Changes In Serum Phosphate Levels Research Articles

Serum phosphate levels and the development of sepsis associated acute kidney injury: evidence from two independent databases.

We aimed to investigate the association between serum phosphate levels and the risk for developing sepsis associated acute kidney injury (SAKI). Septic patients from the Medical Information Mart for Intensive Care IV (MIMIC IV) and the eICU Collaborative Research Database (eICU-CRD) were enrolled. Restricted cubic spline (RCS) was used to visualize the relationship between phosphate levels and the risk of SAKI. Patients were divided into four categories based on their serum phosphate levels. Logistic regression analysis, receiver operating characteristic (ROC) curve and subgroup analysis were performed to evaluate the predictive value of serum phosphate for SAKI. A total of 9,244 and 2,124 patients from the MIMIC IV and eICU-CRD database were included in the final analysis. RCS curve revealed a non-linear correlation between phosphate levels and the risk of SAKI (p for non-linearity <0.05). Each 1 mg/dL increase in phosphate levels was associated with a 1.51 to 1.64-fold increased risk of SAKI (OR 2.51-2.64, p < 0.001) in the MIMIC IV cohort and a 0.29 to 0.38-fold increased risk (OR 1.29-1.38, p < 0.001) in the eICU-CRD cohort. Compared to the normal-low category, hyperphosphatemia and normal-high category were independently associated with an increased risk of SAKI, while hypophosphatemia was independently associated with a decreased risk in the MIMIC IV cohort. A similar trend was observed in the eICU-CRD cohort, but statistical significance disappeared in the hypophosphatemia category and the adjusted model of normal high category. These finding was consistent in subgroup analysis. Elevated serum phosphate, even within the normal range, is an independent risk factor for developing SAKI in septic patients. Abnormal change in serum phosphate levels may be a novel biomarker for early prediction of SAKI occurrence.

The Magnitude of Change in Serum Phosphate Concentration Is Associated with Mortality in Patients with Severe Trauma.

Previous studies have suggested that serum phosphate concentration is a prognostic factor in critically ill patients. However, the association between changes in serum phosphate levels and prognosis of patients with trauma remains unclear. This study included patients with severe trauma who were treated at the emergency department. Delta phosphate (Δ phosphate) was defined as the difference between serum phosphate concentrations measured at baseline and after 24 hours from the initial measurement. Patients were divided into five groups according to their Δ phosphate levels: group I (Δ phosphate <-2 mg/dL), group II (Δ phosphate -2 to -0.5 mg/dL), group III (Δ phosphate -0.5 to 0.5 mg/dL), group IV (Δ phosphate 0.5 to 2 mg/dL), and group V (Δ phosphate ≥2 mg/dL). Overall, 1905 patients with severe trauma were included in the analysis. The 30-day mortality was the lowest in group III and tended to increase in groups with a larger Δ phosphate in both the positive and negative directions (group I: 13.7%, group II: 6.8%, group III: 4.6%, group IV: 6.6%, and group V: 26.8%). In multivariable analysis with group III as the reference group, the odds ratios (ORs) of mortality were statistically significant in group IV [OR, 1.92; 95% confidence interval (CI), 1.05-3.56] and group V (OR, 5.28; 95% CI, 2.47-11.24). An increase in serum phosphate concentrations 24 hours after the initial measurement could be considered as an independent prognostic factor in patients with severe trauma.

Association of serum phosphate and changes in serum phosphate with 28-day mortality in septic shock from MIMIC-IV database

This study aimed to investigate the relationship between serum phosphate levels, changes in serum phosphate levels, and 28-day mortality in patients with septic shock. In this retrospective study, data were collected from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database between 2008 and 2019. Patients were divided into three groups according to the tertiles of serum phosphate levels. Kaplan–Meier curves and log-rank test analyses were used for survival analysis. Multivariate logistic regression, and restricted cubic spline (RCS) curve were used to explore the association between serum phosphate, delta serum phosphate levels and 28-day mortality. In total, 3296 patients with septic shock were included in the study, and the 28-day mortality was 30.0%. Serum phosphate levels were significantly higher in the non-survivor group than in the survivor group. The Kaplan–Meier curves showed significant differences among the three groups. Multivariate logistic regression analysis and the RCS curve showed that serum phosphate levels were independently and positively associated with the 28-day mortality of septic shock. Non-survivors had higher delta serum phosphate levels than survivors. Survival analysis showed that patients with higher delta serum phosphate levels had higher 28-day mortality. A non-linear relationship was detected between delta serum phosphate and 28-day mortality with a point of inflection at − 0.3 mg/dL. Serum phosphate levels were positively and independently associated with 28-day mortality in septic shock. Delta serum phosphate level was a high-risk factor for patients with septic shock.

