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Therapeutic Effects of Add-On Tenapanor for Hemodialysis Patients with Refractory Hyperphosphatemia.
Shigematsu, T, Une, Y, Ikejiri, K, Kanda, H, Fukagawa, M, Akizawa, T
American journal of nephrology. 2021;(6):496-506
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INTRODUCTION Phosphate binders are used to treat hyperphosphatemia. Some patients have inappropriately controlled serum phosphorus levels, which may occur for many reasons, including a high pill burden and adverse events (AEs). Tenapanor selectively inhibits the passive paracellular transfer of phosphate in the gastrointestinal tract, thereby reducing serum phosphorus levels. This novel mechanism of action may contribute to improved phosphate management. The efficacy and safety of tenapanor have not been evaluated in Japanese patients with high serum phosphorus levels despite treatment with phosphate binders. This study aimed to assess the efficacy and safety of add-on tenapanor therapy for reducing serum phosphorus levels in this population. METHODS This multicenter, double-blind, randomized, placebo-controlled trial enrolled patients with refractory hyperphosphatemia undergoing hemodialysis. Patients were randomly assigned in a 1:1 ratio to receive tenapanor or placebo as an add-on to their phosphate binder regimen for 6 weeks. Change in serum phosphorus levels at week 6 (day 43) compared with the baseline value (day 1, week 0) (primary endpoint), achievement of target serum phosphorus levels (serum phosphorus level ≤6.0 or ≤5.5 mg/dL), and safety, based on all AEs and drug-related AEs, were among the outcomes evaluated. RESULTS In total, 24 patients were randomly assigned to the placebo group and 23 to the tenapanor group. The mean serum phosphorus level decreased from 7.01 mg/dL on day 1 to 6.69 mg/dL on day 43 in the placebo group and from 6.77 mg/dL on day 1 to 4.67 mg/dL on day 43 in the tenapanor group. In the placebo and tenapanor groups (modified intent-to-treat population), the mean (standard deviation) change in the serum phosphorus level at day 43 (last observation carried forward [LOCF]) was 0.08 (1.52) mg/dL and -1.99 (1.24) mg/dL, respectively, with a between-group difference of -2.07 (95% confidence interval: -2.89, -1.26; p < 0.001). The target achievement rate (serum phosphorus level ≤6.0 mg/dL at week 6 [LOCF]) was 37.5 and 87.0% in the placebo and tenapanor groups, respectively. Diarrhea was the most common drug-related AE, and it occurred in 8.3 and 65.2% of patients in the placebo and tenapanor groups, respectively. No specific AEs were observed with add-on tenapanor or with phosphate binders. DISCUSSION/CONCLUSION Therapy with existing phosphate binders and add-on tenapanor resulted in a significant decrease in serum phosphorus level compared with the placebo group in patients with refractory hyperphosphatemia despite treatment with phosphate binders. No new safety signals were raised, and add-on tenapanor was generally well tolerated.
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Acute effects of dietary phosphorus intake on markers of mineral metabolism in hemodialysis patients: post hoc analysis of a randomized crossover trial.
Tsai, WC, Wu, HY, Chiu, YL, Yang, JY, Pai, MF, Wu, YR, Lin, WY, Hung, KY, Chien, KL, Hsu, SP, et al
Renal failure. 2021;(1):141-148
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BACKGROUND Long-term dietary phosphorus excess influences disturbances in mineral metabolism, but it is unclear how rapidly the mineral metabolism responds to short-term dietary change in dialysis populations. METHODS This was a post hoc analysis of a randomized crossover trial that evaluated the short-term effects of low-phosphorus diets on mineral parameters in hemodialysis patients. Within a 9-day period, we obtained a total of 4 repeated measurements for each participant regarding dietary intake parameters, including calorie, phosphorus, and calcium intake, and markers of mineral metabolism, including phosphate, calcium, intact parathyroid hormone (iPTH), intact fibroblast growth factor 23 (iFGF23), and C-terminal fibroblast growth factor 23 (cFGF23). The correlations between dietary phosphorus intake and serum mineral parameters were assessed by using mixed-effects models. RESULTS Thirty-four patients were analyzed. In the fully adjusted model, we found that an increase in dietary phosphorus intake of 100 mg was associated with an increase in serum phosphate of 0.3 mg/dL (95% confidence intervals [CI], 0.2-0.4, p < .001), a decrease in serum calcium of 0.06 mg/dL (95% CI, -0.11 to -0.01, p = .01), an increase in iPTH of 5.4% (95% CI, 1.4-9.3, p = .01), and an increase in iFGF23 of 5.0% (95% CI, 2.0-8.0, p = .001). Dietary phosphorus intake was not related to cFGF23. CONCLUSIONS Increased dietary phosphorus intake acutely increases serum phosphate, iPTH, and iFGF23 levels and decreases serum calcium levels, highlighting the important role of daily fluctuations of dietary habits in disturbed mineral homeostasis in hemodialysis patients.
