Phosphate binder therapy for attainment of K/DOQI™ bone metabolism guidelines

Abstract

Phosphate binder therapy for attainment of K/DOQI™ bone metabolism guidelines. Hyperphosphatemia in patients with chronic kidney disease leads to secondary hyperparathyroidism and renal osteodystrophy, and it is independently associated with mortality risk. The exact mechanism by which hyperphosphatemia increases mortality risk is unknown, but it may relate to enhanced cardiovascular calcification. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI™) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease recommends maintenance of serum phosphorus below 5.5 mg/dL, calcium-phosphorus (Ca × P) product less than 55 mg2/dL2, intact parathyroid hormone (iPTH) 150 pg/mL to 300 pg/mL, and bicarbonate (HCO3) greater than 22 mEq/L. Although calcium-based phosphate binders (CBPB) are cost effective, there are long-term safety concerns pertaining to their postulated role in the progression of cardiovascular calcification. Sevelamer hydrochloride has been recommended as an alternative noncalcium phosphate binder. Results from the Calcium Acetate Renagel Evaluation (CARE) study indicate that calcium acetate is more effective than sevelamer hydrochloride in controlling serum phosphorous, Ca × P product, and HCO3 in hemodialysis patients. In the Treat-to-Goal study, dialysis patients treated with sevelamer hydrochloride had slower progression of coronary and aortic calcification than patients treated with CBPB. The mechanism underlying the beneficial effect of sevelamer hydrochloride is unknown but may relate to decreased calcium loading, or to dramatic reductions in low-density lipoprotein (LDL) cholesterol in sevelamer hydrochloride-treated patients. At present, evidence incriminating CBPB in the progression of cardiovascular calcification in end-stage renal disease (ESRD) remains largely circumstantial. As calcium acetate is more efficacious and cost effective than sevelamer hydrochloride, it remains an accepted first-line phosphate binder. This review examines these issues and provides rational guidelines for the use of CBPB in patients on maintenance hemodialysis. Phosphate binder therapy for attainment of K/DOQI™ bone metabolism guidelines. Hyperphosphatemia in patients with chronic kidney disease leads to secondary hyperparathyroidism and renal osteodystrophy, and it is independently associated with mortality risk. The exact mechanism by which hyperphosphatemia increases mortality risk is unknown, but it may relate to enhanced cardiovascular calcification. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI™) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease recommends maintenance of serum phosphorus below 5.5 mg/dL, calcium-phosphorus (Ca × P) product less than 55 mg2/dL2, intact parathyroid hormone (iPTH) 150 pg/mL to 300 pg/mL, and bicarbonate (HCO3) greater than 22 mEq/L. Although calcium-based phosphate binders (CBPB) are cost effective, there are long-term safety concerns pertaining to their postulated role in the progression of cardiovascular calcification. Sevelamer hydrochloride has been recommended as an alternative noncalcium phosphate binder. Results from the Calcium Acetate Renagel Evaluation (CARE) study indicate that calcium acetate is more effective than sevelamer hydrochloride in controlling serum phosphorous, Ca × P product, and HCO3 in hemodialysis patients. In the Treat-to-Goal study, dialysis patients treated with sevelamer hydrochloride had slower progression of coronary and aortic calcification than patients treated with CBPB. The mechanism underlying the beneficial effect of sevelamer hydrochloride is unknown but may relate to decreased calcium loading, or to dramatic reductions in low-density lipoprotein (LDL) cholesterol in sevelamer hydrochloride-treated patients. At present, evidence incriminating CBPB in the progression of cardiovascular calcification in end-stage renal disease (ESRD) remains largely circumstantial. As calcium acetate is more efficacious and cost effective than sevelamer hydrochloride, it remains an accepted first-line phosphate binder. This review examines these issues and provides rational guidelines for the use of CBPB in patients on maintenance hemodialysis. The treatment of hyperphosphatemia in patients with chronic kidney disease (CKD) remains a vexing clinical problem. Hyperphosphatemia not only underlies the development of secondary hyperparathyroidism and renal osteodystrophy, but it is also independently associated with an increased risk of death among dialysis patients1.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,2.Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1432) Google Scholar. Although dietary phosphorus restriction to less than 800 mg/day while maintaining adequate protein intake of 1 g/kg/day is the first line of treatment, patient persistence with dietary therapy is often problematic. Furthermore, intermittent hemodialysis as currently performed 3 times weekly is usually inadequate to maintain normal phosphorus balance. Guidelines issued by the National Kidney Foundation K/DOQI ™3.National Kidney Foundation K/DOQI™ clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-S202Crossref PubMed Scopus (648) Google Scholar provide recommended target ranges for serum phosphorus, serum calcium, Ca × P product, intact parathyroid hormone (iPTH) levels, and serum HCO3 for patients with CKD receiving maintenance dialysis Table 1. Large cross-sectional studies have indicated that a substantial percentage of dialysis patients fail to achieve the K/DOQI™ guidelines for serum phosphorus and Ca × P product, despite treatment with dietary phosphorus restriction, conventional hemodialysis, and phosphate binders1.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,2.Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1432) Google Scholar.Table 1NKF K/DOQI™ recommended target rangesaLaboratory parameterTreatment goalSerum phosphorus3.5 mg/dL–5.5 mg/dLSerum calcium8.4 mg/dL–9.5 mg/dLCa × P product<55 mg2/dL2Intact PTH150 pg/mL–300 pg/mLSerum total CO2>22 mmol/LAbbreviations are: CO2, carbon dioxide; NKF K/DOQI™, National Kidney Foundation Kidney Disease Outcomes Quality Initiative; Ca × P product, calcium-phosphorus product; PTH, parathyroid hormone. Reprinted with permission from Elsevier Science. Open table in a new tab Abbreviations are: CO2, carbon dioxide; NKF K/DOQI™, National Kidney Foundation Kidney Disease Outcomes Quality Initiative; Ca × P product, calcium-phosphorus product; PTH, parathyroid hormone. Reprinted with permission from Elsevier Science. In the setting of CKD, secondary hyperparathyroidism develops as a consequence of phosphate retention and the reduced renal production of active vitamin D, resulting in hyperphosphatemia, hypocalcemia, and increased PTH levels. Over the long term, the same factors cause parathyroid gland hyperplasia and autonomous PTH production (tertiary hyperparathyroidism)4.Silver J. Pathogenesis of parathyroid dysfunction in end-stage renal disease.Adv Renal Replacement Ther. 2002; 9: 159-167Abstract Full Text PDF PubMed Scopus (18) Google Scholar,5.Silver J. Kilav R. Naveh-many T. Mechanisms of secondary hyperparathyroidism.Am J Physiol Renal Physiol. 2002; 283: F367-F376Crossref PubMed Scopus (149) Google Scholar. A chronic decrease in serum calcium and 1,25-dihydroxyvitamin D levels, or an increase in serum phosphorous, leads to a secondary increase in serum PTH as a result of increases in PTH gene expression, synthesis, and secretion, and the eventual proliferation of parathyroid chief cells with gland hyperplasia. Low serum calcium leads to an increase in PTH secretion, an increase in PTH messenger RNA stability, and parathyroid cell proliferation. Chronic increases in serum phosphorous also regulate PTH secretion in a similar manner. The effects of calcium on parathyroid cells are mediated by a membrane-bound calcium-sensing receptor. The pathophysiologic mechanisms summarized in Figure 1 that underlie the development of hyperphosphatemia and secondary hyperparathyroidism in CKD provide the clinical rationale for treatment strategies that include maintenance of normal serum phosphorus levels (dietary phosphorus restriction, dietary phosphate binders, and short daily hemodialysis), maintenance of normal serum calcium (reduced dialysate calcium levels and judicious use of vitamin D analogues), and suppression of PTH secretion (phosphorus control, maintenance of normocalcemia, and treatment with vitamin D analogues and/or calcimimetic agents such as cinacalcet). Large cross-sectional studies have found a mean serum phosphorus level of 6.2 mg/dL in the maintenance hemodialysis population in the United States1.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. Moreover, an alarming 60% of patients had serum phosphorus levels in excess of the 5.5-mg/dL target level recommended by K/DOQI™ guidelines. Although aluminum-containing phosphate binders are efficacious, the long-term use of these compounds has been largely abandoned because of the risk of aluminum accumulation leading to osteomalacia and encephalopathy. As a result, CBPB such as calcium acetate and calcium carbonate have replaced aluminum hydroxide as the most widely prescribed phosphate binders. However, recent concern over the possible risks of calcium loading from these binders has led to the introduction of the considerably more expensive noncalcium, nonaluminum phosphate binder sevelamer hydrochloride (Renagel®)6.Chertow G.M. Burke