Predictions of Serum Phosphate Concentration during Continuous Renal Replacement Therapy Using a Steady-State Mass Balance Model

Introduction: Hypophosphatemia is common during continuous renal replacement therapy (CRRT), but serum phosphate levels can potentially be maintained during treatment by either intravenous phosphate supplementation or addition of phosphate to renal replacement therapy (RRT) solutions. Methods: We developed a steady-state phosphate mass balance model to assess the effects of CRRT dose on serum phosphate concentration when using both phosphate-free and phosphate-containing RRT solutions, with emphasis on low CRRT doses. Results: The model predicted that measurements of serum phosphate concentration prior to (initial) and during CRRT (final) together with clinical data on CRRT dose, treatment duration, and phosphate supplementation can determine model patient parameters, that is, both the initial generation rate and clearance of phosphate prior to CRRT. Model parameters were then calculated from average patient data reported in several previous publications with a standard or high CRRT dose. Using representative model parameters for typical patients, predictions were then made of the effect of low CRRT dose on the change in serum phosphate levels after implementation of CRRT. The model predicted that CRRT at a low dose using phosphate-free RRT solutions will limit, but not eliminate, the incidence of hypophosphatemia. Further, the model predicted that CRRT at a low dose will have virtually no influence on the incidence of hyperphosphatemia when using phosphate-containing RRT solutions. Conclusions: This report identifies the clinical measurements to be used with the proposed model for individualizing the CRRT dose and RRT phosphate concentration to maintain serum phosphate concentrations in a desired range.

Phosphate Homeostasis and Disorders of Phosphate Metabolism.

Phosphate is indispensable for human life and evolutionary changes over several millions of years have established tightly regulated mechanisms to ensure phosphate homeostasis. In this process, calcium and phosphate metabolism have come to be intricately linked together. Three hormones (PTH, FGF23 and Calcitriol) maintain the fine balance of calcium and phosphate metabolism through their actions at three sites (the gut, the kidneys and the skeleton). Disorders that disrupt this balance can have serious clinical consequences. Acute changes in serum phosphate levels can result in life threatening complications like respiratory failure and cardiac arrythmias. Chronic hypophosphataemia predominantly affects the musculoskeletal system and presents as impaired linear growth, rickets, osteomalacia and dental problems. Hyperphosphataemia is very common in the setting of chronic kidney disease and can be difficult to manage. A thorough understanding of calcium and phosphate homeostasis is essential to diagnose and treat conditions associated with hypo and hyperphosphataemia. In this review, we will discuss the calcium and phosphate metabolism, aetiologies and management of hypo and hyperphosphataemia.

Four hundred IU vs One thousand IU of vitamin D supplementation in first episode of nephrotic syndrome

Use of steroids in nephrotic children may lead to changes in bone mineral density and osteoporosis eventually affecting growth on a long term basis. We compared the proportionate changes in bone mineral content (BMC) and density(BMD), Vitamin D levels, Serum Calcium, phosphate and alkaline phosphatase levels in nephrotic children with the aim of giving high Vs low vitamin D doses (1000 IU Vs 400 IU) to two groups; group 1 (n=20) vs group 2 (n=20) respectively. The median BMC in group 1 increased from 11.53±3.48 g to 11.61±3.54 g after 1000 IU Vitamin D supplement and was statistically significant. However group 2 showed insignificant increases in BMC from 11.24±2.71 g to 11.25±2.67 g following 400IU Vitamin D. The change in BMD observed in group 1 from a mean of 0.426 to 0.429g/cm2 whereas in group 2 with 400 IU of vitamin D it didn’t show any significant change. The median vitamin D increased significantly in both groups; from 16.62±7.20 ng/ml to 27.45±6.47 ng/ml in group 1 while in group 2 from 18.72±8.07 ng/ml to 26.18±7.61 ng/ml which was statistically significant. The serum calcium levels normalized irrespective of 1000 IU or 400 IU of vitamin D supplementation. Changes in serum phosphate levels (decline from initial) were statistically significant however the changes in serum ALP were insignificant. We concluded that children supplemented with 1000 IU /day of vitamin D had better osteoprotection as compared to the other group.

