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Effects of Nicotinamide and Lanthanum Carbonate on Serum Phosphate and Fibroblast Growth Factor-23 in CKD: The COMBINE Trial.
Ix, JH, Isakova, T, Larive, B, Raphael, KL, Raj, DS, Cheung, AK, Sprague, SM, Fried, LF, Gassman, JJ, Middleton, JP, et al
Journal of the American Society of Nephrology : JASN. 2019;(6):1096-1108
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Abstract
BACKGROUND Higher serum phosphate and fibroblast growth factor-23 (FGF23) levels may be modifiable to prevent cardiovascular disease in CKD. Short-term studies have reported modest efficacy in phosphate and FGF23 reduction with intestinal phosphate binders in CKD. METHODS To investigate effects of lanthanum carbonate (LC; a phosphate binder) and/or nicotinamide (NAM; an inhibitor of active intestinal phosphate transport) on serum phosphate and FGF23 in stage 3b/4 CKD, we conducted a randomized trial among individuals with eGFR 20-45 ml/min per 1.73 m2 to NAM (750 mg twice daily) plus LC (1000 mg thrice daily), NAM plus LC placebo, LC plus NAM placebo, or double placebo for 12 months. Dual primary end points were change from baseline in serum phosphate and intact FGF23 concentrations. RESULTS Mean eGFR for the 205 participants was 32ml/min per 1.73 m2. At baseline, serum phosphate was 3.7 mg/dl and median FGF23 was 99 pg/ml (10th, 90th percentiles: 59, 205). Mean rates of change in phosphate increased slightly over 12 months in all groups and did not differ significantly across arms. Similarly, percent changes in FGF23 per 12 months increased for all arms except LC plus placebo, and did not differ significantly across arms. Gastrointestinal symptoms limited adherence. Adverse events rates were similar across arms. CONCLUSIONS LC and/or NAM treatment did not significantly lower serum phosphate or FGF23 in stage 3b/4 CKD over 12 months. Although these agents appeared safe, intestinal symptoms limited adherence. Reducing phosphate and FGF23 in nondialysis CKD will require new approaches.
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Effect of 16-weeks vitamin D replacement on calcium-phosphate homeostasis in overweight and obese adults.
Mesinovic, J, Mousa, A, Wilson, K, Scragg, R, Plebanski, M, de Courten, M, Scott, D, Naderpoor, N, de Courten, B
The Journal of steroid biochemistry and molecular biology. 2019;:169-175
Abstract
This randomised placebo-controlled trial aimed to determine the effect of 16-weeks cholecalciferol supplementation on calcium-phosphate homeostasis and bone mineral density (BMD) in overweight and obese adults. Fifty-four vitamin D-deficient (25OHD<50 nmol/L), overweight and obese adults (mean age 32 ± 8.5 years) were included in the trial. Participants were randomly assigned to receive either a bolus oral dose of 100,000 IU cholecalciferol followed by 4000 IU cholecalciferol/d or a matching placebo for 16 weeks. Before and after the intervention, serum calcium, phosphate, 25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone (iPTH) and C-terminal plasma fibroblast growth factor-23 (cFGF-23) concentrations were measured. Whole-body BMD was assessed using dual-energy X-ray absorptiometry (DXA) and diet and sun exposure were assessed using self-administered questionnaires. There were no significant differences in baseline characteristics between the vitamin D and placebo group. After 16-weeks of vitamin D supplementation, mean changes in 25(OH)D concentration were higher in the vitamin D group (57 nmol/L 95% CI 49, 65) compared with placebo (2 nmol/L 95% CI -4, 8), P < 0.001. Additionally, iPTH concentrations declined in the vitamin D group (-1.19 pmol/L 95% CI -1.9, -0.47) compared with placebo (0.14 pmol/L 95% CI -0.49, 0.77), P = 0.006. There were no significant differences in calcium, phosphate, iPTH and cFGF-23 concentrations and whole-body BMD between vitamin D and placebo at follow-up. Inverse correlations were observed between mean change in serum iPTH and cFGF-23 in the vitamin D group only (r=-0.41, P = 0.029). In individuals with greater vitamin D deficiency at baseline (25(OH)D < 30 nmol/L), there was a significant increase in mean whole-body BMD (0.01 g/cm2, 95% CI 0.001, 0.025) however, the mean change in BMD was not different between vitamin D and placebo groups in this sub-group analysis. We conclude that cholecalciferol supplementation for 16 weeks increases serum 25(OH)D concentrations and reduces iPTH concentrations in overweight and obese, but otherwise healthy adults with vitamin D deficiency, and has no effect on calcium, phosphate and iFGF-23 concentrations and whole-body BMD.