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The Percentage of Dietary Phosphorus Excreted in the Urine Varies by Dietary Pattern in a Randomized Feeding Study in Adults.
McClure, ST, Rebholz, CM, Phillips, KM, Champagne, CM, Selvin, E, Appel, LJ
The Journal of nutrition. 2019;(5):816-823
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BACKGROUND Urinary phosphorus excretion has been proposed as a recovery biomarker of dietary phosphorus intake. However, it is unclear whether phosphorus excretion is constant across a range of dietary and nondietary factors. OBJECTIVE We assessed whether percentage urinary phosphorus excretion is constant across 3 dietary patterns in the Dietary Approaches to Stop Hypertension (DASH) trial. METHODS DASH is a completed feeding study of 459 prehypertensive and stage 1 hypertensive adults (52% male, 56% black). After a 3-wk run-in on a typical American (control) diet, participants were randomly assigned to the control diet, a diet rich in fruits and vegetables (FV diet), or a diet rich in fruits, vegetables, and low-fat dairy with reduced saturated fat and cholesterol (DASH diet) for 8 wk. We estimated the percentage phosphorus excretion as urinary phosphorus excretion (from 24 h urine) divided by phosphorus intake (from analyzed food composites). Differences between group means for all 3 diets were compared by ANOVA followed by pairwise comparisons with Tukey's honest significant difference test. RESULTS At the end of the intervention, the mean phosphorus intake was 1176 mg/d (95% CI: 1119, 1233 mg/d), 1408 mg/d (1352, 1464 mg/d), and 2051 mg/d (1994, 2107 mg/d) in the control, FV, and DASH diet, respectively (P < 0.001, all comparisons). The mean phosphorus excretion was 734 mg/d (682, 787 mg/d), 705 mg/d (654, 756 mg/d), and 872 mg/d (820, 923 mg/d) in the control, FV, and DASH diet, respectively (P = 0.74 control vs. FV, P < 0.001 all other comparisons). The mean percentage phosphorus excretion was 63% (60%, 67%), 51% (48%, 54%), and 43% (39%, 46%) in the control, FV, and DASH diet, respectively (P < 0.001, all comparisons). CONCLUSIONS These findings in prehypertensive and stage 1 hypertensive adults strongly suggest that urinary phosphorus excretion should not be used as a recovery biomarker for dietary phosphorus intake, given the wide range of urinary phosphorus excretion across dietary patterns. This trial is registered at clinicaltrials.gov as NCT0000054.
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Comparison of serum concentration of Ca, P, Mg, and Fe between hemifacial spasm patients and healthy controls; prospective randomized controlled study.
Ulusoy, EK, Ulusoy, DM, Kilic, S
Nigerian journal of clinical practice. 2018;(11):1537-1541
Abstract
PURPOSE In this study, we aimed to measure the serum vitamin D level in hemifacial spasmic (HFS) patients and show the role of HFS in the pathogenesis and place in etiology. MATERIALS AND METHODS This study included 43 prospective newly diagnosed HFS patients and 43 healthy volunteers in the neurology clinic. The serum (Ca, P, Mg, Fe) concentration of 4 essential elements was measured with a biochemical device. The groups were correlated in terms of four essential element concentrations. The severity of the disease was measured using Lee's Quality of Life Scale and correlated with the concentration of four trace elements. The results were compared using the independent t-test and Mann-Whitney U-test. RESULTS Concentration of serum Ca, P, and Mg in the HFS patients was found to be lower in the control group which was statistically significant (P < 0.05). There was no statistically difference between the groups in terms of Fe concentration (P > 0.05). There was no significant correlation between trace element concentration and severity of illness and daily life quality in the patient group. CONCLUSION These results show us the role of HFS in the pathogenesis of these four trace elements and the importance of its location in etiology. We think that changes in the concentration of trace elements in HFS can lead to demyelinization, which may lead to spasm.
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Effects of Different Dietary Interventions on Calcitriol, Parathyroid Hormone, Calcium, and Phosphorus: Results from the DASH Trial.
