A Comparison of Calcium-Based Phosphorus Binders for Patients with Chronic Kidney Disease

Transcription

1 A Comparison of Calcium-Based Phosphorus Binders for Patients with Chronic Kidney Disease Michael Emmett, MD The author is with the Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas. Hyperphosphatemia in patients with end-stage renal disease (ESRD) is associated with secondary hyperparathyroidism and renal osteodystrophy, and is independently associated with an increased risk of mortality. Therefore, tight control of serum phosphorus is considered essential in these patients. Ideally, the best phosphorus binder would be inexpensive, nontoxic, well tolerated, and potent. Currently, calcium-based binders are generally considered first-line agents for the treatment of hyperphosphatemia in ESRD. However, excessive calcium absorption may produce hypercalcemia and possibly soft-tissue and vascular deposition. Calcium carbonate is a widely used effective, inexpensive, over-the-counter phosphate binder. Calcium acetate is an alternative phosphorus binder that is a more soluble and efficient phosphate binder. Equimolar doses of calcium acetate bind twice as much phosphorus as calcium carbonate. As a result, phosphorus binding can be achieved with a lower dose of calcium. The NKF/K-DOQI guidelines state that the total dose of elemental calcium provided by calcium-based phosphate binders should not exceed 1,500 mg/day. Calcium acetate more readily permits optimal phosphorus binding within these guidelines. This review focuses on calcium binders. Chronic kidney disease (CKD) is a major health issue in the United States and worldwide. CKD affects about 1 in 9 adults, and about 300,000 patients with end-stage renal disease (ESRD) in the United States require chronic dialysis therapy. 1 The mortality rate among U.S. dialysis patients approaches 20% annually, with cardiovascular disease the single most important cause of death. 2 The risk of cardiovascular mortality is especially great among young dialysis patients, exceeding that of agematched controls by more than 100-fold. 3 Recent studies suggest that alterations in mineral metabolism contribute to the development of cardiovascular disease and to increased mortality. It also has become increasingly apparent that hyperphosphatemia plays a major role in the high morbidity and mortality associated with kidney dysfunction and failure. 4 6 The association of hyperphosphatemia and kidney dysfunction has been known for more than 80 years, 7 but the clinical impact and toxicity of hyperphosphatemia was not well recognized or understood until the early 1970s. 8,9 At that time, Bricker et al. 8,9 delineated the pathophysiologic cascade triggered by hyperphosphatemia. They showed how hyperphosphatemia led to hypocalcemia, progressive secondary hyperparathyroidism, reduced kidney activation of vitamin D, and a spectrum of progressive metabolic bone diseases. They also showed that proportional dietary phosphorus restriction could ameliorate much of this pathologic response. These studies resulted in a worldwide effort to control phosphorus levels in patients with advanced and end-stage kidney disease. The adverse effects of hyperphosphatemia have assumed even more importance recently because several lines of evidence show a strong association between hyperphosphatemia and increased risk of cardiovascular morbidity and mortality. The exact mechanisms responsible for this increased risk remain unknown. 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 (HD) patients, especially sudden death and death from coronary artery disease. 6 These associations have led to recommendations for more rigorous control of serum phosphate. 10 Despite that aggressive treatment of hyperphosphatemia is a universally accepted major therapeutic goal, Block et al. 4 reported that more than 60% of U.S. dialysis patients have serum phosphorus levels above the maximum recommended level of 5.5 mg/dl. 11 Phosphorus enters body fluids from 2 major sources: dietary, via GI absorption, and skeletal, via net MAY 2006 DIALYSIS & TRANSPLANTATION 1

2 resorption. Phosphorus leaves body fluids by deposition into the skeleton and soft tissue, kidney excretion, and, in dialysis patients, via hemoor peritoneal dialysate. Optimal control of serum phosphorus in patients with kidney disease must address the major sources of phosphorus input and maximize phosphorus removal. Phosphorus control strategies currently available include dietary phosphorus restriction, use of drugs that bind phosphorus in the gastrointestinal (GI) tract (thereby reducing its absorption), and dialytic phosphorus removal. The purpose of this review is to highlight the major differences among different calcium salts, the most commonly used class of phosphate binders. Pathogenesis of Hyperphosphatemia Phosphorus is a ubiquitous component of virtually all food. The average daily phosphorus intake in North American and European adults is about 1,000 mg for women and 1,500 mg for men. About 60% 70% of ingested phosphorus is absorbed in the small bowel, largely via a passive, nonsaturable mechanism. In addition, active transcellular phosphorus transport, which is regulated by vitamin