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An introduction to phosphate binders for the treatment of hyperphosphatemia in patients with chronic kidney disease

2005; Elsevier BV; Volume: 68; Linguagem: Inglês

10.1016/s0085-2538(15)51226-x

1523-1755

Eli A. Friedman,

Biomedical Research and Pathophysiology

An introduction to phosphate binders for the treatment of hyperphosphatemia in patients with chronic kidney disease. Chronic kidney disease has the potential to induce sequelae that can have severe and mortal outcomes. In particular, impaired glomerular filtration can cause a hyperphosphatemic state, which, if left unchecked, can lead to secondary hyperparathyroidism, vascular calcification, and renal osteodystrophy. Therapeutic management of hyperphosphatemia must maintain both phosphorus and calcium serum concentrations within the recommended guidelines. The balance of both minerals is regulated by parathyroid hormone; thus, an imbalance of one affects the other. In end-stage renal disease, patients often present with hypocalcemic levels due to the kidneys' inability to generate active vitamin D to promote calcium absorption in the intestine. Absorption of calcium can be increased by the administration of active vitamin D analogues. Minimizing phosphorus intake through a strict dietary regimen, combined with the use of phosphate binders to absorb excess ingested phosphate, can help to maintain serum phosphate levels near the recommended concentration of 5.5 mg/dL. Phosphate-binding compounds have evolved from the original aluminum-based binders pioneered in the 1970s to calcium-based binders such as calcium acetate, and more recently, to the following additions to the nephrologist's armamentarium: sevelamer—a polyhydrochloride polymer, and lanthanum carbonate. One of the top 2 common clinical treatments for hyperphosphatemia, calcium acetate, has an established history of efficacy since the 1980s, and has been shown to be cost effective and well tolerated, as well. An introduction to phosphate binders for the treatment of hyperphosphatemia in patients with chronic kidney disease. Chronic kidney disease has the potential to induce sequelae that can have severe and mortal outcomes. In particular, impaired glomerular filtration can cause a hyperphosphatemic state, which, if left unchecked, can lead to secondary hyperparathyroidism, vascular calcification, and renal osteodystrophy. Therapeutic management of hyperphosphatemia must maintain both phosphorus and calcium serum concentrations within the recommended guidelines. The balance of both minerals is regulated by parathyroid hormone; thus, an imbalance of one affects the other. In end-stage renal disease, patients often present with hypocalcemic levels due to the kidneys' inability to generate active vitamin D to promote calcium absorption in the intestine. Absorption of calcium can be increased by the administration of active vitamin D analogues. Minimizing phosphorus intake through a strict dietary regimen, combined with the use of phosphate binders to absorb excess ingested phosphate, can help to maintain serum phosphate levels near the recommended concentration of 5.5 mg/dL. Phosphate-binding compounds have evolved from the original aluminum-based binders pioneered in the 1970s to calcium-based binders such as calcium acetate, and more recently, to the following additions to the nephrologist's armamentarium: sevelamer—a polyhydrochloride polymer, and lanthanum carbonate. One of the top 2 common clinical treatments for hyperphosphatemia, calcium acetate, has an established history of efficacy since the 1980s, and has been shown to be cost effective and well tolerated, as well. Overall, it is estimated that there are more than 19 million adult Americans affected by chronic kidney disease1.Centers for Disease Control and Prevention (CDC) State-specific trends in chronic kidney failure—United States, 1990–2001.MMWR Morb Mortal Wkly Rep. 2004; 53: 918-920PubMed Google Scholar. The most advanced stage, called end-stage renal disease (ESRD), which is classified as stage 5 by the National Kidney Foundation2.Massry S. K/DOQI guidelines released on bone metabolism and disease in CKD.Nephrol News Issues. 