Evaluation of Minimal Optimal Dose of Intravenous Ferric Carboxymaltose for Treatment of Iron Deficiency Anemia and Risk of Transient Hyperferritinemia.

Iron supplementation is administered orally or intravenously to treat iron-deficiency anemia (IDA). Ferric Carboxymaltose (FCM) "Ferinject®" is an intravenous (IV) iron preparation that has emerged as a safe therapeutic option for treating IDA in the past decade. This study aimed to evaluate safety and efficacy of carboxymaltose in a cohort of patients with IDA not responding to oral therapy. This 12-month retrospective study included 106 patients with IDA, with-or without bariatric surgery, who received (single or multiple doses) of Carboxymaltose 500mg/10mL. Data points included patients' demographics, baseline data for Hb, platelet, ferritin, and MCV pre-and at 1, 2, and 3 months following different doses of IV-Carboxymaltose. Changes in Hb, MCV, platelets, and ferritin levels were recorded in response to Carboxymaltose to assess the optimal dose, risk of hyperferritinemia, and hypophosphatemia. At three months (95 days) follow-up, the median change pre-and post-therapy in hemoglobin was from 9.5 to 11.9g/dL (p < 0.01), MCV 73.6-80.5fL (p < 0.01), and ferritin 5.3-93.8ng/mL. A significant difference was observed between platelet count of patients who underwent bariatric surgery and those who did not. An optimal ferritin response (>30ng/mL) was observed in 87.8% of patients who received first dose, and none of the full three doses showed no response. 37% of patients who received two doses developed hyperferritinemia. Serum phosphate levels were assessed in 28 cases, and hypophosphatemia was observed in 25% of these patients. Carboxymaltose is a reliable option for IDA. IV-FCM therapy helps achieve significant improvement in hemoglobin concentration and MCV from the first dose carrying a low reversible risk of hyperferritinemia following multiple doses. An interesting finding of this study is the discovery of a population of IDA patients requiring periodic assessment for iron reinfusion to sustain normal levels, mostly post-bariatric surgery. Changes in serum phosphate levels reported to occur consecutively with FCM treatment should be further studied.

Erdafitinib's effect on serum phosphate justifies its pharmacodynamically guided dosing in patients with cancer.

A population pharmacokinetic (PK)–pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK‐PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once‐daily oral continuous (0.5–12 mg) and intermittent (10–12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib‐related changes in serum phosphate levels. Phosphate is used as a biomarker for erdafitinib's efficacy and safety: increases in serum phosphate were observed after dosing with erdafitinib, which were associated with fibroblast growth factor receptor target engagement via inhibition of renal fibroblast growth factor 23–mediated signaling. PK‐PD model‐based simulations were performed to assess the approved PD‐guided dosing algorithm of erdafitinib (8 mg once‐daily continuous dosing, with up‐titration to 9 mg based on phosphate levels [<5.5 mg/dl] and tolerability at 14–21 days of treatment). The serum phosphate concentrations increased after the first dose and reached near maximal level after 14 days of continuous treatment. Serum phosphate increased with erdafitinib free drug concentrations: doubling the free concentration resulted in a 1.8‐fold increase in drug‐related phosphate changes. Dose adjustment after at least 14 days of dosing was supported by achievement of >95% maximal serum phosphate concentration. The peak‐to‐trough fluctuation within a dosing interval was limited for serum phosphate concentrations (5.68–5.65 mg/dl on Day 14), supporting phosphate monitoring at any time relative to dosing. Baseline phosphate was higher in women, otherwise, none of the investigated covariate–parameter relationships were considered clinically relevant. Simulations suggest that the starting dose of 8‐mg with up‐titration to 9‐mg on Days 14–21 maximized the number of patients within the target serum phosphate concentrations (5.5–7 mg/dl) while limiting the number of treatment interruptions. The findings from the PK‐PD model provided a detailed understanding of the erdafitinib concentration‐related phosphate changes over time, which supports erdafitinib's dosing algorithm.

