Background
Peritoneal dialysis (PD) is an effective therapeutic method for azotemia induced by end stage renal failure (ESRF). However, PD is often accompanied by calcium–phosphorus and parathyroid hormone metabolism disorders [
1,
2]. These ailments lead to hypocalcemia and secondary hyperparathyroidism, which in turn can become tertiary and cause hypercalcemia [
3,
4]. Meanwhile, excessive calcium amounts are associated with risk of renal osteodystrophy [
5,
6], adynamic bone disease [
7], and metastatic calcification [
6]. Furthermore, severe calcium–phosphorus metabolism impairment may induce unacceptably high cardiovascular morbidity and mortality [
4,
8,
9].
Calcium concentration in the dialysate is a pivotal factor influencing serum calcium, phosphate, and parathyroid hormone (PTH) levels. Calcium levels in the dialysate vary and include l.0 mmol/L, 1.25 mmol/l, 1.5 mmol/L, and 1.75 mmol/L, with 1.25 and 1.75 mmol/L most widely used in commercially available PD solutions. Generally speaking, 1.75 mmol/L dialysate calcium, which is considered the standard dialysate calcium in many counties, may produce soft-tissue calcification and adynamic bone disease; meanwhile, 1.25 mmol/L dialysate calcium may cause hyperparathyroidism and acute arrhythmias.
A few trials have compared 1.75 mmol/L and 1.25 mmol/L dialysate calcium levels for the treatment of patients with ESRF, assessing their effects on health indexes such as serum calcium and intact parathyroid hormone (i-PTH). However, the optimal concentration remains unclear.
Only one meta-analysis of low versus standard dialysate calcium in PD was reported [
10]. This study found that low dialysate calcium was superior to the standard dose in decreasing serum total calcium levels in PD patients, while the effects on i-PTH levels and peritonitis episodes remain controversial. Of these, i-PTH is an important factor in assessing treatment safety and identifying the required calcium concentration; peritonitis is the most common complication occurring during PD. Several studies [
11‐
13] assessed the effects of different dialysate calcium concentrations in PD patients and reported inconsistent results. Therefore, it was necessary to perform an updated meta-analysis to evaluate the optimal dialysate calcium concentration for PD patients.
Methods
This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [
14].
Literature search strategy
The following databases were electronically searched from inception to October 2016: PubMed, EmBase, and Cochrane Central Register of Controlled Trials. All studies comparing 1.25 mmol/L with 1.75 mmol/L dialysate calcium for PD were searched in the above electronic databases by two authors independently. MeSH/Entree and free word retrievals were combined to search the literature as much as possible. The search terms were as follows: “Peritoneal Dialysis” AND “calcium dialysate” AND (“l.0 mmol/l” OR “1.25 mmol/l” OR “1.5 mmol/l” OR “1.75 mmol/l”). To identify additional reports, the reference lists of all retrieved studies and published reviews/meta-analyses were manually searched, and all identified relevant articles were included.
Eligibility criteria
The inclusion criteria for the current study were: (1) participants administered PD or continuous ambulatory peritoneal dialysis (CAPD); (2) 1.25 mmol/L and 1.75 mmol/L dialysate calcium respectively used in the two groups; (3) follow-up exceeding 12 months; (4) study design as randomized controlled trial (RCT) or non-RCT; (5) study reporting at least one of the outcomes of interest, including the primary outcome i-PTH levels, and the secondary outcomes serum total calcium levels, ionized calcium amounts, phosphate concentrations, and peritonitis episodes, at 1- to 2-years of follow-up. Exclusion criteria were: (1) self-controlled study of concentration conversion between 1.25 mmol/L and 1.75 mmol/L dialysate calcium; (2) interventions combined with other treatments; (3) study without follow-up or with follow-up time below 12 months; (4) study without available statistical data.
Study identification
First, all studies retrieved from the three databases were imported into EndNote version 7.0 (Thomson Reuters, New York, NY), with duplicates removed by automatic and manual deletions. Then, all titles of records after duplicate removal were viewed by two authors independently to exclude reviews/meta-analyses and obviously unrelated articles. Finally, full-text articles were reviewed to remove articles not conforming to the set eligibility criteria. A third investigator was involved in case of discrepancy.
Data extraction and quality assessment
The following data were extracted independently by two authors from each study: first author’s name, year of publication, study design, PD pattern, concentration of dialysate calcium, sample size, mean patient age at study entry, follow-up time, dropouts, and interested outcomes at baseline and 1- to 2-year follow-up. The methodological quality assessment of the included studies (both RCTs and non-RCTs) was carried out with the risk of bias tool of the Review Manager software (version 5.3, Nordic Cochrane Centre, Denmark) [
15]. A third investigator was involved in case of discrepancy.
Statistical analysis
All statistical analyses were conducted with the Stata version 12.0 software (Stata Corp., College Station, TX, USA). Subgroup analysis was based on study design (RCT and non-RCT). As the outcomes of interest were reported in different units, standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to describe the mean differences for continuous variables. Dichotomous outcomes were assessed using odds ratios (ORs) with 95% CIs.