2003; 17 (44): 38-41PubMed Google Scholar affects more than 500,000 people in the United States, according to the National Institutes of Health 2002 prevalence report3.US Renal Data System USRDS 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda MD2004Google Scholar. Approximately $15 billion in Medicare expenses are incurred annually by ESRD patients3.US Renal Data System USRDS 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda MD2004Google Scholar, who suffer from bone and cardiovascular complications due to progressive renal insufficiency. An inefficient glomerular filtration rate elevates serum phosphate levels, promoting consequences such as secondary hyperparathyroidism, vascular calcification, and renal osteodystrophy. A survey of more than 6000 hemodialysis patients estimates that the national mean serum phosphate level is 6.2 mg/dL, well above the recommended 5.5 mg/dL maximum4.Block G.A. Prevalence and clinical consequences of elevated Ca x P product in hemodialysis patients.Clin Nephrol. 2000; 54: 318-324PubMed Google ScholarTable 15.Block G.A. Port F.K. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: Recommendations for a change in management.Am J Kidney Dis. 2000; 35: 1226-1237Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar. Hyperphosphatemia is a problem in approximately 60% of U.S. hemodialysis patients, indicating a need for improved therapeutic management4.Block G.A. Prevalence and clinical consequences of elevated Ca x P product in hemodialysis patients.Clin Nephrol. 2000; 54: 318-324PubMed Google Scholar. Another metabolic problem related to ESRD is hypocalcemia caused by the diseased kidney's inability to generate enough active vitamin D for intestinal calcium absorption. As a direct result, an excess of parathyroid hormone (PTH) is secreted, a condition termed secondary hyperparathyroidism6.Martinez I. Saracho R. Montenegro J. Llach F. A deficit of calcitriol synthesis may not be the initial factor in the pathogenesis of secondary hyperparathyroidism.Nephrol Dial Transplant. 1996; 11: 22-28Crossref PubMed Scopus (77) Google Scholar,7.Pavlovic D. Brzac H.T. Prevention and treatment of secondary hyperparathyroidism: Still a challenge for the nephrologist?.Nephrol Dial Transplant. 2003; 18: v45-v46Crossref PubMed Google Scholar. High levels of PTH induce an elevated release of calcium from bone, increasing metabolic calcium concentrations.Table 1Recommended target mineral and hormone concentrations for ESRD patients5.Block G.A. Port F.K. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: Recommendations for a change in management.Am J Kidney Dis. 2000; 35: 1226-1237Abstract Full Text Full Text PDF PubMed Scopus (554) Google ScholarSerum calcium9.2–9.6 mg/dL (2.3–2.4 mmol/L)Serum phosphorus2.5–5.5 mg/dL (0.81–1.78 mmol/L)Calcium-phosphorus product<55 mg2/dL2 ( 6.5 mg/dL) was linked to an increased mortality rate (by 27%), while calcium levels were uncorrelated12.Block G.A. Hulbert-shearon T.E. Levin N.W. Port F.K. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2013) Google Scholar. Similarly, PTH concentrations were independent of risk of death. Comorbidity was found with abnormally high calcium-phosphorous product, but the authors suggest that the increased risk is driven by hyperphosphatemia12.Block G.A. Hulbert-shearon T.E. Levin N.W. Port F.K. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2013) Google Scholar. Braun et al used electron-beam computed tomography (EBCT) to consider the number of calcifications, the surface area, and the average and highest densities of calcifications to compile a coronary artery calcium score for 49 chronic hemodialysis patients and 102 nondialysis patients. A stepwise, multiple regression analysis linked hypertension and older age to higher coronary artery calcium scores, while calcium and parathyroid hormone scores were uncorrelated20.Braun J. Oldendorf M. Moshage W. et al.Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients.Am J Kidney Dis. 1996; 27: 394-401Abstract Full Text PDF PubMed Scopus (703) Google Scholar. This suggests that there is no link between the amount of calcium in the diet and mortality and the development of coronary artery calcification. Coladonato et al have noted that many analyses that correlate dietary intake of calcium to vascular calcification fail to measure calcium intake and, instead, rely on reported or prescribed calcium. These numbers are often highly skewed by the lack of treatment compliance, which is a problem with approximately 65% to 80% of dialysis patients who are prescribed calcium-based phosphate binders18.Coladonato J.A. Szczech L.A. Friedman E.A. Owen Jr., W.F. Does calcium kill ESRD patients—The skeptic’s perspective.Nephrol Dial Transplant. 2002; 17: 229-232Crossref PubMed Scopus (26) Google Scholar. Other studies have suggested that bone turnover rate may have a more significant effect on the development of hypocalcemia than oral calcium intake11.Emmett M. A comparison of clinically useful phosphorus binders for patients with chronic kidney failure.Kidney Int. 2004; : S25-S32Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 18.Coladonato J.A. Szczech L.A. Friedman E.A. Owen Jr., W.F. Does calcium kill ESRD patients—The skeptic’s perspective.Nephrol Dial Transplant. 2002; 17: 229-232Crossref PubMed Scopus (26) Google Scholar, 21.Meric F. Yap P. Bia M.J. Etiology of hypercalcemia in hemodialysis patients on calcium carbonate therapy.Am J Kidney Dis. 1990; 16: 459-464Abstract Full Text PDF PubMed Scopus (68) Google Scholar, 22.Qunibi W.Y. Nolan C.R. Treatment of hyperphosphatemia in patients with chronic kidney disease on maintenance hemodialysis: results of the CARE study.Kidney Int. 2004; : S33-S38Abstract Full Text Full Text PDF Scopus (21) Google Scholar. Also, vascular calcification associated with chronic kidney disease is not a new phenomenon. Well before calcium-based phosphate binders began to be administered for controlling hyperphosphatemia, studies showed that extensive and often severe extraosseous soft tissue calcification was prevalently correlated with patients undergoing chronic dialysis. In a study conducted by Kuzela et al, 79% of dialysis patients had soft tissue calcification involving more than 1 internal viscus, most frequently involving the heart, lungs, stomach, and kidneys, compared with 44% of nondialysis patients (P value < 0.025)23.Kuzela D.C. Huffer W.E. Conger J.D. et al.Soft tissue calcification in chronic dialysis patients.Am J Pathol. 1977; 86: 403-424PubMed Google Scholar. The study was unable to draw correlations between serum calcium, serum phosphate, and calcium-phosphorous product levels with the severity of soft tissue calcification23.Kuzela D.C. Huffer W.E. Conger J.D. et al.Soft tissue calcification in chronic dialysis patients.Am J Pathol. 1977; 86: 403-424PubMed Google Scholar. Hyperparathyroidism can best be managed by restoring active vitamin D, normalizing serum calcium, and reducing hyperphosphatemia Table 3. The reduction of serum phosphate concentrations can be accomplished by administration of phosphate binders ranging from aluminum-based binders, such as aluminum hydroxide and aluminum carbonate, to calcium-based compounds, including calcium acetate and calcium carbonate. Experimentally, magnesium hydroxide and magnesium carbonate were used for controlling phosphate levels, with mixed results. Side effects such as diarrhea, hyperkalemia, and hypermagnesemia were common. Neither agent has been approved by the U.S. Food and Drug Administration17.Malluche H.H. Mawad H. Management of hyperphosphataemia of chronic kidney disease: Lessons from the past and future directions.Nephrol Dial Transplant. 2002; 17: 1170-1175Crossref PubMed Scopus (42) Google Scholar. The newest additions to the nephrologist's armamentarium are the calcium- and aluminum-free compounds, including sevelamer—a poly hydrochloride polymer—and lanthanum carbonate. It is unclear which phosphate binder is the most effective while minimizing potentially harmful side effects. The toxic effects of long-term excess aluminum consumption are well documented, but the potential effects of increasing oral calcium intake are controversial10.Salusky I.B. Goodman W.G. Cardiovascular calcification in end-stage renal disease.Nephrol Dial Transplant. 2002; 17: 336-339Crossref PubMed Scopus (79) Google Scholar,18.Coladonato J.A. Szczech L.A. Friedman E.A. Owen Jr., W.F. Does calcium kill ESRD patients—The skeptic’s perspective.Nephrol Dial Transplant. 