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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2016  |  Volume : 27  |  Issue : 6  |  Page : 1162-1167
Efficacy and safety of calcium acetate-magnesium carbonate in the treatment of hyperphosphatemia in dialysis patients


Department of Medicine A (M8); Laboratory of Kidney Pathology (LR00SP01), Charles Nicolle Hospital; Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia

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Date of Web Publication28-Nov-2016
 

   Abstract 

A phosphate binder combining calcium and magnesium offers an interesting therapeutic option to control hyperphosphatemia in dialysis patients. We investigated the effectiveness and tolerance of calcium acetate-magnesium carbonate (Ca-Mg). This is a 16-week prospective study including 16 dialysis patients. After an initial two-week washout period, serum phosphorus (sPho) ≥1.8 mmol/L, serum calcium (sCa) ≤2.6 mmol/L, and serum magnesium ≤1.5 mmol/L were the main inclusion criteria. The initial dose of Ca-Mg depended on sPho level and was titrated for every two weeks to have a sPho ≤ 1.8 mmol/L. A second two-week washout period followed the 12 weeks of treatment. Ca-Mg significantly reduced the mean sPho levels from 2.14 to 1.75 mmol/L by the end of the 12-week treatment period (P <0.006). Two weeks after the completion of the Ca-Mg study, the mean sPho levels increased to 2.2 mmol/L. The mean sCa levels did not significantly change during the Ca-Mg trial. The mean serum intact parathyroid hormone declined significantly from 446 pg/mL at the beginning of the study to 367 pg/mL at the end of the 12-week treatment period (P = 0.0002). Digestive tolerance was good in all patients which allowed good compliance. There were no episodes of hypercalcemia. However, six patients had a moderate hypermagnesemia (21 episodes) requiring adjustment of treatment dose. The Ca-Mg proved to be effective in the control of hyperphosphatemia in dialysis patients with good clinical and biological tolerance. Thus, in patients with hypercalcemia or poor tolerance to calcium carbonate, Ca-Mg might be a good alternative.

How to cite this article:
Helal I, Elkateb H, Hedri H, Hajri M, Hamida FB. Efficacy and safety of calcium acetate-magnesium carbonate in the treatment of hyperphosphatemia in dialysis patients. Saudi J Kidney Dis Transpl 2016;27:1162-7

How to cite this URL:
Helal I, Elkateb H, Hedri H, Hajri M, Hamida FB. Efficacy and safety of calcium acetate-magnesium carbonate in the treatment of hyperphosphatemia in dialysis patients. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Aug 10];27:1162-7. Available from: http://www.sjkdt.org/text.asp?2016/27/6/1162/194604

   Introduction Top


The incidence rate of patients suffering from chronic kidney disease (CKD) is increasing in Tunisia and currently about 10,000 patients are on dialysis. [1] Hyperphosphatemia is a major clinical manifestation associated with declining kidney function and its development is usually delayed until the later stages of CKD by elevation of parathyroid hormone (PTH) and fibroblast growth factor (FGF)-23 which increase phosphaturia. [2] The effects of high-serum phosphorus (sPho) levels on PTH, and more recently on FGF-23, play a key role in the pathogenesis of CKD mineral and bone disorder. [3],[4]

High sPho is also involved in the development of vascular calcification [5] and associated with high cardiovascular disease and mortality in patients with CKD Stages 3-5. [6],[7] Thus, the Kidney Disease Improving Global Outcomes (KDIGO) and Kidney Disease Outcomes Quality Initiative clinical practice guidelines emphasize the importance of early and effective phosphate control in patients with end-stage renal disease (ESRD). [8],[9]

A range of phosphate binders currently available for long-term use include calcium-based phosphate binders (calcium carbonate and acetate) and calcium-free binders including aluminum hydroxide, lanthanum carbonate, magnesium carbonate, sevelamer hydrochloride, and sevelamer carbonate. [10],[11] Calcium carbonate is the only phosphate binder available in our country, but it is often not well tolerated. Calcium acetate is not available whereas sevelamer and lanthanum carbonate were very expensive in Tunisia. A phosphate binder combining calcium and magnesium offers an interesting therapeutic option to control hyperphosphatemia in dialysis patients. [12] In this study, we investigated the effectiveness and tolerance of calcium acetate-magnesium carbonate (Ca-Mg) in our dialysis population.


