Research Article: Effects of different phosphate lowering strategies in patients with CKD on laboratory outcomes: A systematic review and NMA

Date Published: March 1, 2017

Publisher: Public Library of Science

Author(s): Nigar Sekercioglu, Argie Angeliki Veroniki, Lehana Thabane, Jason W. Busse, Noori Akhtar-Danesh, Alfonso Iorio, Luciane Cruz Lopes, Gordon H. Guyatt, Gianpaolo Reboldi.


Chronic kidney disease-mineral and bone disorder (CKD-MBD), a complication of chronic kidney disease, has been linked to reduced quality and length of life. High serum phosphate levels that result from CKD-MBD require phosphate-lowering agents, also known as phosphate binders. The objective of this systematic review is to compare the effects of available phosphate binders on laboratory outcomes in patients with CKD-MBD.

Data sources included MEDLINE and EMBASE from January 1996 to April 2016, and the Cochrane Register of Controlled Trials up to April 2016. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstracted data and assessed risk of bias in eligible randomized controlled trials (RCTs). Eligible trials enrolled patients with CKD-MBD and randomized them to receive calcium-based phosphate binders (delivered as calcium acetate, calcium citrate or calcium carbonate), non-calcium-based phosphate binders (NCBPB) (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxyhydroxide and ferric citrate), phosphorus restricted diet (diet), placebo or no treatment and reported effects on serum levels of phosphate, calcium and parathyroid hormone.

Our search yielded 1108 citations; 71 RCTs were retrieved for full review and 16 proved eligible. Including an additional 13 studies from a previous review, 29 studies that enrolled 8335 participants proved eligible; 26 trials provided data for quantitative synthesis. Sevelamer, lanthanum, calcium, iron, diet and combinations of active treatments (calcium or sevelamer or lanthanum and combination of calcium and sevelamer) resulted in significantly lower serum phosphate as compared to placebo (moderate to very low quality of evidence). We found no statistically significant differences between active treatment categories in lowering serum phosphate. Sevelamer, lanthanum and diet resulted in lower serum calcium compared to calcium (moderate quality evidence for lanthanum and diet; low quality evidence for Sevelamer). Iron, sevelamer and calcium yielded lower parathyroid hormone levels as compared to lanthanum. Meta-regression analyses did not yield a statistically significant association between treatment effect and trial duration.

We found few differences between treatments in impact on phosphate and differences in parathyroid hormone. Relative to calcium, sevelamer, lanthanum and diet showed significant reduction in serum calcium from baseline. Treatment recommendations should be based on impact on patient-important outcomes rather than on surrogate outcomes.

Partial Text

Chronic kidney disease (CKD) has been linked to negative patient outcomes, including mortality, often due to cardiovascular diseases [1–7]. CKD also contributes to comorbid conditions with extra-renal manifestations, such as disturbances of calcium-phosphate homeostasis collectively referred to as CKD mineral and bone disorder (CKD-MBD). CKD-MBD is a systematic disorder that results in adverse bone outcomes (e.g., fractures due to abnormal structure and composition of bones) and cardiovascular outcomes (i.e., cardiovascular calcifications and subsequent cardiovascular events) [2].

We registered our protocol on PROSPERO (CRD42016032945) and adhered to the Preferred Reporting Items for Systematic Review and Meta-analysis for Network Meta-analysis (PRISMA NMA) guidelines in drafting our manuscript (File A in the S1 Supporting Information File) [29].

This NMA showed only small and unconvincing differences between phosphate binding agents with low to very low quality of evidence. The treatment of hyperphosphatemia with calcium will likely induce hypercalcemia. The combination therapy with sevelamer and calcium will likely cause a decrease in serum parathyroid hormone.