2002; 17: 229-232Crossref PubMed Scopus (26) Google Scholar. Sevelamer is reported to provide equivalent control of serum phosphorus as calcium-based phosphate binders, with fewer potential side effects24.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Abstract Full Text Full Text PDF PubMed Scopus (1269) Google Scholar. A study conducted by Chertow et al indicated that sevelamer may attenuate coronary and aortic calcification, and likely does not induce hypercalcemia24.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Abstract Full Text Full Text PDF PubMed Scopus (1269) Google Scholar. The study found that patients who had rapid progression of calcification also had higher mean serum calcium concentrations, rates of hypocalcemia, and at least 1 hypocalcemic episode24.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Abstract Full Text Full Text PDF PubMed Scopus (1269) Google Scholar. However, multivariate analysis was not conducted to draw a direct relationship between hypocalcemia, hypocalcemic episodes, and the progression of calcification25.Canavese C. Bergamo D. Dib H. et al.Calcium on trial: Beyond a reasonable doubt?.Kidney Int. 2003; 63: 381-382Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar. Furthermore, Fournier et al have suggested that the mild hyperparathyroidism seen in the study may have been corrected more simply by increasing the dose of calcium carbonate without administering aluminum hydroxide or calcitriol26.Fournier A. Benyahia M. Claudia C.P. Sadek T. Calcium on trial: Beyond a reasonable doubt?.Kidney Int. 2003; 63: 382-383Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar. Serum phosphate concentrations can be effectively managed with higher doses of calcium carbonate, without a concomitant increase in serum calcium levels26.Fournier A. Benyahia M. Claudia C.P. Sadek T. Calcium on trial: Beyond a reasonable doubt?.Kidney Int. 2003; 63: 382-383Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar,27.Indridason O.S. Quarles L.D. Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients. Durham Renal Osteodystrophy Study Group.Kidney Int. 2000; 57: 282-292Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar. Additionally, the sevelamer study combined results from 2 groups of patients that received calcium carbonate or calcium acetate28.Cleveland M. Calcium on trial: Beyond a reasonable doubt?.Kidney Int. 2003; 63: 383Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar. These calcium compounds are not equivalent because calcium acetate has superior phosphate-binding capacity, with half the amount of elemental calcium absorbed28.Cleveland M. Calcium on trial: Beyond a reasonable doubt?.Kidney Int. 2003; 63: 383Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar,29.Mai M.L. Emmett M. Sheikh M.S. et al.Calcium acetate, an effective phosphorus binder in patients with renal failure.Kidney Int. 1989; 36: 690-695Abstract Full Text PDF PubMed Scopus (147) Google Scholar. Finally, the sevelamer study design did not control for variables that could affect the rate of cardiovascular calcification, including dialysate calcium, vitamin D dose, and lipid levels, disallowing the conclusion of a causal relationship between cardiovascular calcification and possible calcium loading from calcium-based binders30.Nolan C.R. Qunibi W.Y. Calcium on trial: Beyond a reasonable doubt?.Kidney Int. 2003; 63: 383-384Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar. Other alternative phosphate binders include the rare earth metal, lanthanum, which is currently in clinical trials for control of hyperphosphatemia. Lanthanum cations are efficient phosphate binders, and are not absorbed well by the gastrointestinal tract17.Malluche H.H. Mawad H. Management of hyperphosphataemia of chronic kidney disease: Lessons from the past and future directions.Nephrol Dial Transplant. 2002; 17: 1170-1175Crossref PubMed Scopus (42) Google Scholar. However, lanthanum chloride can accumulate in tissues with extended intake and is toxic in the long term17.Malluche H.H. Mawad H. Management of hyperphosphataemia of chronic kidney disease: Lessons from the past and future directions.Nephrol Dial Transplant. 