A new era in phosphate binder therapy: What are the options?

Transcription

1 & 2006 International Society of Nephrology A new era in phosphate binder therapy: What are the options? IB Salusky 1 1 Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA Dietary restriction of phosphorus and current dialysis prescription are unable to maintain phosphorus levels within the recommended range ( mg/dl) in patients with advanced chronic kidney disease (CKD). Therefore, phosphate binders that limit the absorption of dietary phosphorus are commonly prescribed for this patient group. The first phosphate binders were introduced more than 30 years ago and included aluminum salts; however, although effective binders, the use of these agents was subsequently restricted because of concerns over aluminum accumulation in the central nervous system, bone, and hematopoietic cells. In subsequent years, calcium salts, namely calcium carbonate and calcium acetate, became the most widely used phosphate binders; however, increasing evidence now suggests that prolonged use of these agents increases the total body calcium load, induces adynamic bone, and potentially increases the risk of cardiovascular and soft tissue calcification. Sevelamer is the first phosphate-binding agent that is non-absorbed, calcium-free, and metal-free. To date, this agent has been shown to effectively control serum phosphorus levels in patients with CKD. It may also attenuate coronary and aortic calcification and has a number of other beneficial effects on lipid metabolism and inflammation among others. Lanthanum carbonate is another new agent that is reported to provide similar phosphate control to calcium-based phosphate binders but concerns that the long-term administration of such compound may lead to tissue accumulation may limit its use.. doi: /sj.ki KEYWORDS: phosphate binders; hyperphosphatemia; chronic kidney disease Correspondence: IB Salusky, David Geffen School of Medicine at UCLA, Le Conte Avenue, Box , CHS , Los Angeles, California , USA. isalusky@mednet.ucla.edu Phosphate-binding agents are indicated to the vast majority of adult and pediatric patients undergoing current standard dialysis regimens. 1 Reducing the daily dietary load of phosphorus by restricting the intake of foods with high phosphorus content cannot be undertaken without severely compromising protein intake. Furthermore, long-term compliance with a restricted diet is generally poor. In addition, current dialysis prescription is unable to maintain normal phosphorus balance if an adequate protein intake is given. 1,2 Prolonged nocturnal dialysis has been shown to achieve better control of phosphorus compared to short daily dialysis and the use of phosphate binders may not be required. In some instances, phosphate should be added to the dialysate solution. 3,4 However, such dialytic modality is not yet widely accepted. Therefore, because of these limitations, the majority of patients with advanced chronic kidney disease (CKD) require treatment with phosphate binders to limit the absorption of dietary phosphorus and to maintain serum phosphorus levels within the normal physiological range. Since their first introduction more than 30 years ago, the use of phosphate-binding agents has progressed from aluminum-based binders in the 1970s to the widely used calcium-based agents. Recent years have seen the introduction of newer agents such as sevelamer hydrochloride and lanthanum carbonate (Table 1). Although all the phosphate binders are effective in controlling serum phosphorus levels, the older agents, such as the aluminum- and calcium-based binders can be associated with serious adverse effects. The use of aluminum leads to accumulation and in some cases toxicity, whereas the use of calcium-based binders is associated with the induction of adynamic bone disease, increments in serum calcium levels, more frequent episodes of hypercalcemia, and the development of vascular calcifications. The development of calcium-free-metal-free phosphate binders such as sevelamer opens a new approach to the treatment of the renal bone diseases and the process of vascular calcifications. Lanthanum carbonate, a newly approved calcium-free-metal-based phosphate binder, is effective without inducing changes in serum calcium, but there are concerns with long-term administration. The aim of this review is to provide an update on the advantages and disadvantages of the different available phosphate binders in patients treated with maintenance dialysis. S10