D, becomes important when phosphorus intake is low. 12 Unabsorbed phosphorus is excreted in the stool and, in healthy adults, the absorbed load of phosphorus is quantitively excreted into the urine. Normally, the kidney filters a very large quantity of inorganic phosphorus (about 9,000 mg/day), and then the tubules, primarily the proximal tubules, reabsorb more than 90% of this load. Phosphorus reabsorption is primarily regulated by parathyroid hormone. ECF volume status also affects phosphorus reabsorption. Furthermore, recent research indicates an important role for other phosphatonin hormones such as fibroblast growth factor Adults with normal renal function are generally in zero or slightly negative phosphorus balance. (Children excrete less phosphorus than they absorb from the diet because some is deposited in the skeleton and used for the expanding cellular mass.) Serum phosphorus levels in patients with early and mild kidney insufficiency may remain normal (or even be reduced) as a result of secondary hyperparathyroidism. However, compensating mechanisms fail when kidney dysfunction advances, resulting in positive phosphorus balance, which leads to progressive hyperphosphatemia. 8,9,14 Treatment of Hyperphosphatemia Dietary Restriction of Phosphorus If it were possible to accomplish, restriction of dietary phosphorus (in proportion to the reduction in kidney function) could largely prevent hyperphosphatemia. Secondary hyperparathyroidism could still ensue as a result of deranged vitamin D metabolism, but this could be treated with exogenous vitamin supplementation. However, dietary restriction alone is generally unsuccessful because phosphorus is such a ubiquitous component of most foodstuffs, and proteins are especially rich in phosphorus. 15 This makes it virtually impossible to provide a nutritious and palatable diet and simultaneously markedly restrict phosphorus. The common use of vitamin D supplements also exacerbates this problem because they enhance intestinal phosphorus absorption. 12,16 Nonetheless, it is important to educate these patients to avoid phosphorus-rich foods such as dairy products and cola drinks. Dialysis Dialysis removes a significant quantity of phosphorus, with a 4-hour HD treatment removing about 1,000 mg of phosphorus. 17 As most patients undergo HD 3 times a week, an estimated 3,000 mg of phosphorus is removed a week, an amount well short of the 5,000 6,000 mg of phosphorous a week that most adults absorb. 17,18 Most HD and peritoneal dialysis patients remain hyperphosphatemic unless phosphate binders are used. 19 However, longer, more frequent, or nocturnal HD sessions will remove additional phosphorus and may effectively control serum phosphorus. 20 Phosphate Binders Because dietary restrictions and the commonly used methods of dialysis are not sufficient to achieve target serum phosphorus levels, almost all dialysis patients and many of those with less severe stages of kidney disease require phosphate binders to achieve adequate control. The history of phosphate binders can be divided into 3 overlapping eras. The first is the era of alkaline aluminum salts. Aluminum hydroxide has been used to reduce phosphorus levels and heal uremic bone disease since the early 1940s. 21 When the importance of serum phosphorus control became apparent in the 1970s, the use of aluminum salts became common practice. For many years it was incorrectly believed that aluminum was not absorbed by the GI tract, and so the enormous quantities being ingested were not toxic. This assumption proved to be tragically incorrect. By the early 1980s the toxic effects of aluminum, including osteomalacia, encephalopathy, and microcytic anemia, had been well established. 22,23 Recognition of aluminum toxicity ushered in the second phosphate binder era, when calcium salts replaced alkaline aluminum salt binders. Calcium carbonate was the first widely used calcium-based binder; later calcium acetate (PhosLo, Nabi Biopharmaceuticals) was introduced. Although calcium salt binders are efficacious and cost effective, longterm safety questions about their use arose because of concern about 2 DIALYSIS & TRANSPLANTATION MAY 2006

3 excess calcium absorption, positive calcium balance, hypercalcemia, and their possible relationship to the development of soft-tissue and cardiovascular calcifications. Phosphate binder therapy has recently entered its third era, characterized by the introduction of several novel agents such as lanthanum carbonate (Fosrenol, Shire Pharmaceuticals) and the nonmetallic phosphorus binder sevelamer (Renagel, Genzyme Corporation). Comparison of Calcium-Based Phosphorus Binders In the early 1980s, when nephrologists were seeking an alternative to aluminum salts for binding phosphate in the GI tract, they switched to calcium carbonate. Calcium reacts with phosphorus, forming an insoluble salt. It has been known for many decades that soluble calcium salts will bind dietary phosphorus, albeit less effectively than will aluminum. 24 By the mid-1980s, calcium carbonate, a readily available and inexpensive medication, had become the phosphorus binder of choice. 