Abstract
In patients treated with peritoneal dialysis (PD), lowering the calcium level in PD fluids results in lower serum calcium levels and higher parathyroid hormone (PTH) levels. It is hypothesized that this effect is attenuated when patients are using icodextrin 7.5% for the once-daily long dwell (containing high calcium concentration). In this case series, we included 8 stable PD patients (mean age 68 ± 13 years, 7 male), all using icodextrin 7.5% (containing 1.75 mmol/L calcium) for the once-daily long dwell. The calcium content of the PD fluids for the remaining dwells was lowered from 1.75 mmol/L to 1.25 mmol/L. Bone mineral parameters and phosphate prescription at baseline, 6 weeks after this change, and after 6 months were compared. After lowering calcium concentration of the PD fluids – except for the icodextrin 7.5% – from 1.75 mmol/L to 1.25 mmol/L, calcium levels changed from 2.32 ± 0.11 to 2.29 ± 0.12 (p = NS); intact PTH (iPTH) from 39.6 ± 28.3 to 64.9 ± 34.5 pmol/L (p = 0.045); and alkaline phosphatase from 104.13 ± 48.75 to 101.38 ± 32.39 (p = NS). After 6 months, all bone mineral parameters were similar to baseline levels; however, slightly higher calcium-based phosphate binders were prescribed. Lowering calcium content from 1.75 mmol/L to 1.25 mmol/L in PD fluids in patients on icodextrin resulted in stable calcium values, a temporal increase in iPTH and a modest increase in calcium-based phosphate binder prescription. Using icodextrin for the long once-daily dwell appears to attenuate the effects on bone mineral parameters when lowering the calcium concentration of the short dwells.
Introduction
The prevalence of mineral bone disease (MBD) in patients with chronic kidney disease (CKD) is high. MBD leads to a variety of bone diseases, due to either increased or decreased bone turnover [1]. CKD-MBD is associated with vascular complications including valvular calcifications and cardiovascular death [2‒6]. A disturbance in the calcium balance is one of the main drivers of MBD and adverse outcome. There is substantial evidence that hypercalcemia is associated with increased mortality in patients with CKD [7‒13]. Particularly in hemodialysis patients, it has been shown that high dialyzate calcium levels (i.e., 1.75 mmol/L) are associated with adverse outcomes. Hence, dialyzate calcium levels between 1.25 and 1.5 mmol/L are recommended in these patients [14, 15]. In peritoneal dialysis (PD) patients, however, there are only limited data available on the relation between calcium levels in PD fluids and outcome [16, 17]. Hence, there are no specific recommendations for PD patients in the current KDIGO Clinical Practice Guidelines [18]. Individualized care regarding calcium content in PD fluids and phosphate binder prescription is recommended, targeted at lowering high serum phosphate and maintaining normal serum calcium.
A normal calcium balance in these patients is – among other factors – determined by the calcium content of PD fluids, calcium intake (dietary intake as well as calcium-containing medication) as well as by ultrafiltration volume. Lowering the calcium concentration in PD fluids may lead to a negative calcium balance, resulting in increasing intact parathyroid hormone (iPTH) and alkaline phosphatase (AF) levels, suggestive for high bone turnover. Subsequently, in PD patients treated with low calcium PD fluids, higher doses of calcium-based phosphate binders may be required in order to prevent secondary hyperparathyroidism [19, 20].
Short-term studies have investigated the effects of low versus high calcium concentration in PD fluids on bone mineral parameters [17, 21]. As far as we know, none of these studies have addressed a possible effect of icodextrin 7.5% (containing high calcium, i.e., 1.75 mmol/L) on the calcium balance. It can be hypothesized, however, that the use of icodextrin 7.5% for the once-daily long dwell attenuates changes in bone mineral parameters as previously observed when the calcium concentration in PD fluids was lowered.