Serum Phosphate Profile of Children With Severe Acute Malnutrition Treated With Locally Prepared Therapeutic Feeds: A Prospective Observational Study

Background: Malnutrition in children &lt; 5 years is a public health concern due to its associated high morbidity, mortality and serious long-term consequences. The World Health Organization (WHO) recommends 10 steps for the management of severe acute malnutrition (SAM) children which also involves correction of electrolyte disturbances. Treatment with diets having inadequate amounts of minerals like phosphate can result in refeeding syndrome and other abnormalities. We conducted the study among children with medically complicated SAM to evaluate their serum phosphate levels after receiving locally prepared therapeutic feeds and its associations of other factors. Methods: The study was conducted with 120 hospitalized SAM children aged 6 - 59 months with presence of other illnesses. All children were managed according to the WHO protocol and facility-based management of SAM guidelines of the government of India. Basic demographic details of the child were recorded. Weight of the child was recorded daily, while length/height and mid-upper arm circumference (MUAC) were recorded weekly. We evaluated changes in serum phosphate levels at three time points: on admission, during transition and at discharge. Binary logistic regression analysis was conducted to assess the association of hypophosphatemia with several other indicators. Results: Mean serum phosphate was 4.38 ± 1.07, 4.48 ± 1.16 and 5.13 ± 1.10 mg/dL on admission, during transition and at discharge, respectively. Hypophosphatemia was present among 30 (25%) children on admission, 28 (23.3%) children during transition and 10 (8.3%) children at discharge, which showed a decrease in the prevalence of hypophosphatemia from admission to transition and discharge using the current treatment. The finding also showed positive and significant changes in serum phosphate levels among children who were admitted without edema compared to those admitted with edema. Binary logistic regression estimates showed that older children, children with lower WAZ, hypokalemia, hyponatremia and anemia had higher odds of hypophosphatemia. Male children had lower odds of hypophosphatemia. Conclusion: The nutritional therapy with locally prepared starter and catch-up diet was effective in normalizing hypophosphatemia in the majority of children treated. Serum potassium and serum sodium levels were significantly associated with serum phosphate, indicating the need for careful monitoring of serum phosphate in the presence of hypokalemia and hyponatremia among SAM children. Int J Clin Pediatr. 2021;10(2-3):35-42 doi: https://doi.org/10.14740/ijcp458

呼吸性アルカローシスによる潜在的低リン血症の経時的変化(Changes over time in potential hypophosphatemia due to respiratory alkalosis)

要旨低リン血症の原因に，呼吸性アルカローシスによるリンの細胞内移動が知られているが，臨床的に呼吸性アルカローシス患者での血清リン値の時間的変化を観察した報告はない。我々は，動悸を訴える呼吸性アルカローシスの患者に認められた低リン血症の時間的経過を観察した。本報告では，全例で来院時の採血で呼吸性アルカローシスと低リン血症を認めたが，24時間以内の再検査が行えなかった1症例を除き，3例は12時間以内に再度血液検査が行われ，呼吸性アルカローシスと血清リン値の改善を確認した。呼吸性アルカローシスによる低リン血症は，ホスホフルクトキナーゼやグリセルアルデヒド3リン酸デヒドロゲナーゼなどの解糖系の酵素活性によってATP生成が亢進し，解糖系にリンが取り込まれるため一時的な細胞内リン欠乏が生じるが，リンの絶対量が不足するわけではない。呼吸性アルカローシスは，様々な病態で発生するが，酸塩基平衡の確認をしなければ捉えきれない場合がある。救急外来に搬送される様々な病態によって生じた呼吸性アルカローシスにおいても同様の経過を示す症例の存在が示唆され，常に潜在的な低リン血症の存在に注意する必要がある。そして，低リン血症が認められたときには，その原因を注意深く検討しなくてはならないことを再周知したい。