2 Table 1 Comparison of the various phosphate-binding agents Compound % calcium absorbed (estimate) Phosphorus (mg) bound per mg Ca 2+ absorbed Calcium carbonate B20 30% a B1 mg P bound per B39 mg P bound per 1 g 8 mg Ca absorbed a d CaCO 3 Calcium acetate With meals: 2171%; between meals: 4074% b Magnesium carbonate/calcium carbonate Aluminium hydroxide Aluminium carbonate Sevelamer hydrochloride Contains 450/300 mg calcium acetate B1.04 mg P bound per mg Ca absorbed; c 1mgP bound per 2.9 mg Ca absorbed a B1 mg P bound per 2.3 mg Ca absorbed Estimate of potential binding power Advantages Adverse effects B45 mg P bound per 1 g calcium acetate b None N/A Liquid: mean binding 22.3 mg P per 5 ml; tablet/ cap mean binding 15.3 mg P per tablet/cap e N/A Inexpensive, wide variety of products/availability Less calcium absorption than CaCO 3 ; P binding similar to Al(OH) 3 c Potential to minimize calcium load Effective phosphate binding Hypercalcemia, extraskeletal calcification, GI side effects, constipation Hypercalcemia, extraskeletal calcification, GI side effects Hypermagnesemia; no long-term studies of efficacy and safety Constipation/fecal impaction, bone mineral defects, aluminium toxicity, chalky taste, GI distress, nausea, and vomiting None N/A Same as above Same as above Same as above None N/A Unknown f Non-calcium, nonaluminium. Effective phosphate binder GI, gastrointestinal; N/A, not available. Adapted with permission from the National Kidney Foundation. a Emmett et al b Schiller et al c Sheikh et al d Slatopolsky et al e Balasa et al f Rosenbaum et al GI side effects SELECTING A PHOSPHATE BINDER Aluminum-based binders Until the mid-1980s, the aluminum-containing phosphate binder, aluminum hydroxide, and to a lesser extent aluminum carbonate, constituted the mainstay of treatment for hyperphosphatemia in patients with CKD. 2,5 However, although aluminum salts are highly effective as phosphate binders, it is now recognized that chronic administration of these compounds leads to significant accumulation of aluminum in the central nervous system, bone and hematopoietic cells, and the development of severe toxic effects including encephalopathy, osteomalacia, myopathy, and microcytic anemia. 5,6 Patients with CKD treated with aluminum salts are particularly susceptible to the effects of cumulative ingestion of aluminum because plasma protein binding prevents the removal of high concentrations of aluminum by dialysis. 7 Furthermore, when recommended safe doses of aluminum hydroxide were prospectively compared to calcium-based binders, Salusky et al. 8 demonstrated that, aluminum hydroxide was less effective than calcium carbonate as a phosphate binder, and plasma aluminum levels increased over time and were associated with an increased aluminum body burden. One patient actually developed aluminum bone disease in this study. Thus, if prescribed, aluminum should be used only for 4 8 weeks. 9 Moreover, care should be taken to avoid concomitant use of sodium citrate or calcium citrate, which markedly enhance gastrointestinal absorption of aluminum. 10,11 Calcium-based binders Of the available calcium-based binders, calcium carbonate and calcium acetate are the most widely used, significantly lowering serum phosphorus levels In general, calcium salts are less effective phosphate binders than aluminum salts; this is because the dissolution of ionized calcium carbonate, the most widely used calcium salt, is very ph dependent and is maximal below ph 5 which is in direct contrast to the higher ph necessary for the binding of calcium to phosphorus. 2,15 Although calcium-based phosphate binders are still commonly used, increasing evidence suggests that intestinal absorption of the large doses of calcium required to adequately control phosphorus levels contributes to continued calcium overload, positive calcium balance, increases in serum calcium levels, more episodes of hypercalcemia, adynamic bone disease, and diminished bone buffer capacity. 14,16,17 This increase in total body calcium load potentially increases the risk of cardiovascular and other soft tissue calcification In a study of young adults with CKD stage 5, daily calcium intake from calcium-containing phosphate binders in patients with coronary artery calcification scores determined by electron beam computed tomography, was found to be S11