In this case series, we report changes in bone mineral parameters and phosphate binder prescription in PD patients after switch from high (1.75 mmol/L) to low (1.25 mmol/L) calcium concentration for the short dwells while maintaining icodextrin 7.5% for the once-daily long dwell.
Case Series
As of January 2020, all Baxter Physioneal 35 PD fluids (containing 1.75 mmol/L calcium) were no longer available in the Netherlands. As a result, standard of care in our center (Northwest Clinics, Alkmaar, The Netherlands) was changed. All Physioneal 35 PD fluids (containing 1.75 mmol/L calcium) were replaced by Physioneal 40 (containing 1.25 mmol/L calcium). The use of extraneal (icodextrin 7.5%) was unchanged. At the time of this change, we selected 10 stable PD patients, all using icodextrin 7.5% for the once-daily long dwell. The included patients visited our dialysis center every 6 weeks and underwent routine biochemical measurements, according to standard care. Two patients were lost to follow-up (1 patient received a kidney transplant and 1 patient was transferred to hemodialysis). The data from the remaining 8 patients were used for this study.
We collected data at three timepoints: (1) most recent laboratory values (3 ± 8 weeks) before PD fluid switch (Tbaseline), (2) first routine visit (6 ± 6 weeks) after PD fluid switch (Tpost), and (3) 6 months (24 ± 9 weeks) after PD fluid switch (T6months). Patient characteristics were described at baseline (Tbaseline). Medication was prescribed at the discretion of the treating nephrologist. The outcome parameters of this study were changes in the bone mineral parameters, i.e., serum calcium, phosphate, iPTH, and AF. In addition, changes in phosphate binder prescription were analyzed, subdivided in calcium-free and calcium-based binders.
To compare the laboratory values on the three timepoints, we performed univariate repeated measures ANOVA for the normally distributed continuous variables. To analyze differences in prescribed medication between the three timepoints, Friedman test, repeated measure ANOVA, or Cochran’s Q test were used as appropriate. For the ordinal variables, we used Friedman test, followed by post hoc analysis with Wilcoxon’s signed-rank test if significant, and Cochran’s Q test if response was binary. All statistical analyses were performed with SPSS software, version 22.0 for Windows (IBM, Armonk, NY, USA) and GraphPad Prism 6 for Windows (GraphPad, San Diego, CA, USA). The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000534476).
The baseline characteristics of the 8 included patients are presented in Table 1. Patients were predominantly white male with mean age 68.4 ± 12.9 years. No adverse or unanticipated events were observed after switch to PD fluids with lower calcium concentrations. At baseline, bone mineral parameters were within treatment targets with mean calcium 2.32 ± 0.11 mmol/L, phosphate 1.36 ± 0.23 mmol/L, iPTH 39.6 ± 28.3 pmol/L, and AF 104 ± 49 U/L. Five patients used phosphate binders, and four of them used calcium-based phosphate binders. No patients used cinacalcet before PD fluid switch. All patients used vitamin D analogs. Bone mineral parameters over time are presented in Figure 1. As presented in Table 2, serum calcium and AF values did not change over time. Serum phosphate concentrations showed a significant mean difference between Tbaseline and Tpost (−0.262 [−0.439 to −0.086], p = 0.007), and iPTH concentrations showed a significant mean difference between Tbaseline and Tpost (−25.212 [−49.78 to −0.646]), p = 0.045). As shown in Table 3, there was a significant difference in total phosphate binder use (χ2 = 6.87, p = 0.032). There was also a significant difference in calcium-based phosphate binder use (χ2 = 11.20, p = 0.004).