Nationwide Turkish Cohort Study of Hypophosphatemic Rickets

Objective:Hypophosphatemic rickets (HR) is a rare renal phosphate-wasting disorder, which is usually X-linked and is commonly caused by PHEX mutations. The treatment and follow-up of HR is challenging due to imperfect treatment options.Methods:Here we present nationwide initial and follow-up data on HR.Results:From 24 centers, 166 patients were included in the study. Genetic analysis (n=75) showed PHEX mutation in 80% of patients. The mean follow-up period was 6.7±2.4 years. During the first 3-years of treatment (n=91), mild increase in phosphate, decrease in alkaline phosphatase and elevation in parathyroid hormone (PTH) levels were detected. The height standard deviation scores were -2.38, -2.77, -2.72, -2.47 at initial, 1st, 2nd and 3rd year of treatment, respectively (p>0.05). On follow-up 36% of the patients showed complete or significant improvement in leg deformities and these patients had similar phosphate levels at presentation with better levels in 1st and 2nd years of treatment; even the treatment doses of phosphate were similar. Furthermore, 27 patients developed nephrocalcinosis (NC), the patients showed no difference in biochemical differences at presentation and follow-up, but 3rd year PTH was higher. However, higher treatment doses of phosphate and calcitriol were found in the NC group.Conclusion:HR treatment and follow-up is challenging and our results showed higher treatment doses were associated with NC without any change in serum phosphate levels, suggesting that giving higher doses led to increased phosphaturia, probably through stimulation of fibroblast growth factor 23. However, higher calcitriol doses could improve bone deformities. Safer and more efficacious therapies are needed.

Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2\u2009years of age \u2013 a multicenter retrospective study

BackgroundTuberous sclerosis complex (TSC) is a multisystem disease with prominent neurologic manifestations such as epilepsy, cognitive impairment and autism spectrum disorder. mTOR inhibitors have successfully been used to treat TSC-related manifestations in older children and adults. However, data on their safety and efficacy in infants and young children are scarce. The objective of this study is to assess the utility and safety of mTOR inhibitor treatment in TSC patients under the age of 2 years.ResultsA total of 17 children (median age at study inclusion 2.4 years, range 0–6; 12 males, 5 females) with TSC who received early mTOR inhibitor therapy were studied. mTOR inhibitor treatment was started at a median age of 5 months (range 0–19 months). Reasons for initiation of treatment were cardiac rhabdomyomas (6 cases), subependymal giant cell astrocytomas (SEGA, 5 cases), combination of cardiac rhabdomyomas and SEGA (1 case), refractory epilepsy (4 cases) and disabling congenital focal lymphedema (1 case). In all cases everolimus was used. Everolimus therapy was overall well tolerated. Adverse events were classified according to the Common Terminology Criteria of Adverse Events (CTCAE, Version 5.0). Grade 1–2 adverse events occurred in 12 patients and included mild transient stomatitis (2 cases), worsening of infantile acne (1 case), increases of serum cholesterol and triglycerides (4 cases), changes in serum phosphate levels (2 cases), increase of cholinesterase (2 cases), transient neutropenia (2 cases), transient anemia (1 case), transient lymphopenia (1 case) and recurrent infections (7 cases). No grade 3–4 adverse events were reported. Treatment is currently continued in 13/17 patients. Benefits were reported in 14/17 patients and included decrease of cardiac rhabdomyoma size and improvement of arrhythmia, decrease of SEGA size, reduction of seizure frequency and regression of congenital focal lymphedema. Despite everolimus therapy, two patients treated for intractable epilepsy are still experiencing seizures and another one treated for SEGA showed no volume reduction.ConclusionThis retrospective multicenter study demonstrates that mTOR inhibitor treatment with everolimus is safe in TSC patients under the age of 2 years and shows beneficial effects on cardiac manifestations, SEGA size and early epilepsy.

Postoperative serum phosphate drop is an early marker of liver growth after ALPPS stage 1 and predicts outcome after ALPPS stage 2