P < 0.05 was considered statistically significant. Potential heterogeneity among studies was examined by Cochran’s Q [
16] and
I2 statistics [
17]. A
P value for heterogeneity < 0.10 or
I2 > 50% indicated statistically significant heterogeneity. The random-effects model was then used for analysis. Sensitivity analysis was performed to evaluate the stability of results obtained in the meta-analysis for each outcome. A Galbraith plot was used to determine the possible source of heterogeneity [
18]. Publication bias was assessed by Egger’s [
19] and Begg’s [
20] tests, with significant publication bias reflected by
P < 0.10. The “trim-and-fill” method was used to assess the results in case of publication bias.
Discussion
The main finding of this meta-analysis was that 1.75 mmol/L dialysate calcium could significantly reduce i-PTH levels compared with the 1.25 mmol/L dose in PD patients. However, 1.25 mmol/L dialysate calcium was superior to the 1.75 mmol/l dose in decreasing serum total calcium and ionized calcium amounts in PD patients. No significant differences in phosphate and peritonitis episodes were found between the two dialysate calcium concentrations.
A previous meta-analysis by Cao [
10] and this study showed that low dialysate calcium is superior to high dialysate calcium in decreasing serum total calcium levels in PD patients, while no significant difference in phosphate amounts was found. This updated meta-analysis had new findings. First, four new studies [
11‐
13,
21] were included in the previous meta-analysis, while the present study was more robust than the previous meta-analysis [
10]. Secondly, all the studies included in this meta-analysis had comparisons between 1.25 mmol/L and 1.75 mmol/L dialysate calcium for PD patients, while the previous meta-analysis included one study comparing 1.0 mmol/L dialysate calcium with the 1.75 mmol/L dose for PD patients [
26]. Thirdly, the summary results for i-PTH and peritonitis episodes were obtained, which was not the case in the previous meta-analysis. Finally, sensitivity, subgroup analyses, Galbraith plot, and Egger’s test were performed for each outcome to assess the stability of results, identify the main source of heterogeneity, and test publication bias, respectively.
The main function of PTH is to regulate the metabolism of calcium and phosphorus, which promotes blood calcium accumulation and decalcification of osteoclasts, while reducing blood phosphorus levels [
27,
28]. i-PTH is the most common tool for monitoring the levels of PTH. The present study found that 1.75 mmol/L dialysate calcium significantly reduced i-PTH levels compared with the 1.25 mmol/L dose. Therefore, PD patients with secondary hyperparathyroidism were more indicated for 1.75 mmol/L dialysate calcium. Further, we found that 1.25 mmol/L dialysate calcium was superior to the 1.75 mmol/L dose in decreasing serum total calcium and ionized calcium levels in PD patients, although these findings might vary, according to sensitivity analysis. This could be explained by different patient characteristics, with or without ionized calcium measurements. Thirdly, PD patients with secondary hyperparathyroidism often have hypercalcemia. It is hard to decide which concentration of dialysate calcium is suitable for these patients, and further related studies are required. Fourthly, although no difference was found in phosphate amounts between the two dialysate calcium concentrations, hyperphosphatemia is common in ESRF patients receiving treatment for PD. Indeed, hyperphosphatemia is the main factor causing secondary hyperparathyroidism, and is strongly associated with serious cardiovascular complications such as coronary artery and heart valve calcification [
29,
30]. Fifthly, the present study found no difference in peritonitis episodes between the two dialysate calcium concentrations, although this conclusion may be unreliable since small cohorts were included.
Although the overall- and non-RCT subgroup analysis findings for total and ionized calcium levels showed significant differences, RCT subgroup analysis for these two outcomes showed no statistical significance (Figs.
5 and
6). The two factors might have contributed to such results as follows: first, non-RCTs showed higher amounts compared with RCTs, especially a study by Kang [
24] which contributed 30.09 and 53.37% to overall levels of total and ionized calcium, respectively. Secondly, one RCT [
22] showed an opposite trend compared with the others. Therefore, more large-size randomized controlled trials (RCTs) are needed to verify the pooled results.
The main limitation of this study was the lack of large-sample RCTs. Selection and dropout biases existed in nonrandomized studies [
12,
13,
24]. Meanwhile, all but one study [
22] did not involve independent examiners, which might have contributed to observer bias and distortion (conscious or unconscious) in the perception or reporting of measurements [
31]. Only two studies [
21,
22] adopted blinding of participants and the personnel. Therefore, performance bias was found in the remaining five studies. In addition, ionized calcium, total calcium, phosphate, and intact PTH assays might affect the long-term effect of 1.25 versus 1.75 mmol/L dialysate calcium in PD patients, and these factors were not available in most included studies. Finally, background use of drugs might affect calcium-phosphorus metabolism. Such data were not available, and additional analysis was not conducted; this might alter the treatment effects between the two concentrations of dialysate calcium in PD patients.