3 twice that of patients without calcification. 18 Furthermore, a correlation between the oral dose of elemental calcium, prescribed as a calcium-based phosphate binder, and presence/severity of vascular calcification assessed by ultrasonography has also been reported in other studies. 19,21 In a study of 120 stable patients with end-stage renal disease treated with hemodialysis, Guérin et al. 19 reported an independent positive correlation between dose of calcium carbonate prescribed (grams of elemental calcium per day) and vascular calcification score. Similarly, in a study of 202 patients with end-stage renal disease undergoing maintenance hemodialysis, the dose of calcium carbonate prescribed (grams of elemental calcium per day) was found to be significantly higher among patients with arterial media calcification or arterial intima calcification detected by radiological examination of the pelvis compared with patients with no calcification (2.2 and 2.0 g, respectively, vs 1.1 g; Po0.01). 21 Initially, adynamic bone disease was identified as one of the skeletal manifestations of aluminum bone disease. 22 Subsequently, the first description of adynamic bone induced by the use of calcium-based binders was described in pediatric patients undergoing maintenance dialysis 23 and similar findings were subsequently reported by other investigators. 24,25 The prevalence of this disorder was described by Sherrard et al. 26 in a large cohort of patients treated with dialysis. Thus, the prevalence of this condition began to increase in the mid-1990s, coinciding with the switch from aluminum to calcium-based phosphate binders. 27 The main biochemical characteristics of this state of low-bone turnover were increases in serum calcium levels, more frequent episodes of hypercalcemia and relatively low parathyroid hormone, and alkaline phosphatase levels in dialysis patients as a consequence of over-suppression of parathyroid hormone secretion. More recently, it has been demonstrated that such lesions are associated with increased risk of arterial calcification. 27,28 Thus, K/DOQI guidelines for bone and mineral metabolism that represent a review of the literature until December 2001, recommend that total body calcium load from the use of calcium-based binders be o1.5 g/day of elemental calcium. 9 Magnesium-based binders Magnesium-based binders (e.g., magnesium hydroxide and magnesium carbonate) have been used as alternatives or adjuncts to calcium-based binders for the management of hyperphosphatemia. However, magnesium hydroxide and magnesium carbonate are both less effective than calciumbased binders and larger doses are required which frequently lead to the development of hypermagnesia and diarrhea Sevelamer hydrochloride Sevelamer hydrochloride is a non-absorbed, calcium-free, metal-free phosphate binder. Optimal binding of phosphate by sevelamer occurs at ph 6 7 in the small intestine. Unlike aluminum-based phosphate binders or lanthanum, sevelamer is unable to bind phosphate at a low ph; however, the clinical relevance of this is minimal given that negligible absorption of phosphate occurs in the stomach and at the beginning of the small intestine, where the ph is low. Several previous studies, including the Treat-to-Goal (TTG) 32 and the Renagel in New Dialysis (RIND) trials, 33 have shown that treatment with sevelamer for up to 52 weeks significantly reduces serum phosphorus levels in patients treated with hemodialysis 34,35 and has a minimal effect on serum calcium levels compared with traditional calciumbased phosphate binders. 32,34,36 In the randomized TTG study, treatment of 200 hemodialysis patients with sevelamer (mean dose 6.5 g/day) or a calcium-based phosphate binder (mean dose 4.3 g/day, elemental calcium 1.4 g/day) for 52 weeks provided equivalent control of serum phosphorus but there was a significantly lower incidence of hypercalcemia in the sevelamer group (5 vs 16% of patients; P ¼ 0.04). 32 Results from the Calcium Acetate Renagel Evaluation (CARE) study suggested that calcium acetate was more effective than sevelamer at controlling serum phosphorus and calcium phosphorus (Ca P) product levels in hemodialysis patients. 