Effect of sevelamer on serum phosphorus levels in chronic kidney disease and hemodialysis patients; a systematic review and meta-analysis

Implication for health policy/practice/research/medical education: In this systematic review and meta-analysis, on the effect of sevelamer on serum phosphorus levels in chronic kidney disease and hemodialysis patients; we found that the type of disease, type of sevelamer, and sevelamer dose did not significantly influence the effectiveness of sevelamer in reducing serum phosphorus levels


Introduction
Chronic kidney disease (CKD) is considered a major public health problem worldwide. As the disease progresses, the filtering capacity of the kidney gradually decreases until renal replacement therapy (RRT) becomes necessary (1). In 2017, more than 700 million people worldwide were diagnosed with CKD, and the number of patients requiring RRT is predicted to exceed 5 million by 2030 (2). Failure to implement timely and effective measures has increased the prevalence of end-stage renal disease (ESRD) (3).
Hyperphosphatemia is a common complication in hemodialysis patients (4). Hyperphosphatemia is associated with increased cardiovascular complications and mortality in patients with stage 4 and 5 CKD (5). Removal of phosphate during dialysis and dietary phosphate restriction are clinical procedures to manage serum phosphate levels in CKD patients (6).
The four main phosphate binders, including calciumbased binders (calcium acetate and calcium carbonate), non-calcium-based binders (sevelamer and lanthanum), aluminum-based binders, and iron-based binders, lower serum phosphate levels (7). In addition to decreasing phosphorus absorption, sevelamer (carbonate/ hydrochloride) can also modify adaptive mechanisms (e.g., reduce fibroblast growth factor 23 (FGF23) or parathyroid hormone (PTH)) due to its potential to absorb phosphorus in the intestine without added calcium (8). Some studies suggest that sevelamer reduces mortality in hemodialysis patients (9,10). However, the effect of sevelamer on phosphorus levels in hemodialysis patients remains controversial. Given the conflicting results of previous studies, this systematic review and meta-analysis investigated the effect of sevelamer on serum phosphorus levels in CKD and hemodialysis patients.

Study design
This systematic review and meta-analysis were conducted based on the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guideline, and the study protocol was registered on the PROSPERO (International Prospective Register of Systematic Reviews) website (ID: CRD42023406804).

Search strategy
Reputable international databases of Cochrane, Web of Science, Scopus, and PubMed, and the Google Scholar search engine were searched without a time limit using the following MeSH (Medical Subject Headings) search terms: "Sevelamer; sevelamer hydrochloride; sevelamer carbonate; phosphorus; chronic kidney disease; renal insufficiency, chronic; hemodialysis; renal dialysis; extracorporeal dialysis".
Various combinations of keywords were searched using the operators "AND" and "OR", and the search was updated until February 28, 2023. All relevant studies and references were also searched. The following search strategy was used to find relevant articles in PubMed: (

Inclusion criteria
All randomized clinical trials, observational, and quasiexperimental that investigated the effect of sevelamer on serum phosphate levels in CKD and hemodialysis patients were assessed.

Exclusion criteria
Articles that had investigated the effect of a combination of multiple drugs on serum phosphate levels in CKD and hemodialysis patients, repeated articles, low-quality articles (based on the Cochrane Risk-of-bias tool for randomized trials), articles that had investigated the effect of sevelamer on the lipid profile of CKD and hemodialysis patients, articles that had reported only qualitative results, articles that did not contain sufficient data for data analysis, and those without full text were removed.

Quality evaluation
fter the initial article list was generated, two researchers independently evaluated the quality of the articles using the Cochrane risk-of-bias tool for randomized trials (11). This checklist assesses potential sources of bias in clinical trials in 7 steps. The risk of bias in each step is interpreted as "low," "high," or "unclear." Reviewers examined and solved cases of discrepancy using the inter-reviewer agreement method. In addition, observational studies were evaluated using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist (12).

Data extraction
To avoid bias and errors in data collection, two members of the research team extracted the following data from the relevant articles: first author's name, year of publication, duration of sevelamer use, sample size, mean age of patients, type of disease, type of sevelamer, type of study, sevelamer dose, and comparison group, as well as the mean and standard deviation (SD) of serum phosphate, calcium, PTH, and (Ca×P product) levels before and after the interventions.

Data analysis
Because of the quantitative nature of the initial outcome, the standardized mean difference (SMD) was used to calculate the effect size of the intervention. SMD is a classic effect size statistic that shows the strength of the relationship between a desired intervention and the respective outcome. The closer the SMD value is to 0, the weaker the relationship would be; however, values close to 1 indicate stronger relationships. The selected articles were combined based on the frequency, mean, and SD of different variables. The heterogeneity of the selected articles was assessed using the I2 index and a random effects model. The data were analyzed in STATA 14, and P values < 0.05 were considered significant.