25 Subsequent studies suggested that calcium acetate might be a more effective and safer calcium alternative. The following sections highlight the differences between these 2 salts. Calcium Carbonate and Calcium Acetate: Theoretical and In Vitro Dissolution Rate and Phosphorus-Binding Differences The ph of the gastrointestinal tract affects both the rate of dissolution of calcium salts and the subsequent binding reaction of the ionized calcium with phosphorus. Calcium ions bind phosphorus best at an alkaline ph. The major impact of ph on the phosphorus binding reaction is illustrated in Figure 1, 26 which compares the theoretical phosphorus-binding properties of calcium and aluminum ions when the concentrations of the metal and phosphorus are similar to that expected in the stomach and Figure 1. Theoretical analysis of the effect of ph on the binding of phosphorus by dissolved calcium or aluminum at equilibrium. Aluminum bound virtually all the phosphorus regardless of ph, whereas optimal calcium binding required a ph >5 (initial concentrations: phosphorous 320 mg/600 ml; calcium or aluminum 75 meq/600 ml; adapted from Sheikh et al.). 25 upper small bowel following ingestion of a meal together with a binding salt. It is apparent that aluminum avidly binds phosphorus across the entire ph range, whereas calcium requires a ph higher than 5 for optimal phosphorus binding. However, calcium carbonate dissolves most readily in very acid solutions and is relatively insoluble in an alkaline solution. The opposing effects of ph on solubility and phosphorus binding reduce the therapeutic efficacy of this salt. The acidic conditions required for dissolution impair binding; conversely, at an alkaline ph, which is optimal for binding, the salt will not dissolve. Figure 2 shows an in vitro beaker study of phosphorus binding by calcium carbonate and calcium acetate after 1 hour. 27 Calcium carbonate bound phosphorus poorly regardless of ph. After 4 hours (not shown), in vitro binding improved at a ph of 5, but above and below that Figure 2. In vitro phosphorus binding by calcium acetate and calcium carbonate. One hour of in vitro phosphorus binding of calcium acetate approximated the theoretical binding capacity, whereas calcium carbonate binding of phosphorus was very poor (adapted from Sheikh et al.). 25 MAY 2006 DIALYSIS & TRANSPLANTATION 3

4 ph, it remained very poor because of inadequate dissolution of the salt at high ph and poor calcium binding of the phosphorus at low ph. It takes several days to reach the theoretical maximal binding at any ph. In contrast, calcium acetate, a much more soluble salt (10,000 times more soluble than calcium carbonate), dissolves readily across the entire ph range. After 1 hour, calcium acetate had achieved virtual theoretical maximal phosphorus binding at any ph. Recognition of these major in vitro differences in the phosphorus-binding characteristics of calcium carbonate and calcium acetate led to a series of studies that compared the phosphorus binding of these 2 salts in vivo. Calcium Carbonate and Calcium Acetate: In Vivo Differences as Phosphorus Binders Short-term balance studies of healthy subjects and HD patients showed that a given dose of elemental calcium administered as calcium acetate bound twice as much phosphorus as the same dose of calcium given as calcium carbonate (Figures 3a and 3b). 26,27 These studies also showed that much less calcium was absorbed from calcium acetate than from an equimolar dose of calcium carbonate (Figure 3b). When calcium acetate was ingested with a standard meal, 6.8 mg of meal phosphorus was bound for each milliequivalent of calcium absorbed, compared with 2.5 mg of meal phosphorus bound for each milliequivalent of calcium absorbed with calcium carbonate. With calcium acetate, more calcium was bound to phosphorus, so less calcium was available for absorption. If these results also apply to the chronic setting, then calcium acetate should generate less calcium absorption. Not only should half as much calcium be required to provide equal phosphorus binding, but also an even smaller fraction of this smaller load should be absorbed compared with what would occur with calcium carbonate (because more calcium is used to bind phosphorus and therefore unavailable for absorption). The results of multiple large longterm studies of HD patients have confirmed that the dose of elemental calcium, in the form of calcium acetate, required to control serum phosphorus is about half the dose required when calcium carbonate is used An important unresolved question is whether this translates to half as much (or even less) calcium absorption. Unfortunately, there have been no long-term studies of calcium absorption from the various calcium salts used as phosphorus binders in patients with kidney disease. The only clinical correlates of calcium absorption that have been studied in long-term comparative human trials are average serum calcium concentration and frequency of hypercalcemia. The results of these studies, and their limitations, are described in the next section. Another issue that remains unresolved is the impact of gastric acidity on the dissolution of calcium carbonate and its efficacy as a phosphorus binder. Patients with chronic kidney disease are often hypo- or achlorhydric as a result of gastritis and/or the frequent use of H2 receptor blockers or proton pump inhibitors. 