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Systematic Review and Meta-Analyses of the Effects of Phosphate-Lowering Agents in Nondialysis CKD.
Lioufas, NM, Pascoe, EM, Hawley, CM, Elder, GJ, Badve, SV, Block, GA, Johnson, DW, Toussaint, ND
Journal of the American Society of Nephrology : JASN. 2022;(1):59-76
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Abstract
BACKGROUND Benefits of phosphate-lowering interventions on clinical outcomes in patients with CKD are unclear; systematic reviews have predominantly involved patients on dialysis. This study aimed to summarize evidence from randomized controlled trials (RCTs) concerning benefits and risks of noncalcium-based phosphate-lowering treatment in nondialysis CKD. METHODS We conducted a systematic review and meta-analyses of RCTs involving noncalcium-based phosphate-lowering therapy compared with placebo, calcium-based binders, or no study medication, in adults with CKD not on dialysis or post-transplant. RCTs had ≥3 months follow-up and outcomes included biomarkers of mineral metabolism, cardiovascular parameters, and adverse events. Outcomes were meta-analyzed using the Sidik-Jonkman method for random effects. Unstandardized mean differences were used as effect sizes for continuous outcomes with common measurement units and Hedge's g standardized mean differences (SMD) otherwise. Odds ratios were used for binary outcomes. Cochrane risk of bias and GRADE assessment determined the certainty of evidence. RESULTS In total, 20 trials involving 2498 participants (median sample size 120, median follow-up 9 months) were eligible for inclusion. Overall, risk of bias was low. Compared with placebo, noncalcium-based phosphate binders reduced serum phosphate (12 trials, weighted mean difference -0.37; 95% CI, -0.58 to -0.15 mg/dl, low certainty evidence) and urinary phosphate excretion (eight trials, SMD -0.61; 95% CI, -0.90 to -0.31, low certainty evidence), but resulted in increased constipation (nine trials, log odds ratio [OR] 0.93; 95% CI, 0.02 to 1.83, low certainty evidence) and greater vascular calcification score (three trials, SMD, 0.47; 95% CI, 0.17 to 0.77, very low certainty evidence). Data for effects of phosphate-lowering therapy on cardiovascular events (log OR, 0.51; 95% CI, -0.51 to 1.17) and death were scant. CONCLUSIONS Noncalcium-based phosphate-lowering therapy reduced serum phosphate and urinary phosphate excretion, but there was an unclear effect on clinical outcomes and intermediate cardiovascular end points. Adequately powered RCTs are required to evaluate benefits and risks of phosphate-lowering therapy on patient-centered outcomes.
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Safety and effectiveness of lanthanum carbonate for hyperphosphatemia in chronic kidney disease (CKD) patients: a meta-analysis.
Zhao, L, Liu, A, Xu, G
Renal failure. 2021;(1):1378-1393
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OBJECTIVE The aim of this study was to determine the efficacy and safety of lanthanum carbonate (LC) versus calcium salts, non-LC phosphate binders (PBs), sevelamer, or placebo in patients with chronic kidney disease (CKD). MATERIALS AND METHODS A literature search on PubMed, Embase, and Cochrane Library databases was conducted up to 18 June 2021. Data acquisition and quality assessment were performed by two reviewers. Meta-analysis was performed to evaluate the serum biochemical parameters, adverse events, and patient-level outcomes of LC, non-LC PBs, and sevelamer for hyperphosphatemia in patients with CKD. Heterogeneity across studies was assessed utilizing the I2 statistic and Q-test, and a random effect model was selected to calculate the pooled effect size. RESULTS A total of 26 randomized, controlled trials and 3 observational studies were included. Compared to the other groups, better control effect of serum phosphorus (RR = 2.68, p < 0.001), reduction in serum phosphorus (95%CI = -1.93, -0.99; p < 0.001), Ca × P (95%CI = -13.89, -2.99; p = 0.002), serum intact parathyroid hormone levels (95%CI = -181.17, -3.96, p = 0.041) were found in LC group. Besides, reduced risk of various adverse effects, such as hypotension, abdominal pain, diarrhea, dyspepsia, and a score of coronary artery calcification were identified with LC in comparison to calcium salt, non-LC PBs, or placebo group. Significantly lower risk in mortality with LC treatment vs. non-LC PBs was observed, while no significant difference was identified between LC and calcium salt groups. CONCLUSION LC might be an alternative treatment for hyperphosphatemia in patients with CKD considering its comprehensive curative effect.
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Effect of Phosphate-Specific Diet Therapy on Phosphate Levels in Adults Undergoing Maintenance Hemodialysis: A Systematic Review and Meta-Analysis.