S.K. Lazarus J.M. et al.Poly[allylamine hydrochloride] (RenaGel): A noncalcemic phosphate binder for the treatment of hyperphosphatemia in chronic renal failure.Am J Kidney Dis. 1997; 29: 66-71Abstract Full Text PDF PubMed Scopus (244) Google Scholar,7.Slatopolsky E.A. Burke S.K. Dillon M.A. RenaGel, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. The RenaGel Study Group.Kidney Int. 1999; 55: 299-307Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar. At present in clinical practice, calcium acetate and sevelamer hydrochloride are the 2 most commonly prescribed phosphate binders in the United States. The recently published CARE study was the first prospective, randomized, double-blind, multicenter study comparing the efficacy and safety of calcium acetate and sevelamer hydrochloride for the treatment of hyperphosphatemia in patients with CKD on maintenance hemodialysis8.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 primary end points of the study were to determine whether calcium acetate or sevelamer hydrochloride best achieved recently recommended treatment goals for serum phosphorus (<5.5 mg/dL) and Ca × P product (<55 mg2/dL2). The baseline characteristics of the patients receiving calcium acetate (N = 48) or sevelamer hydrochloride (N = 50) were similar with respect to age, sex, race, years on dialysis, and vitamin D therapy. In addition, patients in both groups had similar baseline values for serum phosphorus, serum calcium, Ca × P product, iPTH, and serum HCO3. At all time points in the 8-week study, the serum phosphorus concentration Figure 2 and the Ca × P product Figure 3 were significantly lower in patients receiving calcium acetate. Comparisons between the 2 groups demonstrated that time-averaged concentrations (weeks 1–8) of serum phosphorus and Ca × P product were significantly lower in calcium acetate-treated patients (serum phosphorus: 1.08 mg/dL difference, P value = 0.0006; Ca × P product: 6.1 mg2/dL2 difference, P value = 0.022). At each treatment week, calcium acetate recipients were 20% to 24% more likely to attain goal serum phosphorus [odds ratio (OR) 2.37; 95% CI 1.28–4.37, P value = 0.0058], and 15% to 20% more likely to attain goal Ca × P product (OR 2.16; 95% CI, 1.20–3.86, P value = 0.0097).Figure 3Mean serum Ca × P product at baseline and weekly during treatment with either calcium acetate or sevelamer hydrochloride. At baseline, Ca × P product was not significantly different between the 2 groups (P = 0.91). However, Ca × P product was significantly lower during treatment with calcium acetate than with sevelamer hydrochloride (6.1 mg2/dL2 difference in Cavg during weeks 1–8, P = 0.0001 by covariate-adjusted regression). To convert from units of mg2/dL2 to mmol2/L2, multiply by 0.08.View Large Image Figure ViewerDownload (PPT) Time-averaged weekly concentrations of serum calcium were higher in patients receiving calcium acetate (0.63 mg/dL difference, P value < 0.0001). Transient hypercalcemia was observed in 8 of 48 (16.7%) calcium acetate recipients. Each of these 8 patients was treated with concomitant intravenous vitamin D. Overall, hypercalcemia was substantially more likely to occur in patients receiving calcium acetate (OR 6.1; 95% CI, 2.8–13.3, P value < 0.0001). Week 8 iPTH levels were not significantly different between the 2 treatment groups. Serum HCO3 levels were significantly lower during treatment with sevelamer hydrochloride. Figure 4 compares the efficacy of calcium acetate and sevelamer hydrochloride with regard to achievement of K/DOQI™ recommended guidelines for serum phosphorus and calcium, Ca × P product, and iPTH. Short- and long-term studies indicate that treatment with sevelamer hydrochloride causes a significant reduction in subjects' serum HCO3 levels compared with patients treated with calcium-containing phosphate binders8.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,9.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. Sevelamer hydrochloride is a quaternary amine anion exchange resin that binds monovalent phosphate in exchange for release of the leaving anion chloride. This anion exchange resin may also exchange chloride for any other anion present in the lumen of the gastrointestinal tract. In the small intestine, the local concentration of HCO3 is in the range of 120 mEq/L, owing to the alkaline secretions from the pancreas. Thus, concentration gradients in the small intestine would favor exchange of chloride for bicarbonate with loss of carbonated sevelamer in the stool. The ongoing gastrointestinal loss of HCO3 in excess of chloride would lead to acid loading and metabolic acidosis through a mechanism akin to chronic diarrhea. Sevelamer hydrochloride can also exchange chloride for bile acid, and thereby function