Results
A total of 532 articles were screened, of which 145, 32, and 9 articles were excluded after title screening, abstract screening, and full text screening, respectively. Another 324 articles that did not meet other exclusion criteria were also removed. Finally, 22 high-quality articles were included in the systematic review and meta-analysis process (Figure 1).
A total of 22 articles published between 1999 and 2023 were assessed with a total sample size of 3221 (1604 people in the sevelamer group and 1617 people in the comparison group). Moreover, 11 articles had examined the effect of sevelamer on CKD patients, whereas the remaining 11 articles investigated hemodialysis patients ( Table 1).
The administration of sevelamer had no significant effect on serum phosphorus levels in CKD and hemodialysis patients compared with those in the comparison group (SMD: 0.01; 95% confidence interval [CI]: -0.32, 0.35) ( Figure 2).
There was a statistically non-significant relationship between sevelamer dose and serum phosphorus levels in

Identification of studies via databases and registers
Identification Screening Included Figure 1. The process of entering the studies into the systematic review and meta-analysis.
Journal of Nephropathology, Vol x, No x, xxx xx https://nephropathol.com 4  A significant decrease in serum phosphorus level was observed in patients who had taken sevelamer for a maximum of 12 weeks compared to those in the comparison group (SMD: -0.27; 95% CI: -0.54, -0.01); however, no significant decrease in serum phosphorus level was observed in those who had taken sevelamer for longer than 12 weeks (Figure 6).
Sevelamer decreased calcium levels in CKD and hemodialysis patients compared to those in the comparison group (SMD: -0.67; 95% CI: -1.23, -0.11); however, Sevelamer did not significantly influence levels of serum PTH and Ca × P product (Table 2).

Discussion
Sevelamer significantly reduced serum phosphorus levels in CKD and hemodialysis patients compared to those in the comparison group. Serum phosphorus levels of patients who had taken sevelamer for a maximum of 12 weeks decreased significantly compared to members of the comparison group. In addition, a significant decrease was observed in serum phosphorus levels of sevelamer users compared to members of the placebo group. The type of disease (hemodialysis or CKD), type of sevelamer (carbonate or hydrochloride), and the sevelamer dose did not significantly influence the effectiveness of sevelamer in reducing serum phosphorus levels. The discrepancy between the present results and the findings of some previous meta-analyses regarding the effectiveness of   sevelamer in lowering serum phosphorus levels can be due to the fact that the type of disease, type of sevelamer, the drug dose, duration of use, age group of patients, and the comparison group in this meta-analysis differed from other studies.
In a meta-analysis, Wang et al investigated the effects of calcium carbonate and calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients. They found a significant decrease in serum phosphorus levels in the calcium acetate group compared with the calcium carbonate group at both 4 weeks (mean difference [MD]: -0.15 mmol/L, 95% CI: -0.28 to -0.01) and 8 weeks (MD: -0.25 mmol/L, 95% CI: -0.40 to -0.11) after administration. However, there was no difference between the two groups in serum calcium, PTH, and Ca × P levels (34). The findings on the changes in PTH and Ca × P levels are consistent with the results of the present study.
Huang et al conducted a meta-analysis with 950 patients and found that LC effectively controls hyperphosphatemia in dialysis patients compared to those in the placebo group (SMD: -0.06; 95% CI: -0.27 to -0.86). In addition, fewer changes were observed in serum PTH and Ca × P product levels of patients who used LC compared with those in the placebo group (SMD: -0.21; 95% CI: -0.48 to 0.06 and SMD: -0.90; 95% CI: -1.13 to -0.66) (35).
In a meta-analysis with 1754 participants, Li et al concluded that ferric citrate significantly reduces serum phosphorus levels in CKD patients compared to those in the placebo group (MD: -1.76 mg/dL, 95% CI: -2.78 to -0.75) (36). This is consistent with the result of the present research.
Guo et al observed no significant difference between ESRD patients taking LC and those in the placebo group in terms of serum phosphate levels (weighted mean difference [WMD]: 0.26, 95% CI: -0.06 to 0.58) and serum calcium levels (WMD: -0.24, 95% CI: -0.77 to 0.29) (37). However, in contrast to the findings of Guo et al, in the present study, sevelamer lowered serum calcium and serum phosphorus levels in hemodialysis patients compared to those in the placebo group.
Zhao et al performed a meta-analysis in 2021 to examine the effects of LC and other phosphate binders on CKD patients. They found that LC can effectively reduce phosphorus levels, Ca × P product, and intact PTH in CKD patients (38). Given the conflicting results of previous meta-analyses on the effect of LC on hyperphosphatemia, researchers are suggested to compare the effects of sevelamer and LC in future clinical trials.

Conclusion
The use of sevelamer decreased serum calcium levels and serum phosphorus levels in hemodialysis patients compared with patients in the comparison and placebo groups, respectively. In addition, a significant reduction in serum phosphorus levels was observed in patients who had taken sevelamer for a maximum of three months compared to those in the comparison group. The use of sevelamer was effective in the short term; however, no conclusive result was obtained on the optimal dose of sevelamer or the best type of sevelamer that reduces serum phosphorus levels. Therefore, researchers are suggested to compare the effects of sevelamer (carbonate and hydrochloride) and the effects of high and low doses of sevelamer on serum phosphorus levels in CKD and hemodialysis patients.

Limitations of the study
Lack of access to the full text of some articles, lack of presentation of results by patients' sex and age, and uneven distribution of studies in different subgroups are the main limitations of the study.