| Abstract|| |
In the present study, a comparative evaluation of the effects of calcium acetate, calcium carbonate, sevelamer hydrochloride and lanthanum carbonate was carried out in 120 patients with end stage kidney disease (ESKD) undergoing hemodialysis. Biochemical parameters, like serum phosphorous, serum calcium and serum alkaline phosphatase level and intact parathyroid hormone level, were measured. A statistically significant reduction in serum phosphorous, serum calcium, calcium × phosphorous and serum alkaline phosphatase level were observed with all phosphate binders during 3 months of treatment. Reduction in serum phosphorous were observed with calcium acetate (1.5 mg/dL), calcium carbonate (1.3 mg/dL), sevelamer hydrochloride (2.1 mg/dL) and lanthanum carbonate (1.79 mg/dL). The reduction of serum alkaline phosphatase was observed more commonly with sevelamer (107.37 IU/L) and lanthanum (104.33 IU/L) treatments than with calcium acetate (93.9 IU/L) and calcium carbonate (86.57 IU/L). There was no statistically significant change in serum calcium observed with sevelamer and lanthanum treatments, while calcium-based phosphate binders caused a significant rise in the serum calcium level. Serum intact parathyroid hormone level was significantly reduced with all phosphate binder treatments. This decline was highest with sevelamer and lowest with calcium carbonate. All treatments were well tolerated and safety profiles were consistent with previous reports in hemodialysis patients. It is concluded that all phosphate binders are safe and effective for the treatment of hyperphosphatemia in patients with ESKD undergoing hemodialysis. However, sevelamer hydrochloride seems to be superior among all with lowering incidence of hypercalcemia.
|How to cite this article:|
Prajapati VA, Galani VJ, Shah PR. A comparative study of phosphate binders in patients with end stage kidney disease undergoing hemodialysis. Saudi J Kidney Dis Transpl 2014;25:530-8
|How to cite this URL:|
Prajapati VA, Galani VJ, Shah PR. A comparative study of phosphate binders in patients with end stage kidney disease undergoing hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2020 Jan 27];25:530-8. Available from: http://www.sjkdt.org/text.asp?2014/25/3/530/132167
| Introduction|| |
Elevated serum phosphate is a common complication of end stage kidney disease (ESKD), affecting up to 70% of dialysis patients.  The clinical consequences of hyperphosphatemia are well documented and include cardiovascular and other metastatic calcifications, secondary hyperparathyroidism and renal bone disease. ,,, Calcification of the vasculature occurs in more than 50% of dialysis patients, , and contributes to the high cardiovascular mortality rate observed in this patient population.  Dietary restriction of phosphorus and current dialysis prescription are unable to maintain phosphorus levels within the recommended range (2.7-5.5 mg/dL) in patients with advanced ESKD. Therefore, phosphate binders that limit the absorption of dietary phosphorus are commonly prescribed in patients of ESKD undergoing dialysis.  There are no published studies available for Indian ESKD patients on hemodialysis with direct comparison of efficacy of all currently used phosphate binders. Therefore, this study was designed to compare their efficacy, adverse effects and cost to establish which phosphate binder is suitable for the Indian population.
| Materials and Methods|| |
This is a retroprospective study in which 120 patients (of either sex) having stage 5 ESKD maintained on hemodialysis for at least three months with serum phosphorus level above 6.5 mg/dL and without significant hypercalcemia or hypocalcemia (serum calcium >11 mg/dL or <7.9 mg/dL) attending the Institute of Kidney Disease and Research Center, Ahmedabad, Gujarat, were recruited. Patients with a history of cancer and/or drug abuse, actual or intended pregnancy, breastfeeding, kidney-transplanted patient, patients with severe gastrointestinal symptoms and parathyroidectomized patients were excluded. Patient's consents were taken before including them in the study. A detailed history, general examination, vital signs and relevant systemic examination were carried out at the time of recruitment (Week 0). Serum phosphorus, serum calcium, serum alkaline phosphatase and intact parathyroid hormone were estimated at the time of recruitment (baseline). Dialysis was performed two times a week. All patients were randomly selected and divided into four groups (n = 30). Calcium acetate (667 mg), calcium carbonate (500 mg), sevelamer hydrochloride (400 mg) and lanthanum carbonate (500 mg) treatment was assigned in the four groups for three months. All phosphate binders in the form of chewable tablets were chewed three times daily with meal. All the patients were on dialysis two times per week. All data were recorded in a specific case record form (CRF). Serum phosphorus, serum calcium and serum alkaline phosphatase were measured after four weeks, eight weeks and 12 weeks of phosphate binder treatment. Intact parathyroid hormone level was estimated after 12 weeks of phosphate binder therapy. The drug-related adverse events that were observed during the study period were noted in the patient's CRF. The cost of 12 weeks treatment with each phosphate binder was calculated from the maximum retail price (MRP) labels on the respective packages.