   Materials and Methods Top


This is a 16-week prospective study including 16 dialysis patients [8 peritoneal dialysis (PD) and 8 hemodialysis (HD)]. All patients received similar HD and PD prescription three times per week with 4 h session lengths and dialysate calcium bath concentration of 1.5 mmol/L. Patients with serum sPh ≥1.8 mmol/L, serum calcium (sCa) ≤2.6 mmol/L, and serum magnesium (sMg) ≤1.5 mmol/L were considered eligible for administration of Ca-Mg phosphate binders. After a two-week washout period (calcium carbonate and/or Vitamin D treatment were stopped), Ca-Mg was administrated in 16 patients (5 men and 11 women), the dose was titrated according to sPh levels (1 tablet ×3/day if sPh was between 1.8 and 2.2 mmol/L, 2 tablets ×3/day if sPh was between 2.3 and 2.7 mmol/L, and 3 tablets ×3/day if sPh was ≥2.8 mmol/L). The initial dose of Ca- Mg was titrated for every two weeks (weeks 4, 6, 8, 10, and 12) to achieve a sPh level ≤1.8 mmol/L. The dose was increased or decreased by 1 tablet ×3/day depending on the levels of sPh, sCa, and sMg. A second two-week wash out period followed the 12 weeks of treatment and Ca-Mg was stopped. All patients were followed up by a dietitian, and phosphorus contents in food were regulated and monitored during the study.

We used the following phosphate binder: calcium acetate (435 mg)-magnesium carbonate (235 mg) (OsvaRen, Fresenius Medical Care). Comedication was maintained according to patient requirements. No other medications were prescribed to control the PTH levels (e.g., calcimimetics). Blood samples were collected for every two weeks. All samples were analyzed at the Charles Nicolle Hospital Laboratory using standard clinical laboratory methods. Intact PTH was estimated by two-site sandwich type chemiluminescence immunoassay (upper limit of normal was 65 pg/mL). Each patient was interviewed nine times during the 16 weeks of the study: every two weeks after the collection of blood samples.


   Statistical Analysis Top


Student's t-test for dependent samples was used to test the variation of Ph, Ca, Mg, and iPTH levels, before and after Ca-Mg administration. All calculations are expressed as mean ± 1 standard deviation, P = 0.05 was considered statistically significant.


   Results Top


Demographic characteristics of the patients are summarized in [Table 1]. In this prospective cohort, we investigated 16 patients with ESRD undergoing dialysis for longer than six months. The mean age of the patients was 48.4 ± 20.2 (20-75) years with sex ratio of 0.45. The median median duration on dialysis was 61.5 months (9-269).
Table 1: Demographic characteristics of the study patients.

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Laboratory determinations before and after Ca-Mg administration are shown in [Table 2]. [Figure 1] depicts the mean sPho throughout the study. The mean sPho levels increased from 1.93 mmol/L at pre-washout to 2.14 mmol/L after washout. Upon initiation of Ca-Mg treatment, the mean sPho levels declined immediately to 1.75 mmol/L and this level was maintained until discontinuation of the drug at week 14 (P = 0.0068). Two weeks after the discontinuation of Ca-Mg, the post-treatment washout period, the mean sPho increased to 2.2 mmol/L (P = 0.065), confirming that control of sPho was most likely due to Ca-Mg treatment. [Figure 2] shows the mean serum sCa levels during the study. The mean sCa levels remained not significantly different from the mean starting levels of 2.3 mmol/L (P = 0.53) throughout the period of Ca-Mg intake. However, it declined after discontinuing Ca-Mg to 2.23 mmol/L (P = 0.71).
Figure 1: Time course of serum phosphorus over the 16-week study period.

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Figure 2: Time course of serum calcium over the 16-week study period.

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Table 2: Laboratory determinations before and after Ca–Mg administration.

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The mean serum intact PTH levels over the course of the study are shown in [Figure 3]. The levels decreased during the washout period from 446 to 420 pg/mL. After the initiation of Ca-Mg treatment, the mean serum intact PTH levels declined immediately, reaching 367 pg/ mL by the end of the 12-week treatment period (P = 0.0002). Two weeks after the discontinuation of Ca-Mg, the mean serum intact PTH increased to 412 pg/mL (P = 0.0002).
Figure 3: Time course of serum parathormone over the 16-week study period.