34 In theory, this could adversely affect the dissolution and efficacy of calcium Figure 3a. Comparison of effect of different phosphorus binders on amount of ingested phosphorus absorbed. In 10 healthy subjects, phosphorus absorption from a meal was reduced by coingestion of calcium carbonate. However, reduction of absorption was significantly greater with either calcium acetate or aluminum hydroxide. Absorption was measured with a one-meal balance technique. The dose of each medication contained 50 meq of the metal (adapted from Sheikh et al.). 25 Figure 3b. Effect of ingestion of calcium carbonate or calcium acetate on absorption of ingested phosphorus and calcium by hemodialysis patients (n ¼ 6). Absorption was measured with a one-meal balance technique. The dose of each medication contained 50 meq of calcium. Calcium acetate bound more phosphorus and was associated with less calcium absorption (adapted from Mai et al.) DIALYSIS & TRANSPLANTATION MAY 2006

5 carbonate. Several studies of this issue reported conflicting results. 35,36 Differences in Calcium Concentration and the Risk of Hypercalcemia The calcium carbonate dose required to control phosphorus in HD patients is in the range of 3 12 g/day (equivalent to g of elemental calcium), 25,29,37 and it is estimated that approximately 20% 30% of this load will be absorbed. 38 The original studies advocating the use of calcium carbonate as a phosphorus binder for hemodialysis patients reported that about a third of the patients developed hypercalcemia. 25 Subsequent studies reported hypercalcemia rates in the range of 20%. 33 It was hoped that switching patients to calcium acetate would reduce the frequency of hypercalcemia. Several studies did report lower serum calcium concentrations and a lower frequency of hypercalcemia with calcium acetate. 31,32 Others found no difference in these parameters when calcium acetate was compared with calcium carbonate. 29,30,33 However, the serum calcium concentration and frequency of hypercalcemia are very indirect indices of calcium absorption and calcium balance. The release of calcium from the skeleton, skeletal buffering of exogenous calcium, bone turnover rate, PTH status, and vitamin D activity are some of the many factors that affect the concentration of blood calcium independently of net calcium balance. Bone turnover rate may have a greater impact on the development of hypercalcemia in dialysis patients than the dose of calcium salt. 39 Vitamin D analogues, used to suppress parathyroid hormone secretion, have a major impact on serum calcium concentration and frequency of hypercalcemia. Because these drugs increase GI calcium absorption and, under some conditions, increase skeletal reabsorption, they can increase positive calcium balance and generate hypercalcemia. 38,40,41 The average serum calcium concentration and the frequency of hypercalcemia can be reduced by lowering the dialysate calcium concentration. 42,43 Another advance likely to have a major impact in this arena is the calcimimetic drug cincalcet HCl (Sensipar, Amgen). This drug activates calcium-sensing receptors and has a number of effects including major inhibition of PTH secretion. Plasma calcium concentration usually falls, so this drug may permit safer use of calcium salts as phosphorus binders. 44,45 However, long-term studies will be required to determine where to position calcimimetics in the current regimen. Other Calcium Salt Binders Other calcium salts, including calcium citrate (Citracal, Mission Pharmaceuticals), calcium lactate, calcium gluconate and calcium salts of essential keto acid analogues, have been investigated as potential phosphorus binders It has been shown that none of these has any advantage over calcium carbonate or acetate. Calcium citrate is a particularly poor phosphorus binder because the citrate anion competes with phosphorus to bind calcium 26 (this is the property of citrate that makes it a critical urinary component for maintaining calcium solubility and reducing the risk of calcium stone formation). Furthermore, soluble citrate salts markedly increase GI absorption of trace elements, including aluminum, and thereby greatly elevate the risk of aluminum toxicity if aluminum salts are ingested. 23,51 Calcium Salt Binders and Cardiovascular Disease The very high rate of peripheral and coronary vascular calcification and cardiac valvular calcification in HD patients, especially young patients, the high cardiovascular mortality of these patients, and the positive correlations of cardiovascular mortality with hyperphosphatemia and with a high level of a calcium-phosphate product have raised major concerns about the current approach to the treatment of calcium and phosphorus derangements and metabolic bone disease. 