2002; 17: 1170-1175Crossref PubMed Scopus (42) Google Scholar. A short-term, single-blind, placebo-controlled study of 196 hemodialysis patients indicated that lanthanum carbonate may be a safe, effective alternative as a phosphate binder31.Finn W.F. Joy M.S. Hladik G. Lanthanum Study Group Efficacy and safety of lanthanum carbonate for reduction of serum phosphorus in patients with chronic renal failure receiving hemodialysis.Clin Nephrol. 2004; 62: 193-201Crossref PubMed Google Scholar. A randomized, double-blind, placebo-controlled phase III study of lanthanum carbonate reported a change in serum phosphorus concentrations from 6.25 (± 1.74) prestudy to 5.94 (± 1.65) at week 11, the end of the study. The placebo group phosphorus concentrations ranged from 6.19 (± 1.78) prestudy to 7.85 (± 1.96) at the end of the study32.Joy M.S. Finn W.F. Lam-302 Study Group Randomized, double-blind, placebo-controlled, dose-titration, phase III study assessing the efficacy and tolerability of lanthanum carbonate: A new phosphate binder for the treatment of hyperphosphatemia.Am J Kidney Dis. 2003; 42: 96-107Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar. Lanthanum carbonate-treated patients had increased incidence of nausea and vomiting over placebo; otherwise, the safety and tolerability profiles for the treatment and control groups were similar31.Finn W.F. Joy M.S. Hladik G. Lanthanum Study Group Efficacy and safety of lanthanum carbonate for reduction of serum phosphorus in patients with chronic renal failure receiving hemodialysis.Clin Nephrol. 2004; 62: 193-201Crossref PubMed Google Scholar,32.Joy M.S. Finn W.F. Lam-302 Study Group Randomized, double-blind, placebo-controlled, dose-titration, phase III study assessing the efficacy and tolerability of lanthanum carbonate: A new phosphate binder for the treatment of hyperphosphatemia.Am J Kidney Dis. 2003; 42: 96-107Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar. While there are lanthanum deposits in bone with chronic usage, preliminary data indicate a localization that does not affect the process of mineralization or the osteoblast number and function33.Behets G.J. Verberckmoes S.C. Haese P.C. De broe M.E. Lanthanum carbonate: A new phosphate binder.Curr Opin Nephrol Hypertens. 2004; 13: 403-409Crossref PubMed Scopus (94) Google Scholar. There still remain several significant benefits to using calcium acetate for controlling hyperphosphatemia. Factors such as high efficacy of phosphate control, decreased toxicity, and lower annual cost are the most compelling34.Nolan C.R. Qunibi W.Y. Calcium salts in the treatment of hyperphosphatemia in hemodialysis patients.Curr Opin Nephrol Hypertens. 2003; 12: 373-379Crossref PubMed Scopus (30) Google Scholar. An 8-week, randomized, double-blind study of 100 hemodialysis patients called the Calcium Acetate Renagel Evaluation, or CARE, study compared the efficacy and toxicity of calcium acetate with sevelamer for serum phosphate control35.Qunibi W.Y. Hootkins R.E. Mcdowell L.L. et al.Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study).Kidney Int. 2004; 65: 1914-1926Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar. The study found serum phosphorus time-averaged concentration levels to be 1.08 mg/dL (P value = 0.0006) lower for calcium acetate-treated patients and the calcium phosphorous product to be 6.1 mg2/dL2 (P value = 0.022) lower, as well35.Qunibi W.Y. Hootkins R.E. Mcdowell L.L. et al.Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study).Kidney Int. 2004; 65: 1914-1926Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar. The calcium acetate recipients attained a serum phosphorus concentration at or below the recommended maximum of 5.5 mg/dL within 3 weeks of treatment, whereas the sevelamer-treated group did not reach the target level within the 8- week study, despite steady dose escalation35.Qunibi W.Y. Hootkins R.E. Mcdowell L.L. et al.Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study).Kidney Int. 2004; 65: 1914-1926Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar. Transient hypocalcemia occurred in 16.7% of the calcium acetate recipients, all of whom were concomitantly treated with intravenous vitamin D35.Qunibi W.Y. Hootkins R.E. Mcdowell L.L. et al.Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study).Kidney Int. 2004; 65: 1914-1926Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar. Qunibi et al recommend that judicious usage of vitamin D treatments for patients taking calcium acetate may minimize the incidences of hypercalcemia35.Qunibi W.Y. Hootkins R.E. Mcdowell L.L. et al.Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study).Kidney Int. 2004; 65: 1914-1926Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar. At least 1 hypocalcemic episode has been observed in 50% of sevelamer-treated patients compared with 27% of calcium acetate-treated patients35.Qunibi W.Y. Hootkins R.E. Mcdowell L.L. et al.Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study).Kidney Int. 2004; 65: 1914-1926Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar. Chertow et al suggest that a nighttime supplemental calcium dose of 900 mg daily may enhance control of hyperparathyroidism22.Qunibi W.Y. Nolan C.R. Treatment of hyperphosphatemia in patients with chronic kidney disease on maintenance hemodialysis: results of the CARE study.Kidney Int. 2004; : S33-S38Abstract Full Text Full Text PDF Scopus (21) Google Scholar,36.Chertow G.M. Dillon M. Burke S.K. et al.A randomized trial of sevelamer hydrochloride (RenaGel) with and without supplemental calcium. Strategies for the control of hyperphosphatemia and hyperparathyroidism in hemodialysis patients.Clin Nephrol. 1999; 51: 18-26PubMed Google Scholar. Week 8 intact PTH levels were comparable between the calcium acetate and sevelamer treatment groups, and overall, both treatments were well tolerated with similar gastrointestinal side effect profiles35.Qunibi W.Y. Hootkins R.E. Mcdowell L.L. et al.Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study).Kidney Int. 2004; 65: 1914-1926Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar. The CARE study did corroborate previous findings that treatment with sevelamer induces lower serum bicarbonate levels, potentially causing metabolic acidosis. Short-term metabolic acidosis can stimulate bone dissolution and resorption, while long-term acidosis can cause metabolic net-negative nitrogen and protein imbalances35.Qunibi W.Y. Hootkins R.E. Mcdowell L.L. et al.Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study).Kidney Int. 2004; 65: 1914-1926Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar,37.Brezina B. Qunibi W.Y. Nolan C.R. Acid loading during treatment with sevelamer hydrochloride: Mechanisms and clinical implications.Kidney Int. 2004; : S39-S45Abstract Full Text Full Text PDF Scopus (65) Google Scholar. Calcium acetate also has the benefit of being a fourth of the cost of sevelamer Table 4 [38]; in 2003, calcium acetate had a yearly cost of ∼$780 compared with the mean pharmacy price of ∼$3300 for treatment with sevelamer [38].Table 4Thirty-day starting dose cost of phosphate binders (author's personal inquiry to local pharmacies—2003)Calcium carbonate$8.06Aluminum hydroxide$19.57Calcium acetate$26.75Sevelamer$108.98 Open table in a new tab Currently, sevelamer hydrochloride and calcium acetate are the 2 most common clinical treatments for minimizing phosphate intake22.Qunibi W.Y. Nolan C.R. Treatment of hyperphosphatemia in patients with chronic kidney disease on maintenance hemodialysis: results of the CARE study.Kidney Int. 2004; : S33-S38Abstract Full Text Full Text PDF Scopus (21) Google Scholar. Ongoing research may help define the optimal treatment program for the management of hyperphosphatemia, which will include a cost effective, nontoxic, palatable phosphate binder that does not induce a metabolic imbalance or detrimentally accumulate in tissues. Stanley Goldfarb of the American Society of Nephrology suggested in March 2004, “While there is some evidence implicating calcium-containing phosphate binders in cardiac calcification and vascular disease in chronic hemodialysis, the hypothesis [that] the calcium-containing binders are the root cause of vascular and cardiac calcification is largely unproven. As calcium acetate is more cost-effective than sevelamer, and is effective in controlling serum phosphate, it is an accepted first-line drug therapy.”