| Statistical Analysis|| |
Data were analyzed using Statistical Package for Social Science (SPSS) version 16.0 (SPSS, Inc., Chicago, IL, USA). Results are presented as mean and standard error of mean (mean ± SEM). All data were compared with baseline readings using one-way ANOVA followed by post hoc Tukey's test. P-value less than 0.05 was considered statistically significant. Adverse effects recorded were calculated as percentage of patients suffering from the adverse reactions at the end of treatment.
| Results|| |
Of a total of 120 patients, 30 patients each were randomly allocated to calcium acetate, calcium carbonate, sevelamer hydrochloride and lanthanum carbonate treatments. Demographic data of the participating patients are shown in the [Table 1]. All 120 patients have successfully completed the study with regular follow-up, checked by nephrologists and weekly two time dialysis. The treatment groups were well balanced with regard to baseline demographics.
Results of the effect of phosphate binders on serum phosphorus, serum calcium, serum calcium × phosphorus product, serum alkaline phosphatase and intact parathyroid hormone are shown in [Table 2]. Mean serum phosphorus was significantly reduced with four weeks, eight weeks and 12 weeks of the calcium acetate, calcium carbonate, sevelamer hydrochloride and lanthanum carbonate treatments. The reduction of mean serum phosphorus was found to be 1.5 mg/dL, 1.3 mg/dL, 2.1 mg/dL and 1.8 mg/dL with calcium acetate, calcium carbonate, sevelamer hydrochloride and lanthanum carbonate treatments, respectively. Sevelamer hydrochloride reduced the highest percentage of mean serum phosphorus concentration at 25.62%, while calcium carbonate reduced the lowest percentage of mean serum phosphorus concentration at 16.23%.
|Table 2: Comparison of laboratory parameters in patients of chronic kidney disease undergoing hemodialysis treated with phosphate binders.|
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The change from baseline in serum calcium was significantly different between calcium-based phosphate binders and non-calcium based-phosphate binder treatment groups after 12 weeks [Table 2]. The mean serum calcium was significantly increased at 4 weeks (P <0.05), eight weeks (P <0.001) and 12 weeks (P <0.001) in calcium acetate-treated patients compared with their baseline. Mean serum calcium was also significantly increased with eight weeks (P <0.05) and 12 weeks (P <0.001) of the calcium carbonate treatment as compared with the pre-treatment levels. While the mean serum calcium level was not significantly increased with the sevelamer hydrochloride treatment, the mean serum calcium was significantly increased only after 12 weeks (P <0.05) of the lanthanum carbonate treatment. Rise in mean serum calcium was observed to be 1.05 mg/dL, 0.96 mg/dL, 0.11 mg/dL and 0.29 mg/dL with calcium acetate, calcium carbonate, sevelamer hydrochloride and lanthanum carbonate treatment, respectively, after 12 weeks. Sevelamer hydrochloride increased the lowest percentage of mean serum calcium at 1.51%, while calcium acetate increased the highest percentage of mean serum calcium at 13.71%.