37 However, hypercalcemic episodes were significantly more frequent with calcium acetate in this study and the absence of a significant effect of sevelamer on serum phosphorus levels was likely attributable to the fact that the dose of sevelamer used was subtherapeutic and not equipotent to the dose of calcium acetate. In addition to controlling serum phosphorus levels with fewer episodes of hypercalcemia, an increasing body of evidence suggests that sevelamer also attenuates the progress of coronary and aortic calcification compared with calcium-based phosphate binders, indicating that the choice of phosphate binder has an important impact on the development of calcification. In the TTG study, which recruited 200 hemodialysis patients, reduction in calcification score from baseline (determined using electron beam computed tomography) for the coronary artery and aorta was significantly greater with sevelamer compared with calcium-based phosphate binders; this difference was observed as early as 6 months and continued to be significant at 1 year (Figure 1). 32 Furthermore, Block et al. 33 reported similar findings in 129 patients new to dialysis. In this study, there was minimal evidence of disease progression among those patients with no evidence of coronary artery calcification at study entry, regardless of phosphate-binder therapy used; however, in those patients with mild coronary artery calcification (430) at baseline, treatment with a calciumbased phosphate binder (mean dose elemental calcium 2.3 g/day) resulted in more rapid progression of coronary artery calcification compared with sevelamer (mean dose 8 g/day) (Figure 2). It should be noted that the current K/DOQI guidelines represent a review of the literature until December 2001 and therefore bring into question the recommended dose of calcium-based binders containing elemental calcium (o1.5 g/day), particularly in view of the importance of S12

4 Baseline calcification score (mean ±s.d.) P =0.002 P =0.03 P =0.04 P=0.01 Coronary artery 26 weeks Aorta Coronary artery Sevelamer Calcium 52 weeks Aorta Figure 1 Absolute change from baseline calcification scores in patients treated with sevelamer or a calcium-based phosphate binder: results from the TTG study. 32 % Increase in CACS (mean ± s.d.) P= P= P= months Sevelamer Calcium 12 months 18 months Figure 2 Percentage increase in coronary artery calcification scores during treatment with sevelamer or a calcium-based phosphate binder in patients with a baseline coronary artery calcification score controlling phosphorus levels without disturbing calcium homeostasis and vascular calcification. Sevelamer has also been shown to be as effective as calcium carbonate in controlling parathyroid hormoneinduced bone disease, without increasing serum calcium levels, during therapy with active vitamin D sterols. 38 In this study, pediatric peritoneal dialysis patients with bone biopsyproven secondary hyperparathyroidism were randomly assigned to calcium carbonate or sevelamer for 8 months, together with intermittent doses of oral calcitriol or doxercalciferol, after which they underwent repeat bone biopsy. Bone formation rates improved in both treatment groups, reaching the normal range in about 75%. However, serum calcium levels and Ca P product increased in the calcium carbonate group but remained unchanged with sevelamer, suggesting that sevelamer increases the safety of treatment with active vitamin D sterols in patients with secondary hyperparathyroidism. 38 In a post hoc analysis of data from the TTG study, Raggi et al. 39 showed that treatment with calcium salts, but not sevelamer, was associated with an unexpected reduction in thoracic trabecular and cortical bone attenuation. The observations in calcium-treated subjects were paralleled by changes in biochemical markers of bone turnover (total and bone-specific alkaline phosphatase, osteocalcin, and parathyroid hormone), and by progressive coronary artery and aortic calcification. The mechanisms underlying these changes have yet to be elucidated but the findings may have important implications for the management of hyperphosphatemia and hyperparathyroidism in CKD. As discussed in more detail elsewhere in this supplement 40, sevelamer has been shown also to have a number of other beneficial effects, including reductions in serum lowdensity lipoprotein-cholesterol 32,41,42 and inflammatory markers. 41,43 Lanthanum carbonate Lanthanum carbonate is a non-calcium, metal-based phosphate binder that has only recently become available for the management of hyperphosphatemia in patients on dialysis (US Food and Drug Administration approval in 2004). Lanthanum carbonate is reported to provide similar phosphate control to calcium-based phosphate binders in patients on dialysis but with a lower incidence of hypercalcemia. 