Baseline characteristics
. | Total population (N = 8) . |
---|---|
Sex (N males) | 7 |
Age, years | 68.4±12.9 |
Race (N white) | 7 |
Residual kidney function eGFR, mL/min | 3.86±3.19 |
Residual urinary output, mL | 916±833 |
Time on PD therapy, months | 14.5 [11.3–30.5] |
Exchange volume, mL/24 h | 9,877±2,064 |
APD, % | 75 |
CAPD, % | 25 |
. | Total population (N = 8) . |
---|---|
Sex (N males) | 7 |
Age, years | 68.4±12.9 |
Race (N white) | 7 |
Residual kidney function eGFR, mL/min | 3.86±3.19 |
Residual urinary output, mL | 916±833 |
Time on PD therapy, months | 14.5 [11.3–30.5] |
Exchange volume, mL/24 h | 9,877±2,064 |
APD, % | 75 |
CAPD, % | 25 |
Presented as mean±SD or median [interquartile range].
Bone mineral laboratory parameters over time
. | Tbaseline . | Tpost . | T6months . | p value . |
---|---|---|---|---|
Calcium, mmol/L | 2.32±0.11 | 2.29±0.12 | 2.32±0.09 | 0.735 |
Phosphate, mmol/L | 1.36±0.23 | 1.63±0.38 | 1.54±0.34 | 0.024* |
PTH, pmol/L | 39.63±28.27 | 64.85±34.46 | 49.54±20.72 | 0.008* |
Alkaline phosphatase, U/L | 104.1±48.8 | 101.4±32.4 | 110.7±42.4 | 0.56 |
. | Tbaseline . | Tpost . | T6months . | p value . |
---|---|---|---|---|
Calcium, mmol/L | 2.32±0.11 | 2.29±0.12 | 2.32±0.09 | 0.735 |
Phosphate, mmol/L | 1.36±0.23 | 1.63±0.38 | 1.54±0.34 | 0.024* |
PTH, pmol/L | 39.63±28.27 | 64.85±34.46 | 49.54±20.72 | 0.008* |
Alkaline phosphatase, U/L | 104.1±48.8 | 101.4±32.4 | 110.7±42.4 | 0.56 |
Laboratory values represent means ± standard deviation.
Tbaseline: 3 ± 8 weeks prior to change in PD fluids, Tpost: 6 ± 6 weeks after change in PD fluids, T6months: 24 ± 9 weeks after change in PD fluids. *Significant differences between the three timepoints.
Prescription of phosphate binders
. | Tbaseline . | Tpost . | T6months . | p value . |
---|---|---|---|---|
Calcium-free phosphate binders (tablets) | 1.50 [0.00–3.00] | 1.50 [0.00–3.00] | 1.50 [0.00–3.75] | 1.000 |
Calcium-based phosphate binders (tablets) | 1.00 [0.00–2.75] | 1.00 [0.00–4.00] | 3.50 [2.00–5.50] | 0.004a |
Mean calcium content, mg | 151±175 | 206±238 | 371±227 | 0.001 |
Cinacalcet, % | 0 | 0 | 37.5 | 0.050 |
Vitamin D analogs, % | 100 | 100 | 100 |
. | Tbaseline . | Tpost . | T6months . | p value . |
---|---|---|---|---|
Calcium-free phosphate binders (tablets) | 1.50 [0.00–3.00] | 1.50 [0.00–3.00] | 1.50 [0.00–3.75] | 1.000 |
Calcium-based phosphate binders (tablets) | 1.00 [0.00–2.75] | 1.00 [0.00–4.00] | 3.50 [2.00–5.50] | 0.004a |
Mean calcium content, mg | 151±175 | 206±238 | 371±227 | 0.001 |
Cinacalcet, % | 0 | 0 | 37.5 | 0.050 |
Vitamin D analogs, % | 100 | 100 | 100 |
aSignificant differences between Tbaseline and T6months (Z = −2.23, p = 0.026) and Tpost and T6months (Z = −2.26, p = 0.024).
Discussion
In this case series, no changes in serum calcium levels were observed in PD patients that were switched from PD fluids with high calcium to low calcium while maintaining on icodextrin 7.5% for the long once-daily dwell. However, iPTH levels did increase 6 weeks after this switch but returned to baseline values after 6 months. After 6 months, slightly more calcium-based phosphate binders were prescribed.