Background: The accelerated hypertrophy after ALPPS stage-1 is based on rapid cell devision. This process demands tremendous amounts of phosphate for the synthesis of nucleotidetriphosphates during DNA replication. The aim of this study was to analyze whether changes in serum phosphate levels are associated with liver growth and posthepatectomy liver failure (PHLF) after ALPPS. Methods: Serum phosphate changes within the first 7 postoperative days (POD) after ALPPS stage-1 were assessed in 49 patients. All patients underwent volumetric imaging of the future liver remnant before ALPPS and at POD 7 after stage-1. The association of serum phosphate drop (PD) after ALPPS stage-1 with liver hypertrophy after stage-1 and with incidence of PHFL after stage-2 were investigated. Results: After ALPPS stage-1, serum phosphate levels decreased from 1.1 mmol/l (IQR 0.92-1.2) preoperatively to a nadir of 0.7 mmol/l (IQR 0.54-1.02; p< 0.001). The median PD was 40.9%/day (IQR -68.9 to -17.3%/d). Patients with a PD >40%/day showed significantly accelerated liver hypertrophy (median +264ml; IQR 196-347ml) after ALPPS stage-1 as compared with patients with a drop ≤40%/day (median +183ml; IQR 112-211ml; p=0.018). ROC analysis confirmed a PD >40%/day after stage-1 as a predictor of PHLF after ALPPS stage-2 according to 50-50 (AUC 0.769, p=0.015) and ISGLS criteria (AUC 0.760, 0.006). Conclusion: Serum PD represents a novel early predictor of liver growth and PHLF in patients undergoing ALPPS.

Évaluation d’interventions éducatives auprès du patient dialysé

The treatment of end-stage renal disease requires a significant number of drug treatments. At patient level, daily management is somewhat difficult: Number of prescribed pills, medication side effects, treatment of asymptomatic diseases… The objective of the study was to investigate the effect of guidance tailored to each patient receiving hemodialysis, performed by the pharmacist (educational interventions). Adult haemodialysis patients with hyperphosphatemia despite phosphate binders were eligible for study entry. The study was controlled with a retrospective group. The primary end point was a change in serum phosphate levels. The secondary end points were therapy adherence, knowledge regarding phosphate management and patient satisfaction with the programme. Sixteen patients in each group participated in the study. The mean serum phosphate level at endpoint was decreased by 0.25 mmol/L in the intervention group (0.41 mmol/L for patients with expectancy for this reduction) and by 0.11 mmol/L in the control group. Five patients normalized their serum phosphate level in the intervention group against three patients in the control group. The mean score of adherence decreased from 1.75 to 1.50. The main factors affecting adherence were forgetfulness or carelessness in taking medications and number of daily doses. This study showed the feasibility of an improvement in serum phosphate level and adherence driven by therapeutic education, though effect was highly amplified by the motivation induced by pharmaceutical guidance. Patients emphasize the importance of the involvement of pharmacist in their care.

Phosphate Kinetics in Hemodialysis: Application of Delayed Pseudo One-Compartment Model

Background/Aims: Various body-regulating mechanisms try to counteract rapid changes in serum phosphate levels during hemodialysis (HD). Neither recently proposed nor other existing standard compartment models are able to capture clinically observed intradialytic serum phosphate rebound. Methods: Phosphate serum concentration was frequently measured during 75 HD sessions in 25 patients. Time delay was introduced into the standard pseudo one-compartment model in order to reflect the time needed for the body-regulating mechanism to affect serum phosphate level. Results: Measured serum phosphate concentration at the end of 4 h dialysis session was on average larger than 1 h earlier (p value = 0.015). The model with time delay reproduced successfully 19 out of 21 and 9 out of 10 sessions with and without recorded intradialytic rebound, respectively. Conclusion: The intradialytic serum phosphate rebound is associated with the time delay reflecting efficacy of body-regulating mechanisms, that is, the larger the delay the larger is the intradialytic rebound.

An integrated understanding of the physiological response to elevated extracellular phosphate

Recent studies have suggested that changes in serum phosphate levels influence pathological states associated with aging such as cancer, bone metabolism, and cardiovascular function, even in individuals with normal renal function. The causes are only beginning to be elucidated but are likely a combination of endocrine, paracrine, autocrine, and cell autonomous effects. We have used an integrated quantitative biology approach, combining transcriptomics and proteomics to define a multi-phase, extracellular phosphate-induced, signaling network in pre-osteoblasts as well as primary human and mouse mesenchymal stromal cells. We identified a rapid mitogenic response stimulated by elevated phosphate that results in the induction of immediate early genes including c-fos. The mechanism of activation requires FGF receptor signaling followed by stimulation of N-Ras and activation of AP-1 and serum response elements. A distinct long-term response also requires FGF receptor signaling and results in N-Ras activation and expression of genes and secretion of proteins involved in matrix regulation, calcification, and angiogenesis. The late response is synergistically enhanced by addition of FGF23 peptide. The intermediate phase results in increased oxidative phosphorylation and ATP production and is necessary for the late response providing a functional link between the phases. Collectively, the results define elevated phosphate, as a mitogen and define specific mechanisms by which phosphate stimulates proliferation and matrix regulation. Our approach provides a comprehensive understanding of the cellular response to elevated extracellular phosphate, functionally connecting temporally coordinated signaling, transcriptional, and metabolic events with changes in long-term cell behavior.