Hassoon, A, Michos, ED, Miller, ER, Crisp, Z, Appel, LJ
Nutrients. 2018;(3)
Abstract
The "Dietary Approaches to Stop Hypertension" (DASH) diet, rich in fiber and low-fat dairy, effectively lowers blood pressure. DASH's effect on calcitriol and other markers of bone-mineral metabolism is unknown. This secondary analysis of the DASH trial aimed to determine the effect of dietary patterns on blood concentrations of calcitriol, parathyroid hormone (PTH), ionized calcium, and urinary excretion of calcium and phosphorus. Outcomes were available in 334 participants in the trial. After a 3-week run-in on the control diet, participants were randomized to control, fruits and vegetables (F&V), or DASH diets. Outcomes were assessed at the end of run-in, and during the last week of the intervention period. Mean age of participants was 45.7 ± 10.7 years, 46% female, and 57% African-American. Mean ± Standard Deviation(SD) baseline serum concentrations of calcitriol, PTH, and ionized calcium were 37.8 ± 9.2 pg/mL, 46.1 ± 18.5 pg/mL and 5.2 ± 0.23 mg/dL, respectively. Mean (±SD) urinary calcium and phosphorus excretions were 150.1 ± 77.8 and 708.0 ± 251.8 mg/24 h, respectively. Compared with control, DASH reduced calcitriol -3.32 pg/mL (p = 0.004). Otherwise, there was no significant effect on other biomarkers. DASH lowered serum calcitriol perhaps more among African-Americans. These results raise important questions about the interpretation and clinical significance of low calcitriol concentrations in the setting of recommended diets.
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Efficacy and safety of sucroferric oxyhydroxide compared with sevelamer hydrochloride in Japanese haemodialysis patients with hyperphosphataemia: A randomized, open-label, multicentre, 12-week phase III study.
Koiwa, F, Yokoyama, K, Fukagawa, M, Terao, A, Akizawa, T
Nephrology (Carlton, Vic.). 2017;(4):293-300
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AIM: We aimed to investigate the non-inferiority of PA21 (sucroferric oxyhydroxide) to sevelamer hydrochloride (sevelamer) in terms of efficacy and safety in Japanese haemodialysis patients with hyperphosphataemia. METHODS In this Phase III, open-label, multicentre study, 213 haemodialysis patients with hyperphosphataemia were randomized to PA21 or sevelamer treatment for 12 weeks. The primary outcome was adjusted serum phosphorus concentration at the end of treatment; the non-inferiority of PA21 was confirmed if the upper limit of the two-sided 95% confidence interval (CI) is ≤0.32 mmol/L. Secondary outcomes were corrected serum calcium and intact-parathyroid hormone concentrations. Adverse events (AEs) and adverse drug reactions (ADRs) were evaluated. RESULTS The adjusted mean serum phosphorus concentration at the end of treatment confirmed the non-inferiority of PA21 for lowering serum phosphorus compared with sevelamer (1.62 vs 1.72 mmol/L; difference, -0.11 mmol/L; 95% CI, -0.20 to -0.02 mmol/L). The mean daily tablet intake was 5.6 ± 2.6 and 18.7 ± 7.1 tablets in the PA21 and sevelamer groups, respectively. The incidences of AEs and ADRs were not significantly different between the two groups. CONCLUSION The non-inferiority of PA21 to sevelamer was confirmed for the treatment of Japanese haemodialysis patients with hyperphosphataemia. PA21 was effective, safe, and well tolerated, while having a considerably lower pill burden than sevelamer.
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Serum Phosphorus and Risk of Cardiovascular Disease, All-Cause Mortality, or Graft Failure in Kidney Transplant Recipients: An Ancillary Study of the FAVORIT Trial Cohort.
Merhi, B, Shireman, T, Carpenter, MA, Kusek, JW, Jacques, P, Pfeffer, M, Rao, M, Foster, MC, Kim, SJ, Pesavento, TE, et al
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2017;(3):377-385
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BACKGROUND Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs. PREDICTOR Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization. RESULTS During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54). LIMITATIONS We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites. CONCLUSIONS Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted.
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Replacing Phosphorus-Containing Food Additives With Foods Without Additives Reduces Phosphatemia in End-Stage Renal Disease Patients: A Randomized Clinical Trial.