The mean Ca × P was also significantly reduced in all treatment groups [Table 2]. The mean Ca × P was significantly reduced with 8 weeks (P <0.05) and 12 weeks (P <0.001) of the calcium acetate treatment. Mean Ca × P was significantly reduced with 12 weeks (P <0.001) of the calcium carbonate treatment, while mean Ca × P level was significantly reduced with four weeks, eight weeks, and 12 weeks of the sevelamer hydrochloride and lanthanum carbonate treatments. Reduction of mean Ca × P was found to be 4.56 mg 2 /dL 2 , 3.04 mg 2 /dL 2 , 15.09 mg 2 /dL 2 and 11.57 mg 2 /dL 2 with calcium acetate, calcium carbonate, sevelamer hydrochloride and lanthanum carbonate treatment, respectively, after 12 weeks. Sevelamer hydrochloride decreased the highest percentage of mean Ca × P at 24.51%, while calcium carbonate decreased the lowest percentage of mean Ca × P at 5.21%.
Serum alkaline phosphatase was reduced significantly with all treatment groups [Table 2]. Mean serum alkaline phosphatase was significantly reduced with eight weeks (P <0.05) and 12 weeks (P <0.001) of the calcium acetate treatment, while the calcium carbonate-treated group reduced the mean serum alkaline phosphatase level only after 12 weeks (P <0.05) of treatment. Moreover, the mean serum alkaline phosphatase was significantly reduced with four weeks (P <0.05), eight weeks (P <0.001) and 12 weeks (P <0.001) of the sevelamer hydrochloride and lanthanum carbonate treatments. The reduction of mean serum alkaline phosphatase was found to be 93.9 IU/L, 86.57 IU/L, 107.37 IU/L and 104.33 IU/L with calcium acetate, calcium carbonate, sevelamer hydrochloride and lanthanum carbonate treatment, respectively, after 12 weeks. Sevelamer hydrochloride decreased the highest percentage of mean serum alkaline phosphatase at 24.14%, while calcium carbonate decreased the lowest percentage of mean serum alkaline phosphatase at 19.34%.
As shown in [Table 2], the mean intact para-thyroid hormone was significantly reduced with all treatment groups. The mean intact parathyroid hormone was significantly reduced with 12 weeks of calcium acetate (P <0.001), calcium carbonate (P <0.05), sevelamer hydrochloride (P <0.001) and lanthanum carbonate (P <0.001) treatments. The reduction of mean intact parathyroid hormone was found to be 55.36 pg/mL, 46.8 pg/mL, 102.2 pg/mL and 73.96 pg/mL with calcium acetate, calcium carbonate, sevelamer hydrochloride and lanthanum carbonate, respectively. Sevelamer hydrochloride decreased the highest percentage of mean intact parathyroid hormone at 29.18%, while calcium carbonate decreased the lowest percentage of mean intact parathyroid hormone at 13.41%.
Overall, all phosphate binders were well tolerated, and the observed safety profiles were consistent with reports of previous studies of phosphate binders in hemodialysis patients. No serious adverse effects related to treatment were reported. The incidences of adverse events during phosphate binder treatments are shown in [Table 3]. The percentage of patients experiencing adverse effects considered to be related to treatment was similar in the sevelamer hydrochloride (10%) and lanthanum carbonate (13.3%) treatment groups. More patients in the calcium carbonate group experienced gastro-intestinal adverse events related to treatment than in the calcium acetate group (33.3% versus 6%). Compared with other phosphate binders, calcium carbonate-treated patients had higher gastrointestinal adverse events than the other three phosphate binder treatments.
Cost comparison of all phosphate binders are shown in [Table 4]. By comparison of cost for all phosphate binders and observing the MRP labels on the respective package of drugs, calcium carbonate was found to be the cheapest while lanthanum carbonate was the most costly drug. Lanthanum carbonate and sevelamer hydrochloride were six times costlier than calcium carbonate and calcium acetate.
| Discussion|| |
Hyperphosphatemia is a frequent complication in patients with ESKD. There is considerable evidence regarding inadequate phosphorus control and increased morbidity and mortality in patients with ESKD. , Deterioration of renal function in ESKD-impaired calcium excretion and excess of calcium is therefore transported into cellular and interstitial compartments. Although this helps maintain calcium homeostasis, it predisposes the patient to vascular calcification.  This process is exacerbated in those on hemodialysis by calcium absorption from dialysate, abnormalities in bone buffering and turnover and ingestion of calcium-based phosphate binders to treat hyperphosphatemia.  Serum phosphorus levels >6.5 mg/dL, calcium × phosphorus product >70 mg 2 /dL 2 and serum parathyroid hormone levels >495 pg/mL are each strongly associated with increased risk of cardiac mortality in hemodialysis patients, especially sudden death and death from coronary artery disease.  These associations have led to recommendations for more rigorous control of serum phosphate and calcium.