1 6,52 55 Two of the most important unresolved questions in this regard are: (1) Is cardiovascular calcification merely a marker for progressive cardiovascular disease, or does calcification itself play a major pathogenic role? (2) Does ingestion of large amounts of calcium salts and the resultant positive calcium balance generate cardiovascular disease, or is it a marker for uncontrolled hyperphosphatemia? One direct but unblinded comparison of calcium salt binders and sevelamer (Renagel, Genzyme Corporation) found that coronary and aortic calcification was less likely to progress when a noncalcium resin was used. 56 However, sevelamer also has a major LDL-reducing effect, which confounds interpretation of these results. 56 Also, several calcium salts were utilized in this study. Although there is no definitive evidence that calcium salts themselves produce cardiovascular calcification or disease, it would be prudent to avoid excessive calcium loading. The most recent NKF/K- DOQI mineral-metabolism guidelines state that the total dose of elemental calcium provided by the calcium-based phosphate binders should not exceed 1,500 mg/day, and the total intake of elemental calcium (including dietary calcium) should not exceed 2,000 mg/day. 11 Almost all studies have shown that to achieve equal degrees of serum phosphorus control, the dose of elemental calcium required with calcium acetate is about 50% of the dose required with calcium carbonate. Therefore, phosphorus control with calcium acetate would be more likely MAY 2006 DIALYSIS & TRANSPLANTATION 5

6 to fall within the K-DOQI calcium restriction guidelines. Appropriate Administration of Calcium Salts as Phosphorus-Binding Agents Timing and Dose Ingested phosphorus binders primarily combine with dietary phosphorus. Therefore, they should be ingested together with, or in close temporal proximity to, each meal. For calcium salts, this will maximize binding to dietary phosphorus and thus minimize calcium absorption (Figure 4). 57 The binder may be ingested immediately before, after, or during the meal. A 2-hour interval markedly decreases phosphorus binding and increases calcium absorption. 57 In addition, patients should try to adjust each dose of phosphorus binder in proportion to the estimated phosphorus load of each meal. Slatopolsky et al. 42 found that dialysis patients ingested an average of 245 mg of phosphorus with breakfast, 23 mg with lunch, and 484 mg with dinner. This suggests that patients should take the largest dose of phosphorus binder with dinner, an intermediate dose with breakfast, and the smallest dose (or none) with lunch. Conclusions Hyperphosphatemia continues to be a great problem in patients with advanced and end-stage kidney disease. Management of hyperphosphatemia includes dietary restriction of phosphorus-rich foods, removal with dialysis and administration of phosphorus binders. Calcium salt binders became drugs of choice after aluminum toxicity was recognized. The first effective calcium salt binder was calcium carbonate. However, the very large doses of calcium that were often required to achieve adequate phosphorus control caused a high frequency of hypercalcemia. More recently, major concern has been raised about excessive positive calcium balance and the possibility that this contributes to cardiovascular calcification, morbidity, and mortality. Calcium acetate is a more efficient phosphate binder, most likely because of its much greater solubility at both acidic and alkaline phs. 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 carborare. Short-term studies have shown that an even smaller fraction of this smaller load is absorbed. However, direct measurement of calcium absorption from calcium acetate in those receiving chronic therapy has not been done. Nonetheless, the available evidence indicates that calcium acetate is probably a more efficient calcium salt binder and may generate a lower calcium balance. Therefore, calcium acetate should be considered the calciumbased binder of choice in the management of uremic hyperphosphatemia. The role of calcimimetic drugs remains unclear, but they may become a major component of the armamentarium available for treatment of hyperphosphatemia and metabolic bone disease. Finally, very few studies have addressed the concept of combined therapy. There is no theoretical reason that smaller doses of multiple agents would not prove to be the best approach. Certainly, any calcium salts ingested by patients should almost always be taken with meals in order to provide maximal phosphorus-binding potential. The only reason such salts should be administered at night or when fasting would be that rare situation when a calcium load needs to be administered via the enteral route to a patient with chronic kidney disease. Figure 4. Effect of time of ingestion of calcium acetate compared to time of meal on absorption of calcium and phosphorus. Administration of calcium acetate (50 meq of calcium) with a meal (or just before or after not shown) resulted in significantly greater phosphorus binding and less calcium absorption compared with that with administration of calcium acetate during fasting, n ¼ 6 healthy normal subjects (adapted from Schiller et al.). 56 References 1. US Renal Data System. USRDS 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Edited by NIo Health. Bethesda, Md: National Institute of Diabetes and Digestive and Kidney Diseases; Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure 6 DIALYSIS & TRANSPLANTATION MAY 2006

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