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Digestive tolerance was good in all patients which allowed a good compliance. There were no episodes of hypercalcemia. However, six patients had moderate hypermagnesemia (21 episodes: 8 under 3 tablets/day and 13 under 6 tablets/day) requiring adjustment of treatment dose. [Figure 4] shows variations of serum magnesium levels before and after Ca-Mg treatment.
Figure 4: Time course of serum magnesium over the 16-week study period.

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   Discussion Top


Maintaining sPh levels is an important therapeutic goal to improve clinical outcomes in CKD patients. [8],[9] Calcium-based phosphate binders have a good clinical efficacy and are the most widely used drugs in clinical practice; however, in patients with ESRD, if there are positive calcium balance and bone pathology that impair buffering this calcium excess, extraosseous calcification may develop or progress. [13],[14] In daily clinical practice, it is difficult to calculate the correct calcium balance, which means we may need to choose a non-calciumbased phosphate binder to treat hyperphosphatemia. Calcium-based phosphate binders are advisable to be prescribed in young and nondiabetic patients and in the early stages of CKD, but should be avoided when there is hypercalcemia (>10.5 mg/dL), adynamic bone disease, and in patients with vascular calcifications. According to the KDIGO guidelines, the total daily dose of calcium-based phosphate binders should not exceed 1.5 g/day. At present, there are three non-calcium-based phosphate binders available: sevelamer, lanthanum carbonate, and magnesium salts.

The only phosphate binder available in Tunisia is calcium carbonate. Sevelamer is not available in our country given its high cost. [15] Therefore, we conducted this prospective study to test the effectiveness and tolerance of Ca- Mg, which is less expensive than sevelamer. Our results demonstrate that treatment with Ca-Mg significantly reduced the sPho levels in dialysis patients. Mean sPho significantly decreased during 12 weeks of Ca-Mg treatment and there was a significant rebound two weeks after the discontinuation of the drug, confirming that the observed lowered mean sPho levels were due to Ca-Mg treatment. Serum intact PTH levels significantly decreased during Ca-Mg treatment. This decline was anticipated because sCa and phosphorus are known to regulate PTH secretion. [3],[4] As expected, the increase in sPho during the washout period prompted a corresponding increase of intact PTH.

The efficacy and tolerance of Ca-Mg were evaluated in two randomized, comparative clinical studies: a Phase III non-inferiority study versus sevelamer and a supporting study versus calcium carbonate. [16],[17] In a direct comparison with fifty patients, the medication of Ca-Mg was found to be more effective than calcium carbonate in reducing the serum phosphate levels. Moreover, administration of Ca- Mg did not increase the calcium levels. In contrast, no data have shown that hypercalcemia occurs less frequently than when calcium carbonate is administered. Only very few study results with Ca-Mg are available; in clinical practice, non-calcium-containing phosphate binders are preferred when sCa levels are high. Based on the data available, the side effect profile of Ca-Mg was comparable to other calcium-containing phosphate binders. The side effects which occurred most frequently were hypercalcemia and irritation of the gastrointestinal tract. Specific side effects for Ca-Mg are hypermagnesemia and diarrhea. Clinical data regarding the effect of Ca-Mg on cardiovascular calcifications and bone diseases are missing.


   Conclusion Top


We conclude from our study that Ca-Mg has many similarities to other calcium-containing phosphate binders in the treatment of hyperphosphatemia for ESRD patients undergoing dialysis with a low level of sCa. Some data suggest that Ca-Mg is possibly more effective than calcium carbonate in the reduction of phosphate levels without increasing the calcium levels. However, the research data are very limited, and the effects on vascular calcifications or bone diseases in the long run are unknown. In this prospective study, Ca- Mg proved to be effective in the control of hyperphosphatemia in dialysis patients with a good clinical and biological tolerance. Thus, in patients with hypercalcemia or poor tolerance to calcium carbonate, Ca-Mg might be a good alternative. The therapeutic value of Ca-Mg is deemed similar to calcium acetate, calcium carbonate, and calcium carbonate/calcium gluconate in the treatment of hyperphosphatemia.