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Effects of Dapagliflozin on Circulating Markers of Phosphate Homeostasis.
de Jong, MA, Petrykiv, SI, Laverman, GD, van Herwaarden, AE, de Zeeuw, D, Bakker, SJL, Heerspink, HJL, de Borst, MH
Clinical journal of the American Society of Nephrology : CJASN. 2019;(1):66-73
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BACKGROUND AND OBJECTIVES The sodium glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin is a novel drug for the treatment of diabetes mellitus. Recent studies suggest that SGLT-2 inhibitors affect phosphate homeostasis, but their effects on phosphate-regulating hormones in patients with diabetic kidney disease are still unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a post-hoc analysis of a double-blind, randomized, crossover trial in patients with type 2 diabetes with early-stage diabetic kidney disease on stable renin-angiotensin-aldosterone system blockade, with an albumin-to-creatinine ratio between 100 and 3500 mg/g, eGFR≥45 ml/min per 1.73 m2, and glycosylated hemoglobin≥7.2% and <11.4%. Patients were randomized to dapagliflozin 10 mg/d or placebo during consecutive 6-week study periods, separated by a 6-week wash-out. We investigated effects on circulating phosphate, calcium, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) levels. RESULTS Thirty-one patients (age 62 years; 23% female) were analyzed. Compared with placebo, dapagliflozin increased serum phosphate by 9% (95% confidence interval, 4% to 15%; P=0.002), PTH increased by 16% (3% to 30%; P=0.01), FGF23 increased by 19% (0.3% to 42%; P=0.05), and serum 1,25(OH)2D decreased by -12% (-25% to 4%; P=0.12). Calcium and 25(OH)D were unaffected. We found no correlation between changes in markers of phosphate homeostasis and changes in eGFR or 24-hour albumin excretion during dapagliflozin treatment. CONCLUSIONS Dapagliflozin increases serum phosphate, plasma PTH, and FGF23. This effect was independent of concomitant changes in eGFR or 24-hour albumin excretion.
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The Effects of Sodium Phosphate Supplementation on Physiological Responses to Submaximal Exercise and 20 km Cycling Time-Trial Performance.
Brown, JA, Glaister, M
Journal of dietary supplements. 2019;(5):564-575
Abstract
The aim of this study was to examine the effects of sodium phosphate (SP) supplementation on physiological responses to submaximal exercise and 20 km cycling time-trial performance. Using a randomized, double-blind, crossover design, 20 endurance-trained male cyclists (age: 31 ± 6 years; height: 1.82 ± 0.07 m; body mass: 76.3 ± 7.0 kg; maximal oxygen uptake [V̇O2max]: 57.9 ± 5.5 mL·kg-1·min-1) completed two supplementation trials separated by a 14-day washout period. The trials consisted of 10 minutes of cycling at 65% V̇O2max followed by a 20 km time trial. Expired air was monitored throughout each trial for the evaluation of V̇O2, minute ventilation (V̇E), and respiratory exchange ratio (RER). Heart rate was monitored during each trial along with ratings of perceived exertion (RPE) and blood lactate concentration. For four days before each trial, participants ingested 50 mg·kg fat-free mass-1·day-1 of either SP or placebo. There were no effects (p ≥ .05) of supplementation on physiological responses during cycling at 65% V̇O2max. There were also no effects of supplementation on time-trial performance (placebo: 32.8 ± 2.2 min; SP: 32.8 ± 2.3 min). Nevertheless, relative to placebo, SP increased V̇E (mean difference: 3.81 L·min-1; 95% confidence interval: [0.16, 7.46 L·min-1]), RER (mean difference: 0.020; 95% confidence interval: [0.004, 0.036]), and RPE (mean difference: 0.39; 95% confidence interval: [0.04, 0.73]) during time trials, as well as post time-trial blood lactate concentration (mean difference: 1.06 mmol·L-1; 95% confidence interval: [0.31, 1.80 mmol·L-1]). In conclusion, SP supplementation has no significant effects on submaximal physiological responses or 20 km time-trial performance.
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Effects of oral activated charcoal on hyperphosphatemia and vascular calcification in Chinese patients with stage 3-4 chronic kidney disease.
Gao, Y, Wang, G, Li, Y, Lv, C, Wang, Z
Journal of nephrology. 2019;(2):265-272
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BACKGROUND The relationship between oral activated charcoal (OAC) and hyperphosphatemia and vascular calcification is not completely clear. We observed and recorded the effects of OAC on hyperphosphatemia and vascular calcification in stage 3-4 chronic kidney disease (CKD). METHODS In a randomized controlled study, we included 97 patients with stage 3-4 CKD. In the first phase of the experiment, the patients were randomly divided into the OAC group and placebo group. The endpoint of this phase was the development of hyperphosphatemia. The patients with hyperphosphatemia were selected into the second phase of the study. These patients underwent coronary artery multidetector computed tomography (MDCT) and were randomly divided into three groups: the OAC group, the calcium carbonate (CC) group and the lanthanum carbonate (LC) group. RESULTS The first and second phases of the experiment were followed for 12 months. In the first phase of the experiment, there was a statistically significant difference in the proportion of patients with hyperphosphatemia between the OAC and placebo groups (28.57% vs. 79.17%, X2 = 24.958, P = 0.000). In the second phase, the differences in coronary calcification score (CACS) between the OAC group, the CC group and the LC group were statistically significant (525.5 ± 104.2 vs 688.1 ± 183.7 vs 431.4 ± 122.5, P < 0.01). CONCLUSION Oral activated charcoal effectively delays the onset of hyperphosphatemia in patients with chronic kidney disease. OAC appears to delay the development of vascular calcifications in stage 3-4 CKD patients.
