Systematic Review and Meta-Analyses of the Effects of Phosphate-Lowering Agents in Nondialysis CKD
Authors: Lioufas Nicole M. , Pascoe Elaine M. , Hawley Carmel M. , Elder Grahame J. , Badve Sunil V. , Block Geoffrey A. , Johnson David W. , Toussaint Nigel D. 
Published: October 2021

Significance Statement
This systematic review summarized evidence from randomized controlled trials concerning benefits and risks of noncalcium-based phosphate-lowering treatment in nondialysis CKD compared with placebo, calcium-based phosphate binders, and no study medication. Noncalcium-based phosphate-lowering therapy reduced serum phosphate and urinary phosphate excretion, but with unclear effect on clinical outcomes and intermediate cardiovascular end points. There was an associated increase risk of constipation and vascular calcification with noncalcium-based phosphate binders compared with placebo. This study highlights the need for more adequately powered trials to evaluate the benefits and risks of phosphate-lowering therapy on patient-centered outcomes in people with CKD.

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.