Several other studies have investigated the role of calcium concentration in PD dialyzate fluids. In 2019, Jin et al. [19] published a meta-analysis of these studies, also performing subgroup analysis by study design (randomized controlled trial and non-randomized controlled trial). They concluded that calcium levels decreased after lowering the calcium concentration in the PD fluids from 1.75 mmol/L to 1.25 mmol/L. Moreover, iPTH levels were significantly lower with 1.75 mmol/L dialyzate calcium as compared to 1.25 mmol/L. However, none of the studies included in this meta-analysis investigated the role of icodextrin 7.5% on the observed calcium changes. Our hypothesis that the use of icodextrin 7.5% for the once-daily long dwell attenuates changes in calcium and iPTH concentrations have, to the best of our knowledge, never been studied. As compared to the data from the abovementioned meta-analysis [19], we did not observe significant changes in total serum calcium, while the meta-analysis showed otherwise. Regarding iPTH, in our study, a temporal rise in iPTH levels was observed, but this rise was significantly less prominent as compared to some of the previous studies in which no icodextrin 7.5% dwell was prescribed. For example, Sanchez et al. [17] noted a rise in iPTH of 47% (from 226.2 ± 228 to 332 ± 188.7) and Sun et al. [22] noted a rise of 54% (from 124.5 ± 16.7 to 191.9 ± 114.7). In our study, the increase was 25% (from 39.63 ± 28.27 to 49.54 ± 20.72). In our case series, AF levels remained stable, which is in line with a previous study [23].
Phosphate levels increased after intervention, which could not be well explained. Possibly it was normal variation augmented by the small sample size. However, subsequently, we observed an increase in the prescription of calcium-based phosphate binders, while prescription of calcium-free remained stable. It is plausible that the treating physician preferred calcium-containing binders over calcium-free binders due to rising iPTH levels and calcium levels in the low-normal range.
The study is limited by the small sample size, and it is uncontrolled and observational character. No additional laboratory samples were drawn, other than those for routine clinical care. The change in calcium concentration in the PD fluids in this study was driven by the fact that PD fluids with high calcium levels were withdrawn from the market in the Netherlands. The present study suggests that it appears safe to reduce calcium levels, thereby likely avoiding a positive calcium balance with potential harmful effects. It has been shown previously that a rise in PTH can be well managed with calcium-containing phosphate binders or calcimimetics [23]. Although robust data on calcium balance and clinical outcome in PD patients are lacking, conservative use of high calcium-containing PD fluids seems appropriate. In conclusion, the use of icodextrin for the once-daily long dwell appears to have an attenuating effect on bone mineral parameters when calcium content of PD fluid is changed from a high (1.75 mmol/L) to a low (1.25 mmol/L) calcium concentration. Although changes in serum calcium appear negligible, a rise in iPTH should be anticipated. A timely increase in calcium prescription via phosphate binders can help restore calcium balance, preventing progressive hyperparathyroidism, high bone turnover, and hyperphosphatemia. More studies are needed to address the role of icodextrin in bone mineral parameters in PD patients and its effect on clinical outcomes.
Statement of Ethics
This study protocol was reviewed, and the need for approval was waived by the Scientific Committee of the Northwest Clinics, Alkmaar, The Netherlands. Written informed consent was obtained from the patients for publication of the details of their medical case and any related data from their electronic hospital files.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was supported financially by an unrestricted grant from Baxter International Inc.
Author Contributions
Lara Verschuur and Anouschka Liefting collected the data. Lara Verschuur was responsible for the data analysis and wrote the draft version of this manuscript. Bastiaan van Dam, Erik Penne, and Fenneke Frerichs contributed to reviewing, editing, and revising of the manuscript. Erik Penne was responsible for the final revisions. All authors read and approved the final manuscript.
Data Availability Statement
All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.