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Can we IMPROVE cardiovascular outcomes through phosphate lowering in CKD? Rationale and protocol for the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease (IMPROVE-CKD) study.
Lioufas, N, Toussaint, ND, Pedagogos, E, Elder, G, Badve, SV, Pascoe, E, Valks, A, Hawley, C, ,
BMJ open. 2019;(2):e024382
Abstract
INTRODUCTION Patients with chronic kidney disease (CKD) are at heightened cardiovascular risk, which has been associated with abnormalities of bone and mineral metabolism. A deeper understanding of these abnormalities should facilitate improved treatment strategies and patient-level outcomes, but at present there are few large, randomised controlled clinical trials to guide management. Positive associations between serum phosphate and fibroblast growth factor 23 (FGF-23) and cardiovascular morbidity and mortality in both the general and CKD populations have resulted in clinical guidelines suggesting that serum phosphate be targeted towards the normal range, although few randomised and placebo-controlled studies have addressed clinical outcomes using interventions to improve phosphate control. Early preventive measures to reduce the development and progression of vascular calcification, left ventricular hypertrophy and arterial stiffness are crucial in patients with CKD. METHODS AND ANALYSIS We outline the rationale and protocol for an international, multicentre, randomised parallel-group trial assessing the impact of the non-calcium-based phosphate binder, lanthanum carbonate, compared with placebo on surrogate markers of cardiovascular disease in a predialysis CKD population-the IM pact of P hosphate R eduction O n V ascular E nd-points (IMPROVE)-CKD study. The primary objective of the IMPROVE-CKD study is to determine if the use of lanthanum carbonate reduces the burden of cardiovascular disease in patients with CKD stages 3b and 4 when compared with placebo. The primary end-point of the study is change in arterial compliance measured by pulse wave velocity over a 96-week period. Secondary outcomes include change in aortic calcification and biochemical parameters of serum phosphate, parathyroid hormone and FGF-23 levels. ETHICS AND DISSEMINATION Ethical approval for the IMPROVE-CKD trial was obtained by each local Institutional Ethics Committee for all 17 participating sites in Australia, New Zealand and Malaysia prior to study commencement. Results of this clinical trial will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER ACTRN12610000650099.
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Does Adding Various Accelerators to Mineral Trioxide Aggregate Have a Negatively Effect on Push-Out Bond Strength?
İlker, A, Sarıyılmaz, E, Çakici, F
Medical principles and practice : international journal of the Kuwait University, Health Science Centre. 2019;(1):36-40
Abstract
OBJECTIVE This study compares the effect of the white mineral trioxide aggregate (WMTA) accelerators, including disodium hydrogen orthophosphate (Na2HPO4; 2.5 wt%), calcium chloride (CaCl2; 5 and 10 wt%), and KY jelly, on the push-out bond strength of WMTA. The null hypothesis was that the WMTA accelerators would not affect the push-out bond strength of WMTA. MATERIALS AND METHODS Slices (2-mm-thick) were obtained from 75 human mandibular molar distal roots. The slices were enlarged up to size 6 Gates-Glidden burs to obtain a 1.5-mm canal diameter. The slices were randomly divided into 4 experimental groups and a control group (n = 15 in each group). Freshly prepared WMTA mixture was placed into the root slices and stored at 37°C in a 100% humidified atmosphere for 60 days. The force required to dislodge the WMTA cement from the root slice was determined using a universal testing machine. The push-out bond strength was calculated. RESULTS Push- out bond strength of 5- and 10-wt% CaCl2, and 2.5-wt% Na2HPO4 WMTA groups was significantly lower than in the KY-jelly and control groups (p < 0.05). The mean push-out bond strength of KY jelly was lower than in the control group but not statistically significant. CONCLUSION The addition of KY jelly to WMTA did not have an adverse effect on the push-out bond strength of WMTA, in contrast to the other accelerators, including Na2HPO4 and CaCl2, which reduced the push-out bond strength.
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A randomized controlled trial of different serum phosphate ranges in subjects on hemodialysis.