Comparison of Calcium Acetate and Sevelamer on Vascular Function and Fibroblast Growth Factor 23 in CKD Patients: A Randomized Clinical Trial

Fibroblast growth factor 23 (FGF-23) is a marker of endothelial dysfunction and atherosclerotic complications in patients with chronic kidney disease (CKD). Because previous studies suggested that sevelamer may exert effects on FGF-23 level and endothelial function independently of its phosphate-lowering action, we tested the effect of sevelamer versus calcium acetate on vascular function and FGF-23 levels. Randomized prospective open-label trial. Patients with stage 4 CKD with hyperphosphatemia (n = 100). An 8-week intervention with sevelamer (n = 47) and calcium acetate (n = 53). The primary study outcome was change in flow-mediated vasodilatation in the forearm. The secondary outcome was change in FGF-23 levels. Serum phosphate levels decreased in both treatment arms (P < 0.001), but more markedly in the sevelamer group (P < 0.001). Flow-mediated vasodilatation increased from 6.1% to 7.1% (P < 0.001) in sevelamer-treated patients, whereas it was unchanged in the calcium-acetate group (6.0% vs 6.0%). In a combined analysis, treatment-induced changes in flow-mediated vasodilatation were (P < 0.001) associated with simultaneous changes in FGF-23 levels (-27.1% [-33.2% to -8.8%] for the sevelamer group; 3.5% [-8.4% to 12.1%] for the calcium acetate group), as well as with C-reactive protein and fetuin A levels. These relationships were confirmed in multiple regression analysis adjusting for changes in serum phosphate levels and other factors. Unblinded randomized controlled study that cannot establish mechanisms of effect. In hyperphosphatemic patients with stage 4 CKD, treatment with phosphate lowering induces measurable improvements in flow-mediated vasodilatation. Furthermore, independently of serum phosphate level, FGF-23 level changes induced by phosphate binders are associated with simultaneous changes in flow-mediated vasodilatation. These observations are compatible with the hypothesis that FGF-23 may contribute to vascular dysfunction in this population.

Acute parathyroid hormone increase by oral peptones administration after roux-en-Y gastric bypass surgery in obese subjects: Role of phosphate in the rapid control of parathyroid hormone release

It is generally considered that changes in serum phosphate levels do not alter parathyroid hormone (PTH) secretion in the absence of concomitant changes in ionized serum calcium level in humans. An acute rise in PTH was shown after phosphate administration by intraduodenal gavage in rats. We aimed to study gastrin, phosphate, PTH, ionized calcium (iCa), and blood pH responses to oral peptones in morbidly obese patients before and after roux-en-Y gastric bypass (RYGB) surgery. These parameters were evaluated in response to an oral peptone load in 24 (18 male and 6 female) obese subjects before and 6 months after RYGB surgery. In 12 gastric bypass patients, we also evaluated PTH and phosphate after peptones plus aluminum hydroxide administration to suppress phosphate absorption. Before RYGB, peptones increased gastrin (P < .001), and decreased iCa (P < .01) without changes in PTH or pH. Both phosphate and PTH markedly increased after RYGB with the peptones oral load (P < .01), without changes in pH, iCa, or gastrin. There was a significant, direct relationship between the increase of phosphate and the increase of PTH in the patients treated with aluminum hydroxide (r(2) = 0.78; P < .0001). Rapid delivery of peptones in the jejunum in bypassed obese patients results in a significant rise in phosphate and PTH, in the absence of changes of other PTH regulators, possibly mediated by a signaling from the gastrointestinal tract. RYGB patients provide an opportunity to study the control of PTH secretion, with potential relevant clinical implications.