St-Jules, DE, Rozga, MR, Handu, D, Carrero, JJ
Clinical journal of the American Society of Nephrology : CJASN. 2020;(1):107-120
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BACKGROUND AND OBJECTIVES Hyperphosphatemia is a persistent problem in individuals undergoing maintenance hemodialysis, which may contribute to vascular and bone complications. In some dialysis centers, dietitians work with patients to help them manage serum phosphate. Given the regularity of hyperphosphatemia in this population and constraints on kidney dietitian time, the authors aimed to evaluate the evidence for this practice. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS There was a systematic review and meta-analysis of clinical trials. MEDLINE, Embase, CINAHL, Web of Science, Cochrane Central Register of Controlled Trials, and other databases were searched for controlled trials published from January 2000 until November 2019 in the English language. Included studies were required to examine the effect of phosphate-specific diet therapy provided by a dietitian on serum phosphate in individuals on hemodialysis. Risk of bias and certainty of evidence were assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method. RESULTS Of the 8054 titles/abstracts identified, 168 articles were reviewed, and 12 clinical trials (11 randomized, one nonrandomized) were included. Diet therapy reduced serum phosphate compared with controls in all studies, reaching statistical significance in eight studies, although overall certainty of evidence was low, primarily due to randomization issues and deviations from protocol. Monthly diet therapy (20-30 minutes) significantly lowered serum phosphate in patients with persistent hyperphosphatemia for 4-6 months, without compromising nutrition status (mean difference, -0.87 mg/dl; 95% confidence interval, -1.40 to -0.33 mg/dl), but appeared unlikely to maintain these effects if discontinued. Unfortunately, trials were too varied in design, setting, and approach to appropriately pool in meta-analysis, and were too limited in number to evaluate the timing, dose, and strategy of phosphate-specific diet therapy. CONCLUSIONS There is low-quality evidence that monthly diet therapy by a dietitian appears to be a safe and efficacious treatment for persistent hyperphosphatemia in patients on HD.
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Effects of lower versus higher phosphate diets on fibroblast growth factor-23 levels in patients with chronic kidney disease: a systematic review and meta-analysis.
Tsai, WC, Wu, HY, Peng, YS, Hsu, SP, Chiu, YL, Chen, HY, Yang, JY, Ko, MJ, Pai, MF, Tu, YK, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2018;(11):1977-1983
Abstract
BACKGROUND Elevated fibroblast growth factor-23 (FGF23) levels increase the risk of cardiovascular diseases in patients with chronic kidney disease (CKD). We aimed to compare the effects of different dietary interventions, lower versus higher phosphate levels, on FGF23 in patients with CKD. METHODS We conducted electronic literature searches of Medline, PubMed, Embase and the Cochrane Library for publications up to 29 October 2016 for randomized clinical trials that compared lower versus higher phosphate dietary interventions in adults with CKD. The primary outcome was the difference in change-from-baseline FGF23 levels between intervention groups. Considering the difference in measurement units between intact FGF23 and C-terminal FGF23 assays, the treatment effect was analysed as the standardized mean difference (SMD) with the 95% confidence interval (CI). RESULTS We identified five trials enrolling a total of 94 normophosphataemic patients with Stage 3B CKD. The study duration ranged from 1 to 12 weeks. Compared with higher phosphate diets, lower phosphate diets tended to reduce FGF23 levels (SMD -0.74, 95% CI -1.54 to 0.07, P = 0.07). Subgroup analyses showed a trend (P for interaction = 0.09) towards a better FGF23-lowering effect by lower phosphate diets in studies using the intact FGF23 assay (SMD -1.14, 95% CI -2.24 to -0.04) than those using the C-terminal FGF23 assay (SMD -0.05, 95% CI -0.67 to 0.57). CONCLUSIONS Short-term dietary phosphate restriction tends to reduce FGF23 levels in patients with moderately decreased kidney function, and the FGF23-lowering effects tend to be more prominent when measured with the intact FGF23 assay.
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Comparative Efficacy and Safety of Phosphate Binders in Hyperphosphatemia Patients With Chronic Kidney Disease.
Yang, X, Bai, Q, Li, Y, Liu, H, Guo, H, Zhang, X
JPEN. Journal of parenteral and enteral nutrition. 2018;(4):766-777
Abstract
BACKGROUND In this study, we coordinated a network meta-analysis to establish the efficacy and safety of different agents used in the treatment of hyperphosphatemia patients with chronic kidney disease. METHODS PubMed, CNKI, and Embase were systematically searched to retrieve relevant studies. Outcomes were presented by mean differences, odds ratios, and corresponding 95% credible intervals for continuous outcomes and binary outcomes, respectively. Each therapy was ranked according to the value of surface under the cumulative ranking curve. Consistencies between direct and indirect comparisons were assessed with a node-splitting plot. RESULTS In terms of efficacy end points (including levels of serum phosphate, serum calcium, serum intact parathyroid hormone, and serum calcium × phosphorus product), all 7 kinds of agents outperformed or performed at least equally to placebo, with iron-based phosphate-binding agents being potentially the most effective. As for safety end points (including mortality, adverse events, and all-cause discontinuation), almost all agents were equivalent in term of mortality and all-cause discontinuation except in the comparison between iron-based phosphate-binding agents and placebo. Meanwhile, iron-based phosphate-binding agents colestilan and nicotinic acid performed poorly compared with placebo in terms of adverse events. Furthermore, iron-based phosphate-binding agents were potentially the safest agents followed sequentially by calcium-based phosphate-binding agents and placebo. CONCLUSION Iron-based phosphate-binding agents were the preferable agents when considering efficacy and safety simultaneously.