de Fornasari, ML, Dos Santos Sens, YA
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2017;(2):97-105
Abstract
OBJECTIVE The purpose of the study was to verify the effects of replacing phosphorus-containing food additives with foods without additives on phosphatemia in end-stage renal disease (ESRD) patients. DESIGN Randomized clinical trial. SETTING Adult patients on hemodialysis for ≥6 months at a single center. SUBJECTS A total of 134 patients with phosphorus levels of >5.5 mg/dL were included and were randomized into an intervention group (n = 67) and a control group (n = 67). INTERVENTION The IG received individual orientation to replace processed foods that have phosphorus additives with foods of similar nutritional value without these additives. The CG received only the nutritional orientation given before the study. Clinical laboratory data, nutritional status, energy and protein intake, and normalized protein nitrogen appearance (nPNA) were evaluated at the beginning of the study and after 90 days. RESULTS There was no initial difference between the groups in terms of serum phosphorus levels, nutritional status, and energy intake. After 3 months, there was a decline in phosphorus levels in the IG (from 7.2 ± 1.4 to 5.0 ± 1.3 mg/dL, P < .001), but there was no significant difference in the CG (from 7.1 ± 1.2 to 6.7 ± 1.2 mg/dL, P = .65). In the IG, 69.7% of the patients reached the serum phosphorus target of ≤5.5 mg/dL; however, only 18.5% of the CG subjects reached this level (P < .001). CONCLUSION At the end, there was no difference between the two groups in terms of nutritional status, energy intake, protein intake, and nPNA. The replacing phosphorus-containing food additives with foods without additives reduced serum phosphorus without interfering in the nutritional status of ESRD patients.
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The impact of education and cooking methods on serum phosphate levels in patients on hemodialysis: 1-year study.
Vrdoljak, I, Panjkota Krbavčić, I, Bituh, M, Leko, N, Pavlović, D, Vrdoljak Margeta, T
Hemodialysis international. International Symposium on Home Hemodialysis. 2017;(2):256-264
Abstract
INTRODUCTION Control of serum phosphate is important for patients on hemodialysis. The aim of the study was to determine if education based on phosphorus-reducing techniques in food preparation and thermal processing, and accordingly prepared and applied diets, will lead to better outcomes than a standard education program to improve phosphate control in patients on hemodialysis. METHODS Forty-seven patients on hemodialysis were divided between an intervention and a control group. All subjects received training about nutrition for hemodialysis patients by trained dietitian. In addition, subjects in the intervention group received additional training in phosphorus-reducing techniques in food preparation and received two hospital meals prepared using suggested cooking methods to reduce the phosphate content of food during dialysis treatment. Serum phosphate, serum albumin, and anthropometric parameters were measured, while nPCR was calculated, at the baseline and during the 1-year study. FINDINGS No differences in serum phosphate levels were observed between intervention (1.68 mmol/L [1.48-2.03]) and control group (1.88 mmol/L [1.57-2.2]) at baseline (P = 0.130). Although not statistically significant between groups the mean reduction was more apparent in the intervention group (-0.3 mmol/L (-0.4 to 0.1) vs. -0.2 (-0.5 to 0.1)), and lead to significantly reduction of phosphate binder therapy. During the study, the nPCR and anthropometric status of the patients did not change significantly. DISCUSSION Providing additional education to hemodialysis patients on the specific cooking methods and accordingly prepared meals may decrease serum phosphate levels without significantly affecting nutritional status which may be useful in helping to prevent and treat hyperphosphatemia.
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Efficacy and safety of nicotinamide in haemodialysis patients: the NICOREN study.
Lenglet, A, Liabeuf, S, El Esper, N, Brisset, S, Mansour, J, Lemaire-Hurtel, AS, Mary, A, Brazier, M, Kamel, S, Mentaverri, R, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2017;(5):870-879
Abstract
BACKGROUND Nicotinamide (NAM) has been proposed as an alternative treatment to phosphate binders for hyperphosphataemia in chronic kidney disease. METHODS The NICOREN multicentre, open-label and randomized study was designed to examine non-inferiority and safety of NAM when compared with sevelamer (SEV) in chronic haemodialysis patients. One hundred patients were randomized to either NAM or SEV treatment for 24 weeks. Serum biochemistry and NAM's main metabolite, N -methyl-2-pyridone-5-carboxamide (2PY), were measured to assess compliance, efficacy and safety. RESULTS After 24 weeks, we observed a comparable decrease in serum phosphorus in the NAM and SEV treatment arms, from 2.1 ± 0.4 to 1.8 ± 0.5 and 2.3 ± 0.5 to 1.7 ± 0.5 mM (P = not significant), respectively. The criterion for non-inferiority was, however, not met due to a more limited number of patients being included than planned. Treatment discontinuation due to adverse events was 1.6 times higher in the NAM than in the SEV group with only 55% of study completers in the NAM arm versus 90% in the SEV arm. Thrombocytopenia was observed in four NAM-treated patients. Serum 2PY levels were comparable at baseline, but increased markedly in the NAM group, but not in the SEV group, at 24 weeks (P < 0.0001). CONCLUSIONS Thus, both drugs are equally effective in lowering serum phosphorus, but patients' tolerance of NAM was largely inferior to that of SEV. Extremely high 2PY levels may contribute to NAM's side effects.