Effects of fasting, feeding, and bisphosphonate administration on serum calcitriol levels in phosphate-deprived rats

In a recent study, we showed in phosphate-deprived rats that morning feeding decreased serum phosphate and increased serum calcium values as compared with similar rats fasted overnight, and high doses of bisphosphonates did not reduce the magnitude of hypercalcemia. In the present study, we evaluated in phosphate-deprived rats whether serum calcitriol values were: (1) affected by the differences in serum phosphate induced by morning feeding and overnight fasting, (2) correlated with changes in serum phosphate levels, and (3) influenced by bisphosphonate administration. Four groups of rats were studied: (1) low-phosphate diet (LPD; P < 0.05%), (2) LPD + the bisphosphonate pamidronate (APD), (3) normal diet (ND; P 0.6%), and (4) ND + APD. Both diets contained 0.6% calcium. In rats receiving APD, high doses (0.8 mg/kg) were given subcutaneously four times during the study. On day 11, rats were sacrificed after an overnight fast or two to four hours after morning feeding. In the fed phosphate-deprived rats (LPD and LPD + APD), serum phosphate levels were less (P < 0.05) and serum calcium levels were greater (P < 0.05) than in similar rats fasted overnight. In rats on the ND (ND and ND + APD), no differences were observed between fed and fasted rats. In phosphate-deprived rats, serum calcitriol levels were greater (LPD, P < 0.05) or tended to be greater (LPD + APD, P = 0.10) in the fed than in the fasted groups. In APD-treated rats, serum calcitriol values were greater than in rats not given APD whether rats were (1) fed or fasted, or (2) on an LPD or ND. An inverse correlation was present between serum phosphate and serum calcitriol (r = -0.58, P = 0.001). In a stepwise regression model in which serum calcitriol was the dependent variable and independent variables were APD administration and serum calcium, phosphate, and PTH, serum phosphate (P = 0.003) had an inverse and APD (P < 0.001) administration a direct effect on serum calcitriol (r2 = 0.59). Calcitriol synthesis is rapidly inducible in rats during chronic phosphate deprivation, and the increase in serum calcitriol values is best attributed to feeding-induced decreases in serum phosphate. APD administration independently increases serum calcitriol levels in rats on normal and phosphate-deprived diets. Finally, whether our results in the rat are applicable to the clinical setting should be evaluated because in previous human studies of dietary phosphate restriction, serum calcitriol measurements were performed the morning after an overnight fast.

Persistent, progressive hypophosphataemia after voluntary hyperventilation

Hyperventilation (HV) and respiratory alkalosis are associated with hypophosphataemia, although the extent and duration of HV required to produce changes in serum phosphate levels are not known. We sought to characterize the effects of HV, with or without dextrose loading, on serum phosphate levels and other biochemical parameters. HV was monitored by controlling the end-tidal partial pressure of carbon dioxide (PETCO(2)). The effect of dextrose was studied because infusion of a glucose load is known to promote a fall in serum phosphate via stimulation of glycolysis. Eight healthy volunteers were enrolled in four study protocols: (1) HV for 20 min to a PETCO(2) of 25-30 mmHg (mild); (2) HV for 20 min to a PETCO(2) of 15-20 mmHg (severe); (3) mild HV with intravenous dextrose loading, and (4) dextrose loading alone. Periodic measurements of serum phosphate, venous pH, serum 2,3-diphosphoglycerate (2,3-DPG) and other parameters were made. Serum phosphate fell during HV and continued to decline after cessation of HV. Dextrose loading alone caused a fall in serum phosphate that continued for at least 30 min after cessation of the infusion (P<0.0002). HV combined with dextrose resulted in a greater decline in serum phosphate than either variable alone (P=0.003). The maximal decline in serum phosphate occurred in severe HV, with a mean decrease of 0.38 mmol/l at 20 min after cessation of HV (P<0.0001). Serum phosphate was still significantly lowered compared with baseline at 90 min after cessation of HV (P=0.001). Other significant changes seen with HV included a decrease in serum glucose (P<0.01), a decrease in serum potassium (P<0.05) and an increase in venous pH (P<0.007). Serum 2, 3-DPG levels did not change significantly in any study protocol. Thus relatively mild acute HV produces significant changes in serum phosphate. In both mild and severe HV this effect is progressive after cessation of HV. This phenomenon has not been shown before, and may have significant clinical implications.