to lower serum cholesterol by acting as a bile acid sequestrant similar to cholestyramine. In the large intestine, where sevelamer hydrochloride reaches its final equilibrium with intestinal fluids before expulsion from the body, phosphate, HCO3, and bile acid anions represent minor luminal constituents. The predominant anions in the colon are short-chain fatty acid anions (SCFAA) such as acetate, propionate, and n-butyrate, with total concentrations of 150 mmol/L, constituting more than 70% of luminal anions10.Hurst P.E. Morrison R.B.I. Timoner J. et al.The effect of anion-exchange resins on faecal anions. Comparison with calcium salts and aluminium hydroxide.Clin Sci. 1963; 24: 189-200Google Scholar,11.Rubinstein R. Howard A.V. Wrong O.M. In vivo dialysis of faeces as a method of stool analysis. IV. The organic anion component.Clin Sci. 1969; 37: 549-564PubMed Google Scholar. These SCFAA are derived from bacterial fermentation of food residues (mainly carbohydrate), and are HCO3 precursors, normally being absorbed by the intestinal mucosa and incorporated into intermediary metabolism. Every mole of SCFAA removed from the body by sevelamer, and replaced by chloride from the resin, thus represents a loss of a mole of HCO3 from the body and its replacement by chloride, equivalent to a gain by the body of a mole of hydrochloric acid. Each of these mechanisms could theoretically lead to generation of a net dietary acid load during treatment with sevelamer hydrochloride Figure 5. Since sevelamer hydrochloride contains 17% chloride, complete exchange of chloride for phosphate, HCO3, bile acid, or SSFAA would lead to a potential net acid load of approximately 4 mEq for each 800-mg sevelamer hydrochloride tablet. Dietary acid loading during treatment with sevelamer hydrochloride has been confirmed in an animal model12.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. Normal rats fed a diet containing sevelamer hydrochloride develop a significant decrease in urine pH and a significant increase in urinary ammonium excretion as measured by an ion-specific electrode. Acidemia should clearly be avoided in patients with chronic renal failure, since it has 2 major systemic consequences. Metabolic acidosis has several effects on bone, causing physiochemical dissolution of bone and cell-mediated bone resorption by inhibition of osteoblast function and stimulation of osteoclast function13.Bushinsky D.A. Net calcium efflux from live bone during chronic metabolic, but not respiratory, acidosis.Am J Physiol. 1998; 256: F836-F842Google Scholar, 14.Bushinsky D.A. Frick K.K. The effects of acid on bone.Curr Opin Nephrol Hypertens. 2000; 9: 369-379Crossref PubMed Scopus (101) Google Scholar, 15.Bushinsky D.A. Nilsson E.L. Additive effects of acidosis and parathyroid hormone on mouse osteoblastic and osteoclastic function.Am J Physiol. 1995; 269: C1364-C1370PubMed Google Scholar. Chronic metabolic acidosis also induces a net negative nitrogen and total body protein balance, which improves following HCO3 supplementation16.Bailey J.L. Wang X. England B.K. et al.The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent ubiquitin-proteasome pathway.J Clin Invest. 1996; 97: 1447-1453Crossref PubMed Scopus (342) Google Scholar,17.Ballmer P.E. Mcnurlan M.A. Hulter H.N. et al.Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans.J Clin Invest. 1995; 95: 39-45Crossref PubMed Google Scholar. These data suggest that metabolic acidosis is both catabolic and antianabolic. These considerations underscore the urgent need for further studies of acid-base balance during long-term treatment with sevelamer hydrochloride. Given the detrimental effects of metabolic acidosis on nitrogen balance and bone, the K/DOQI™ guidelines recommend maintaining serum total carbon dioxide greater than 22 mmol/L3.National Kidney Foundation K/DOQI™ clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-S202Crossref PubMed Scopus (648) Google Scholar,18.National Kidney Foundation K/DOQI™ clinical practice guidelines for nutrition in chronic renal failure.Am J Kidny Dis. 2000; 35: S1-S140PubMed Google Scholar. Vascular calcification is an important issue in dialysis patients because it is associated with increased risk of cardiovascular mortality. However, the underlying causes of excessive cardiovascular calcification in patients with advanced CKD are incompletely understood, and are the subject of intense study19.Qunibi W.Y. Nolan C.R. Ayus J.C. Cardiovascular calcification in patients with end-stage renal disease: A century-old phenomenon.Kidney Int. 2002; : 73-80Abstract Full Text Full Text PDF Scopus (119) Google Scholar. Cardiovascular calcification is most likely a multifactorial process with numerous potential pathogenic factors, including hyperparathyroidism, phosphate loading with hyperphosphatemia, hypertension, abnormal glucose metabolism, abnormalities in lipid metabolism, treatment with vitamin D analogues and, possibly, deficiencies of kidney-derived inhibitors of vascular calcification, such as bone morphogenic protein Figure 620.Davies M.R. Lund R.J. Hruska K.A. BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure.J Am Soc Nephrol. 