In the present study, the efficacy and safety of four different types of phosphate binders, calcium-based phosphate binders - calcium acetate and calcium carbonate, non-calcium phosphate binders - sevelamer hydrochloride and lanthanum carbonate, were compared by measuring the changes in the level of different laboratory parameters, i.e. serum phosphorus, serum calcium, calcium × phosphorus product, serum alkaline phosphatase and intact para-thyroid hormone. The results of this study suggested that all four studied phosphate binders reduced serum phosphorous level significantly after four weeks of the treatment. Our result is similar to other reported studies. However, sevelamer hydrochloride was shown to be more effective at controlling the serum phosphorous level.
It has been reported that calcium carbonate and calcium acetate were found to be associated with hypercalcemia, coronary calcification, adynamic bone disease and decreased bone buffer capacity.  Several studies reported lower serum calcium concentrations and a lower frequency of hypercalcemia with calcium acetate, , while others found no difference in these parameters when calcium acetate was compared with calcium carbonate. ,, However, the bone turnover rate may have a greater impact on the development of hyper-calcemia in dialysis patients than the dose of calcium salt.  The recently published KDIGO guidelines recommended limiting calcium intake from phosphate binders in patients with chronic kidney disease stages 3-5 disease.  In our study, rise in serum calcium level was more significant with calcium-based phosphate binders than non-calcium-based phosphate binders. There was not much difference observed between calcium carbonate and calcium acetate for rise in serum calcium level. However, rise in calcium was highest with calcium acetate and lowest with sevelamer hydrochloride.
The calcium × phosphorus product is recommended to be kept below 55 mg 2 /dL 2 for reducing the incidence of vascular calcification and cardiovascular mortality.  In the present study, serum phosphorus was significantly reduced by all treatments, with a corresponding reduction in the calcium × phosphorus product, and this beneficial effect was sustained over time. However, only non-calcium binders decreased the calcium × phosphorous product within a specified limit at the end of 12 weeks of treatment. In this study, maximum reduction of the calcium × phosphorous product was seen with sevelamer treatment while the lowest reduction in the calcium × phosphorous product was seen with calcium carbonate treatment in comparison with all other phosphate binder treatments.
The level of alkaline phosphatase is an indicator of osteoblast activity. Usually, in ESKD, there is hyperphosphatemia and hypocalcemia that produces hyperparathyroidism, which in turn leads to high-turnover bone disease. In such a situation, the alkaline phosphatase level will rise.  In the present study, no statistically significant difference was observed between calcium acetate and calcium carbonate treatments and also between sevelamer hydrochloride and lanthanum carbonate treatment groups for reduction of serum alkaline phosphatase. In our study, sevelamer hydrochloride produced the highest reduction of alkaline phosphatase and calcium carbonate produced the least reduction among all phosphate binders used.
Hyperphosphatemia has been implicated in different ways in the genesis of parathyroid hyperfunction as directly on parathyroid gland and indirectly by decreasing ionized calcium and 1,25(OH)2D3. It stimulates hyperplasia of the parathyroid glands and osteitis fibrous cystica (high-turnover bone disease).  One review reported that calcium carbonate and calcium acetate are equally effective in decreasing phosphorous and parathyroid hormone levels, with a similar incidence of hypercalcemia.  Similar results were also observed in our study. Sevelamer hydrochloride showed the maximum decrease of intact parathyroid hormone levels, while calcium carbonate showed the lowest reduction among all four phosphate binders studied.