Bhargava, R, Kalra, PA, Hann, M, Brenchley, P, Hurst, H, Hutchison, AJ
BMC nephrology. 2019;(1):37
Abstract
BACKGROUND Hyperphosphataemia in dialysis subjects is associated with increased mortality. However cause and effect has not been proven, and the ideal phosphate target range is unknown despite KDOQI's call for studies over 12 years ago. The design and conduct of a randomized controlled trial is challenging because maintaining two groups within differing target ranges of serum phosphate has not been achieved over a long follow-up of 1 year, in a trial setting, before. The SPIRiT study examines the subject acceptance, recruitment and retention rates for such a study in which subjects were randomised to two distinct serum phosphate concentrations, then titrated and maintained over 12 months. METHODS A two center trial of 104 hemodialysis subjects randomized to lower range LRG 0.8-1.4 mmol/L or 2.5-4.3 mg/dL) and higher range (HRG 1.8-2.4 mmol/L or 5.6-7.4 mg/dL) serum phosphate groups. Two months' titration and ten months' maintenance phase. Interventions were non-calcium phosphate binders, self-help questionnaires, with blood tests at specified time intervals. RESULTS Thirteen percent of the eligible dialysis population were successfully recruited. A mean separation by serum phosphate of 1.1 mg/dL was achieved and maintained between the groups over 10 months. Drop-out rate was 27% with mortality 10%. Nine subjects in the HRG (17.6%) and two subjects in the LRG (3.8%) died during the study, however the study was not powered to detect significant differences in outcomes. CONCLUSION Randomizing dialysis subjects to separate treatment targets for serum phosphate can achieve a clinically significant sustained separation over 12 months. A large scale longer term study is required to examine outcomes including mortality. TRIAL REGISTRATION The trial registration number is ISRCTN24741445 - Date of registration 16th January, retrospectively registered.
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Efficacy and Safety of Tenapanor in Patients with Hyperphosphatemia Receiving Maintenance Hemodialysis: A Randomized Phase 3 Trial.
Block, GA, Rosenbaum, DP, Yan, A, Chertow, GM
Journal of the American Society of Nephrology : JASN. 2019;(4):641-652
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BACKGROUND Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), reduces paracellular phosphate transport. METHODS In this phase 3 randomized, double-blind trial, we randomly assigned patients with hyperphosphatemia receiving maintenance hemodialysis to receive twice-daily oral tenapanor (3, 10, or 30 mg [the latter down-titrated, if needed]) for 8 weeks. Patients were then rerandomized 1:1 to receive either their previously assigned dose or placebo for a 4-week 'withdrawal' period. We measured serum phosphate levels over the course of the trial. The primary end point was mean change in serum phosphate over the 4-week withdrawal period for the tenapanor group (using pooled data) versus the placebo group. RESULTS Of 219 patients randomized, 152 completed both study phases. During the initial 8-week treatment period, all three treatment groups experienced significant decreases in mean serum phosphate (reductions of 1.00, 1.02, and 1.19 mg/dl, corresponding to the 3, 10, and 30 mg [down-titrated] dose groups, respectively). Tenapanor also showed a significant benefit over placebo during the withdrawal period, with a mean increase of 0.85 mg/dl in the placebo group versus a mean increase of 0.02 mg/dl in the pooled tenapanor group. Adverse events were largely limited to softened stool and a modest increase in bowel movement frequency, resulting from increased stool sodium and water content, stemming from tenapanor's mechanism of action. CONCLUSIONS Tenapanor significantly reduced elevated serum phosphate in patients with hyperphosphatemia receiving maintenance hemodialysis. Adverse effects were limited to those induced by its known mechanism of action, which increases stool sodium and water content.
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Optimization of phosphate recovery as struvite from synthetic distillery wastewater using a chemical equilibrium model.
Kumari, S, Jose, S, Jagadevan, S
Environmental science and pollution research international. 2019;(29):30452-30462
Abstract
This study investigates the feasibility of recovery of phosphorus via struvite precipitation from a synthetic anaerobically treated distillery spent wash by optimizing the process using a chemical equilibrium model, namely Visual MINTEQ. Process parameters such as Mg2+, [Formula: see text], and [Formula: see text] ion concentrations and pH were used as inputs into the model. Increasing the molar ratio of [Formula: see text] from 0.8:1 to 1.6:1 at pH 9 led to an increase in phosphate recovery from 88.2 to 99.5%. The model and experimental results were in good agreement in terms of phosphate recovery, indicating that the Visual MINTEQ model can be used to pre-determine the process parameters for struvite synthesis. Increasing the concentration of calcium ion adversely affected the synthesis and purity of struvite, whereas the presence of melanoidins had no significant impact. This study demonstrates that phosphorus recovery through struvite precipitation is a sustainable approach to reclaim phosphorus from high-strength industrial wastewater.