2003; 14: 1559-1567Crossref PubMed Scopus (172) Google Scholar. Thus, it may be overly simplistic to implicate oral calcium loading from CBPB as the single most important pathogenic factor in the development of cardiovascular calcification in dialysis patients. Data from observational studies suggest that coronary artery calcium scores and large-vessel calcification correlate with the prescribed daily dose of CBPB21.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2331) Google Scholar,22.Guérin A.P. London G.M. Marchais S.J. Metivier E. Arterial stiffening and vascular calcifications in end-stage renal disease.Nephrol Dial Transplant. 2000; 15: 1014-1021Crossref PubMed Scopus (863) Google Scholar. The Treat-to-Goal study demonstrated that maintenance dialysis patients treated with sevelamer hydrochloride have slower progression of coronary and aortic calcification than patients treated with calcium-containing phosphate binders9.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. In a more recent post hoc analysis of Treat-to-Goal study results, Chertow et al concluded that oral calcium loading resulting from treatment with CBPB is the key factor associated with progressive coronary artery and aortic calcification in dialysis patients23.Chertow G.M. Raggi P. Chasan-taber S. et al.Determinants of progressive vascular calcification in hemodialysis patients.Nephrol Dial Transplant. 2004; 19: 1489-1496Crossref PubMed Scopus (243) Google Scholar. Although the authors conclude that their findings were most likely due to excess calcium loading during treatment with CBPB, the design of the study makes it virtually impossible to test the validity of this hypothesis. Unfortunately, the study was not designed such that non–phosphate-binder exposure to calcium was kept similar between the calcium-based binder and sevelamer hydrochloride treatment groups. Instead, supplemental (nonbinder) sources of calcium were provided to the sevelamer hydrochloride-treated patients in at least 3 forms: (1) the study design allowed for the use of calcium carbonate supplements at night on an empty stomach to treat hypocalcemia in the sevelamer hydrochloride treatment group; (2) the dialysate calcium concentration was adjusted during the study in order to maintain normal serum calcium levels; (3) sevelamer hydrochloride-treated patients received larger doses of vitamin D analogues, which might be expected to enhance gastrointestinal absorption of dietary calcium. These observations suggest that some factor other than simple oral calcium loading from the use of CBPB may be responsible for the finding that sevelamer hydrochloride-treated patients have slower progression of cardiovascular calcification. Moreover, given these deficiencies in study design, it was virtually impossible for the Treat-to-Goal study investigators to conclude from any type of post hoc analysis that their finding of a slower rate of progression in the sevelamer hydrochloride treatment group was due to reduced calcium loading. The failure to achieve equivalent control of LDL and total cholesterol is another critical issue with regard to interpretation of the Treat-to-Goal study results. In comparison with CBPB-treated patients, because sevelamer hydrochloride is a bile acid sequestrant, sevelamer hydrochloride-treated patients had significantly lower levels of total cholesterol (182 ± 49 mg/dL vs. 141 ± 28 mg/dL; P value < 0.0001) and LDL cholesterol (103 ± 43 mg/dL vs. 65 ± 21 mg/dL; P value < 0.0001)9.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. Because LDL levels have been shown to play an important role in progression of coronary artery calcification in the general population, the Treat-to-Goal investigators should have controlled the LDL level in the 2 treatment groups to similar levels. In this regard, lowering LDL cholesterol with hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor therapy has been reported to ameliorate or even reverse coronary artery calcification in at least 2 studies24.Callister T.Q. Raggi P. Cooil B. et al.Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography.N Engl J Med. 1998; 339: 1972-1978Crossref PubMed Scopus (628) Google Scholar,25.Achenbach S. Ropers D. Pohle K. et al.Influence of lipid-lowering therapy on the progression of coronary artery calcification: A prospective evaluation.Circulation. 