44,45 In a large 6-month, multicenter, randomized study (n ¼ 800), phosphate control was similar with lanthanum carbonate (elemental lanthanump3.0 g/day) and calcium carbonate (elemental calcium of g/day, median dose 3.0 g/day), with approximately 65% of patients in both groups achieving control of serum phosphate (p5.58 mg/dl); however, the incidence of hypercalcemia was markedly higher in the calcium carbonate group (20.2 vs 0.4% of patients). 45 Similarly, in a 12-month randomized study in patients on dialysis, a comparable level of phosphate control with lanthanum (at dosesp3.75 g/day) and calcium carbonate (p9.0 g/day) was contrasted by a higher incidence of hypercalcemia in the calcium carbonate group (49 vs 6% of patients). 44 In a bone histology study, lanthanum carbonate was not associated with the development of adynamic bone when compared with calcium-based treated patients. Although short-term clinical studies of up to 12 months duration suggest that lanthanum is well tolerated in humans, recent animal studies suggest that significant tissue accumulation of lanthanum may occur After administration of lanthanum to rats for 28 days in two studies and for up to 110 days in a third study, tissue deposition of lanthanum was reported in several organs including the lung, kidney, and bone and was highest in the liver. Deposition of lanthanum was also markedly increased in uremic compared with non-uremic animals suggesting that renal failure may accelerate the accumulation of lanthanum Long-term bone data from dialysis patients S13

5 treated with lanthanum for 44 years did not reveal any evidence of osteomalacia, a frequently reported toxicity associated with aluminum-based phosphate binders. 27 However, these data are based on just 11 patients and it is unclear what dose of lanthanum was prescribed. 27 Moreover, more recently, Spasovski et al. 51 demonstrated that plasma and bone lanthanum content increased after 1 year of therapy with lanthanum carbonate in hemodialysis patients; in contrast, such values did not change in patients treated with calcium-based binders. After 1 year of discontinuation of lanthanum carbonate therapy, bone lanthanum content remained elevated in a substantial proportion of patients. In light of the findings in humans and animal studies, and based on previous experience with aluminum-based phosphate binders and the potential toxicity associated with metal accumulation, further studies are required to determine the long-term tolerability of lanthanum carbonate in patients with chronic renal failure. Furthermore, the long-term consequences of lanthanum carbonate administration on the growing skeleton remained to be defined, as studies in rats have shown that lanthanum is deposited into developing bone including the growth plate. In summary, lanthanum carbonate offers another calcium-free option for the effective management of hyperphosphatemia but does not appear to have any additional benefits on vascular calcification, inflammation, and lipid metabolism, and carries at least a theoretical risk of accumulation. CONCLUSION The limitations of traditional therapies for the treatment of hyperphosphatemia emphasize the need for safe and effective phosphate binders. This is particularly important given our current understanding of the relationship between abnormalities of mineral metabolism and the process of vascular calcification. Sevelamer is a novel, non-calcium, non-metalbased binder that has shown effective control of serum phosphorus and Ca P levels in hemodialysis patients, and represents an important therapeutic advance for the management of hyperphosphatemia and the control of secondary hyperparathyroidism. REFERENCES 1. Bleyer AJ. Phosphate binder usage in kidney failure patients. Expert Opin Pharmacother 2003; 4: Emmett M. A comparison of clinically useful phosphorus binders for patients with chronic kidney failure. Kidney Int 2004; 66(Suppl 90): S25 S Pierratos A. Nocturnal home haemodialysis: an update on a 5-year experience. Nephrol Dial Transplant 1999; 14: Toussaint N, Boddington J, Simmonds R et al. Calcium phosphate metabolism and bone mineral density with nocturnal hemodialysis. Hemodial Int 2006; 10: Molony DA, Murthy B. 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