In the present study, the overall beneficial effect of non-calcium-based phosphate binders, sevelamer hydrochloride and lanthanum carbonate were observed more than calcium-based phosphate binders, calcium acetate and calcium carbonate on ESKD patients under-going hemodialysis. On comparing calcium-based phosphate binders, calcium acetate was found to be a more efficient phosphate binder than the calcium carbonate and, also, it has much greater solubility at both acidic and alkaline pH. The most important advantage of calcium acetate in comparison with calcium carbonate is that it binds equal amounts of phosphorus with a dose of elemental calcium only one-half as large as that required for calcium carbonate. One research also suggested that calcium acetate should be considered the calcium-based binder of choice in the management of uremic hyperphosphatemia.  However, there is some evidence implicating calcium-containing phosphate binders in the progression of vascular and cardiac calcification in patients receiving chronic hemodialysis, but the hypothesis that the calcium-containing binders are the root cause of vascular and cardiac calcification remains largely unproven. , One direct but unblinded comparison of calcium salt binders and sevelamer was reported that coronary and aortic calcification was less likely to progress with sevelamer. 
In our study, there was not much difference observed between the effects of sevelamer and lanthanum on laboratory parameters tested at the end of 12 weeks treatment. However, sevelamer effects were superior to lanthanum. Some studies have reported that sevelamer atenuates the progression of vascular calcification and prevents reduction in thoracic vertebral bone mineral density. , Hyperuricemia may be associated with a number of disorders in patients with chronic renal failure, including insulin resistance, dyslipidemia, hypertension and cardiovascular disease.  Sevelamer hydrochloride was also reported to significant decrease uric acid in hemodialysis patients. , Sevelamer has been shown also to have a number of other beneficial pleotropic effects,  such as reductions in serum low-density lipoprotein cholesterol ,, and inflammatory markers. , Lanthanum carbonate did not appear to have any additional benefits on vascular calcification, inflammation and lipid metabolism, and carries at least a theoretical risk of accumulation.  However, one recent study reported that lanthanum had more phosphorous binding capacity than sevelamer. 
After evaluating the adverse event profile of all the phosphate binders in the present study, calcium acetate was observed to be better tolerated than any other phosphate binders, while calcium carbonate produced a higher rate of adverse events such as gastrointestinal intolerance and constipation. The gastrointestinal adverse effects produced by phosphate binders in the present study were observed with a similar rate as have been reported in the study conducted in hemodialysis patients. 
On calculating the cost of a comparable dosage regimen of calcium acetate, calcium carbonate, sevelamer hydrochloride and lanthanum carbonate, it was observed that calcium carbonate was the cheapest and lanthanum was much costlier than the others. Comparisons of price between calcium acetate, calcium carbonate, sevelamer hydrochloride and lanthanum carbonate showed vast differences. Sevelamer hydrochloride and lanthanum carbonate were approximately six times costlier than calcium acetate and calcium carbonate. The high cost of treatment of sevelamer hydrochloride and lanthanum carbonate makes it beyond the reach of a good proportion of the Indian population. There is no other reported study for cost comparison of all phosphate binders to the best of our knowledge. One study comparing a calcium-based phosphate binder and sevelamer concluded that sevelamer should be considered a desirable approach to treating hyperphosphatemia in patients on hemodialysis, and one year of treatment with sevelamer provides good value for money.  Another study also reported that sevelamer was associated with reduced medicare inpatient and total costs compared with calcium binders; however, when the costs of binders were incorporated, the per member per month (PMPM) costs favored calcium-treated patients.  However, overall long-term treatment cost with sevelamer may reduce because of the other beneficial actions of sevelamer.
This study confirms that all the phosphate binders can reduce serum phosphorus significantly with four weeks of treatment in ESKD patients on hemodialysis. However, sevelamer hydrochloride was shown to be more effective as it reduced serum phosphorus, serum calcium, calcium × phosphorus product, serum alkaline phosphatase and intact parathyroid hormone more than calcium acetate, calcium carbonate and lanthanum carbonate in ESKD patients on hemodialysis. Thus, it represents an important therapeutic advance for the management of hyperphosphatemia and the control of secondary hyperparathyroidism. But, the high cost of sevelamer hydrochloride can limit its use for the poor socioeconomic population. Calcium acetate can be used for poor socio-economic people with hyperphosphatemia and hypocalcemia.
Conflict of interest : None.
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Dr. Varsha J Galani
Department of Pharmacology, A. R. College of Pharmacy, Vallabh Vidyanagar 388120, Gujarat
[Table 1], [Table 2], [Table 3], [Table 4]