2002; 106: 1077-1082Crossref PubMed Scopus (306) Google Scholar, 1 coauthored by Dr. Raggi, a senior author of the Treat-to-Goal study24.Callister T.Q. Raggi P. Cooil B. et al.Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography.N Engl J Med. 1998; 339: 1972-1978Crossref PubMed Scopus (628) Google Scholar. Preliminary results of a recent study from Japan demonstrate that progression of aortic calcification in dialysis patients was significantly retarded during treatment with colestimide (a bile acid sequestrant similar to sevelamer hydrochloride) in combination with atorvastatin compared with the progression rate during the observation period before lipid-lowering therapy was instituted26.Nitta K. Akiba T. Nihei H. Colestimide co-administered with atorvastatin attenuates the progression of vascular calcification in hemodialysis patients.Nephrol Dial Transplant. 2004; 19: 2156Crossref PubMed Scopus (12) Google Scholar. The authors speculate that the decrease in aortic calcification resulted from control of serum phosphorus and LDL cholesterol levels. Thus, available information suggests that the dramatic reduction of LDL cholesterol is a very compelling potential explanation for the reduced rate of cardiovascular calcification in sevelamer hydrochloride-treated dialysis patients. The critically important issue of increased cardiovascular calcification and mortality in dialysis patients can only be addressed by well-designed studies that control for not only the type of phosphate binder but also for the myriad potential risk factors associated with vascular calcification. Until such studies are available, it is premature to abandon calcium-based phosphate binders in favor of sevelamer hydrochloride because the latter is less efficacious for control of serum phosphorus and Ca × P product, and considerably more expensive. Projected daily and annual costs based on The Red Book® wholesale prices indicate that calcium acetate therapy is significantly more economical than sevelamer hydrochloride therapy. Based on week 8 doses in the CARE study and per-pill prices of calcium acetate and sevelamer hydrochloride at $0.15 and $0.64, respectively, daily per-patient costs for calcium acetate and sevelamer hydrochloride are estimated at $1.64 and $11.40, respectively. The projected annual per-patient cost of binder therapy is substantially less with calcium acetate ($600 vs. $ 4100 for sevelamer hydrochloride). Thus, if sevelamer hydrochloride were to be universally adopted as the first-line phosphate binder, the cost for treatment of the roughly 300,000 dialysis patients in the United States would increase by more than $1 billion per year. The lipid-lowering effect of sevelamer hydrochloride may have a beneficial role in slowing the progression of cardiovascular calcification in dialysis patients9.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, cost-benefit analysis reveals that combined treatment with an HMG-CoA reductase inhibitor and calcium-containing phosphate binders would be a far more cost-effective alternative. Given the superior efficacy of calcium acetate for control of serum phosphorus and Ca × P product, it appears to be the more cost-effective choice as first-line treatment for hyperphosphatemia in patients with ESRD on maintenance dialysis27.Manns B. Stevens L. Miskulin D. et al.A systematic review of sevelamer in ESRD and an analysis of its potential economic impact in Canada and the United States.Kidney Int. 2004; 66: 1239-1247Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar. Nevertheless, in the occasional patient who develops persistent hypercalcemia during calcium acetate treatment, despite appropriate reduction in vitamin D dosage, it may be prudent to reduce the dose of calcium acetate and add a non–calcium-containing binder, such as sevelamer hydrochloride. The CARE study demonstrates that patients with CKD on maintenance hemodialysis are more effectively treated with calcium acetate than with sevelamer hydrochloride, and more frequently achieve the K/DOQI™ treatment goals for serum phosphorus, Ca × P product, and HCO3. The pathophysiology of excess cardiovascular calcification in patients with CKD on maintenance dialysis is multifactorial, and it is overly simplistic to implicate calcium loading from calcium-based phosphate binders as the predominant factor leading to vascular calcification. Based on available evidence, it is premature to abandon efficacious and relatively inexpensive calcium-based phosphate binder therapy in favor of sevelamer hydrochloride, which is a less effective phosphate binder and considerably more expensive. Cost-benefit analysis clearly favors calcium acetate as the first-line therapy of choice for treatment of hyperphosphatemia in dialysis patients.