted odds of AVS (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.04 to 1.31, p = 0.01), MAC (OR: 1.12, 95% CI: 1.00 to 1.26, p = 0.05), and AAC (OR: 1.12, 95% CI: 0.99 to 1.25, p = 0.05). In contrast, serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations were not associated with aortic or mitral calcification. Higher serum phosphate levels within the normal range were associated with valvular and annular calcification in a community-based cohort of older adults. Phosphate may be a novel risk factor for calcific aortic valve disease and warrants further study.

Association of Serum Phosphate with Vascular and Valvular Calcification in Moderate CKD

Within the normal range, higher serum phosphate concentrations are associated with cardiovascular events and mortality in individuals with chronic kidney disease (CKD) and in those with normal kidney function. Experimental models suggest that phosphate has a direct calcifying effect on vascular smooth muscle. We examined associations of serum phosphate concentrations with vascular and valvular calcification in 439 participants from the Multi-Ethnic Study of Atherosclerosis who had moderate CKD and no clinical cardiovascular disease. Serum phosphate concentrations were within the normal range (2.5 to 4.5 mg/dl) in 95% of study participants. The prevalence of calcification in the coronary arteries, descending thoracic aorta, aortic valve, and mitral valve was 67, 49, 25, and 20%, respectively, measured by electron-beam or multi-detector row computed tomography. After adjustment for demographics and estimated GFR, each 1-mg/dl increment in serum phosphate concentration was associated with a 21% (P = 0.002), 33% (P = 0.001), 25% (P = 0.16), and 62% (P = 0.007) greater prevalence of coronary artery, thoracic, aortic valve, and mitral valve calcification, respectively. Adjustment for traditional risk factors for atherosclerosis, parathyroid hormone, or 1,25-dihydroxyvitamin D levels did not alter these associations. In conclusion, higher serum phosphate concentrations, although still within the normal range, are associated with a greater prevalence of vascular and valvular calcification in people with moderate CKD. It remains to be determined whether lowering phosphate concentrations will impact calcification risk in the setting of kidney disease.

Aortic calcification in haemodialysis patients with diabetes mellitus

Certain metabolic disorders, such as hyperphosphatemia induce vascular calcification in haemodialysis patients; it is unclear, however, whether these disorders contribute to aortic calcification in diabetic haemodialysis patients. This study examined the risk factors of aortic calcification in a large number of haemodialysis patients, and compared risk factors between diabetic and non-diabetic patients. The subjects were 667 patients on maintenance haemodialysis: 184 with type 2 diabetes and 483 without. Aortic calcification was measured semi-quantitatively using a plain computed tomography image of the abdominal aorta, and an aortic calcification index (ACI) was calculated. The ACI of the diabetic subjects was significantly higher than that of those without diabetes (57.3+/-22.1 vs 44.8+/-28.3%, P < 0.0001), although the dialysis vintage of the former was significantly shorter (P < 0.001). Multiple regression analyses showed that diabetes was a significant independent risk factor for increased ACI. Multiple regression analyses, performed separately in diabetics and non-diabetics, revealed that advanced age, higher systolic blood pressure, smoking and longer haemodialysis vintage were common independent risk factors significantly associated with increased ACI in both patient groups (R2 = 0.296, P < 0.0001 for non-diabetics; R2 = 0.193, P < 0.0001 for diabetics). Higher serum phosphate concentration was not significantly associated with increased ACI in diabetic patients (P = 0.429), although it was a significant independent factor in non-diabetic patients (beta = 0.150, P < 0.0005). Aortic calcification in diabetic haemodialysis patients is more advanced, compared with non-diabetic patients, even with short haemodialysis vintage. Since disorders of mineral metabolism are not significantly associated with aortic calcification in diabetic haemodialysis patients, aortic calcification in these patients could be affected by metabolic abnormalities associated with the diabetic state per se, independent of other confounding factors; and aortic calcification may be advanced even before haemodialysis induction.

Polyethylene Glycol versus Sodium Phosphate in Bowel Cleansing for Colonoscopy: a Randomized Trial

There have been conflicting results regarding the adverse effects of established bowel cleansing regimens. The aim of the present study was to compare the effects of three bowel cleansing regimens on subjective well-being, electrolyte balance, cardiac arrhythmia, and the microscopic post-cleansing appearance of the colonic mucosa. A total of 231 consecutive outpatients were randomly assigned to receive bowel preparation for colonoscopy with either 4 l polyethylene glycol (PEG; group I, n = 76); 2 l PEG plus 10 mg Bisacodyl (group II, n = 71); or 90 ml sodium phosphate (group III, n = 84). After bowel preparation, the participants completed a questionnaire on symptoms. Endoscopists blinded to the regimen used gave scores for the quality of cleansing at endoscopy, ranging from poor (0) to very good (5). Blood samples were taken before and after bowel cleansing, electrocardiographic monitoring was used during colonoscopy, and mucosal biopsy samples were taken in the sigmoid colon. Bowel preparation in group II was poorer (mean score 3.26) than in groups I (3.88) and III (4.01); P < 0.001 (II vs. III), P < 0.001 (I vs. II). The frequency of arrhythmias and post-cleansing mucosal inflammation was similar in all three groups. Lower serum potassium and higher serum phosphate concentrations were found in group III in comparison with the other groups ( P < 0.001). No differences were detected regarding the effectiveness and safety of bowel preparation with PEG alone and sodium phosphate in individuals without cardiac, renal, or hepatic failure, despite a significantly stronger alteration of the electrolyte balance with sodium phosphate.