   Acknowledgments Top


We wish to thank all the participants and all contributors to this study, the study coordinators, their dedication and hard work, and we are grateful to Fresenius Medical Care and MEDICASE, Tunisia.

Conflict of interests: None declared.

 
   References Top

1.
Counil E, Cherni N, Kharrat M, Achour A, Trimech H. Trends of incident dialysis patients in Tunisia between 1992 and 2001. Am J Kidney Dis 2008;51:463-70.  Back to cited text no. 1
    
2.
Spasovski GB. Bone health and vascular calcification relationships in chronic kidney disease. Int Urol Nephrol 2007;39:1209-16.  Back to cited text no. 2
    
3.
Slatopolsky E, Brown A, Dusso A. Role of phosphorus in the pathogenesis of secondary hyperparathyroidism. Am J Kidney Dis 2001; 37 1 Suppl 2:S54-7.  Back to cited text no. 3
    
4.
Prié D, Ureña Torres P, Friedlander G. Latest findings in phosphate homeostasis. Kidney Int 2009;75:882-9.  Back to cited text no. 4
    
5.
Mathew S, Tustison KS, Sugatani T, Chaudhary LR, Rifas L, Hruska KA. The mechanism of phosphorus as a cardiovascular risk factor in CKD. J Am Soc Nephrol 2008;19:1092-105.  Back to cited text no. 5
    
6.
Kestenbaum B, Sampson JN, Rudser KD, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 2005;16(2):520-8.  Back to cited text no. 6
    
7.
Voormolen N, Noordzij M, Grootendorst DC, et al. High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients. Nephrol Dial Transplant 2007;22:2909-16.  Back to cited text no. 7
    
8.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009;113:S1-130.  Back to cited text no. 8
    
9.
National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42 4 Suppl 3:S1-201.  Back to cited text no. 9
    
10.
Frazão JM, Adragão T. Non-calcium-containing phosphate binders: comparing efficacy, safety, and other clinical effects. Nephron Clin Pract 2012;120:c108-19.  Back to cited text no. 10
    
11.
Plagemann T, Prenzler A, Mittendorf T. Considerations about the effectiveness and cost effectiveness of therapies in the treatment of hyperphosphataemia. Health Econ Rev 2011; 1:1.  Back to cited text no. 11
    
12.
Navaneethan SD, Palmer SC, Craig JC, Elder GJ, Strippoli GF. Benefits and harms of phosphate binders in CKD: a systematic review of randomized controlled trials. Am J Kidney Dis 2009;54:619-37.  Back to cited text no. 12
    
13.
Bushinsky DA. Contribution of intestine, bone, kidney, and dialysis to extracellular fluid calcium content. Clin J Am Soc Nephrol 2010; 5 Suppl 1:S12-22.  Back to cited text no. 13
    
14.
Braun J. Extraosseous calcification in patients with chronic renal failure - no escape? Nephrol Dial Transplant 2005;20:2054-9.  Back to cited text no. 14
    
15.
Hamida FB, Fatma LB, Barbouch S, et al. Effect of sevelamer on mineral and lipid abnormalities in hemodialysis patients. Saudi J Kidney Dis Transpl 2008;19:183-8.  Back to cited text no. 15
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16.
De Francisco AL, Leidig M, Covic AC, et al. Evaluation of calcium acetate/magnesium carbonate as a phosphate binder compared with sevelamer hydrochloride in haemodialysis patients: a controlled randomized study (CALMAG study) assessing efficacy and tolerability. Nephrol Dial Transplant 2010;25: 3707-17.  Back to cited text no. 16
    
17.
Covic A, Passlick-Deetjen J, Kroczak M, et al. A comparison of calcium acetate/magnesium carbonate and sevelamer-hydrochloride effects on fibroblast growth factor-23 and bone markers: post hoc evaluation from a controlled, randomized study. Nephrol Dial Transplant 2013;28:2383-92.  Back to cited text no. 17
    

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Correspondence Address:
Imed Helal
Department of Medicine A (M8), Charles Nicolle Hospital, Tunis
Tunisia
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DOI: 10.4103/1319-2442.194604

PMID: 27900961

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