The benefits of phosphate-lowering medications on clinical outcomes in patients with nondialysis-dependent chronic kidney disease (NDD-CKD) remain unclear, but a new systematic review and meta-analysis finds that few trials examined these medications in relation to clinical outcomes in the predialysis population, such as cardiovascular events and death.

“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,” Nigel Toussaint, MD, of The Royal Melbourne Hospital in Victoria, Australia, and colleagues wrote in the Journal of the American Society of Nephrology.

The authors conducted a systematic review and meta-analyses of 20 randomized controlled trials (RCTs) involving 2498 patients, including some kidney transplant recipients. The RCTs compared noncalcium-based phosphate binders with placebo, calcium-based binders, or no study medication. Non-calcium-based phosphate-lowering therapy included sevelamer, lanthanum carbonate, bixalomer, aluminium hydroxide, nicotinamide, colestilan, and the iron-based phosphate binders ferric citrate and sucroferric oxyhydroxide.

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Compared with placebo, noncalcium-based phosphate binders significantly reduced serum phosphate by a weighted mean difference (WMD) of 0.37 and urinary phosphate excretion by a standardized mean difference (SMD) of 0.61, the investigators reported. Use of noncalcium-based binders was significantly associated with 7% increased odds of constipation and higher vascular calcification scores (SMD 0.47), however. Similar results were obtained in analyses combining placebo and no study medication. Few studies compared noncalcium phosphate binders with calcium-based binders, precluding meaningful analyses.

Data on the effects of phosphate-lowering therapy on cardiovascular events and all-cause mortality were scarce and nonsignificant, the investigators reported. The overall quality of the evidence was considered low with a low risk for bias.

“The recently updated Kidney Disease Improving Global Outcomes (KDIGO) CKD-MBD Guidelines highlighted the lack of trial data in the non-dialysis CKD population demonstrating that lowering serum phosphate improves patient-centered outcomes, and questioned the efficacy and safety of phosphate binders in this population,” Dr Toussaint’s team wrote.

They also noted, “This review raises further concern about the paucity of proven benefits of phosphate binder therapy in the non-dialysis CKD population, albeit predominantly with normophosphatemia and mild hyperphosphatemia in the RCTs to date.”

The investigators encouraged future, longer RCTs of at least 2 to 3 years to evaluate benefits of phosphate binders on hard clinical outcomes.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Lioufas N, Pascoe E, Hawley C, et al. Systematic review and meta-analyses of effects of phosphate-lowering agents in non-dialysis chronic kidney disease. J Am Soc Nephrol. Published online October 13, 2021. doi:10.1681/ASN.2021040554