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Targeting serum calcium in chronic kidney disease and end-stage renal disease: is normal too high?

2016; Elsevier BV; Volume: 89; Issue: 1 Linguagem: Inglês

10.1016/j.kint.2015.10.001

1523-1755

W. Charles O’Neill,

Thyroid and Parathyroid Surgery

Hypocalcemia is common in advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD), and it is standard practice to correct this back to the normal range, presumably to prevent symptomatic hypocalcemia and help control hyperparathyroidism. However, there are few studies to support this approach, and recent data suggest that this promotes vascular calcification and adynamic bone disease. Whether setting a lower target will improve outcomes has not been tested, but existing data suggest that this may have minimal risks and substantial potential benefits and should be explored. Hypocalcemia is common in advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD), and it is standard practice to correct this back to the normal range, presumably to prevent symptomatic hypocalcemia and help control hyperparathyroidism. However, there are few studies to support this approach, and recent data suggest that this promotes vascular calcification and adynamic bone disease. Whether setting a lower target will improve outcomes has not been tested, but existing data suggest that this may have minimal risks and substantial potential benefits and should be explored. Physicians are often obsessed with maintaining biochemical parameters in the normal range, but "normal" can be a moving target, as evidenced by ranges that vary with age, gender, or race. Such variation also applies to conditions of altered physiology and metabolism, where changes in biochemical parameters can be a homeostatic response and, even when not, correcting these back to the normal range observed in healthy individuals can be of no benefit or even detrimental. Examples include estrogen therapy for postmenopausal women and restoring normal levels of thyroid hormone, cortisol, or glucose in severely ill patients. Nephrologists have also learned this lesson in the correction of anemia in CKD and ESRD. However, we continue to fully correct the hypocalcemia in advanced CKD and ESRD despite evidence that this may be harmful. While published guidelines recommend that serum calcium in these patients be maintained within the normal range or the lower portion of this range,1National Kidney FoundationK/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S77-S84Google Scholar, 2Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work GroupKDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD).Kidney Int Suppl. 2009; 113: S1-S130PubMed Google Scholar this comes with the lowest rating for strength and quality of evidence. There have been no prospective studies examining the effect of different serum calcium levels on clinical outcomes in advanced CKD or ESRD. A general problem with targeting parameters to normal ranges is that these ranges may vary with age, gender, or ethnicity and are often dynamic in relationship to meals or time of day. Serum calcium is particularly challenging since it is the ionized component, rather than the total, that is physiologically relevant. Since total calcium includes calcium ions bound to anionic proteins or complexed with smaller anions, primarily phosphate, both of which are pH-dependent, the varying degrees of hyperphosphatemia, hypoalbuminemia, and acidosis in advanced CKD and ESRD lead to a very poor correlation between total and ionized serum calcium. Both hypocalcemia and hypercalcemia are poorly predicted, and there is a bias toward underestimation of ionized calcium,3Gauci C. Moranne O. Fouqueray B. et al.Pitfalls of measuring total blood calcium in patients with CKD.J Am Soc Nephrol. 2008; 19: 1592-1598Crossref PubMed Scopus (107) Google Scholar which is probably explained by the reduced albumin levels and acidosis. Formulas that attempt to correct for these interactions do not reduce this variability, though there is less bias.3Gauci C. Moranne O. Fouqueray B. et al.Pitfalls of measuring total blood calcium in patients with CKD.J Am Soc Nephrol. 2008; 19: 1592-1598Crossref PubMed Scopus (107) Google Scholar Thus, for a given total serum calcium, patients with advanced CKD or ESRD tend to have a higher ionized serum calcium than normal individuals. This by itself may be a reason to lower the target for total serum calcium. The problem is compounded by the lack of a standardized reference range for serum calcium, which is instead established by individual laboratories or commercial suppliers of the assays or analyzers. While guidelines exist for determining normal ranges,4Horowitz G.L. Altaie S. Boyd J.C. et al.Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline.3rd ed. Clinical and Laboratory Standards Institute, Wayne, PA2010: 28Google Scholar including subject selection, sample size, and biologic variables, the validity of given reference ranges and applicability to patient samples may vary since screening of reference subjects may not be rigorous and analyte-specific. Thus, in the case of serum calcium, the reference population may not be screened for vitamin D status, kidney stones, osteoporosis, or even CKD. Reference ranges also may not adequately reflect biologic variables. Of particular relevance to CKD and ESRD, serum total calcium (but not ionized calcium) decreases with age because of decreased serum proteins,5Sokoll L.J. Dawson-Hughes B. Effect of menopause and aging on serum total and ionized calcium and protein concentrations.Calcif Tissue Int. 1989; 44: 181-185Crossref PubMed Scopus (38) Google Scholar yet normal ranges are not adjusted accordingly. Since the CKD and ESRD population is undoubtedly much older than the reference population, adherence to stated normal ranges will result in ionized calcium levels that are above normal in some patients. The normal range is also not corrected for acidosis, which is invariably present in the predialysis samples routinely obtained in hemodialysis patients. This again causes the normal range to be too high. While serum calcium normally varies little with meals, there is a postprandial decline in CKD,6Isakova T. Gutierrez O. Shah A. et al.Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD.J Am Soc Nephrol. 2008; 19: 615-623Crossref PubMed Scopus (136) Google Scholar which, since most determinations are not fasting, can also lead to an inappropriately high normal range. The nocturnal decline in serum calcium7Jubiz W. Canterbury J.M. Reiss E. Tyler F.H. Circadian rhythm in serum parathyroid hormone concentration in human subjects: correlation with serum calcium, phosphate, albumin, and growth hormone levels.J Clin Invest. 1972; 51: 2040-2046Crossref PubMed Scopus (201) Google Scholar is unlikely to affect measurements in patients. While hypocalcemia is a late event in CKD,8Levin A. Bakris G.L. Molitch M. et al.Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease.Kidney Int. 2007; 71: 31-38Abstract Full Text Full Text PDF PubMed Scopus (1153) Google Scholar altered mineral metabolism occurs much earlier, manifest as secondary hyperparathyroidism (sHPT). The major cause is reduced synthesis of 1,25-dihydroxyvitamin D in the kidney, which stimulates parathyroid hormone (PTH) secretion directly and also indirectly through decreased intestinal absorption of calcium. In addition, there is reduced mobilization of calcium from bone due to decreased sensitivity of bone to PTH in conjunction with calcitriol deficiency.9Cunningham J. Locatelli F. Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options.Clin J Am Soc Nephrol. 2011; 6: 913-921Crossref PubMed Scopus (380) Google Scholar The precipitating factor is impaired renal excretion of phosphate that initially increases FGF23 levels and eventually results in hyperphosphatemia, both of which inhibit 25-hydroxyvitamin D 1α-hydroxylase in the kidney. This is compounded by the loss of renal tissue and consequent availability of the enzyme. Hyperphosphatemia also stimulates PTH release.10Slatopolsky E. Finch J. Denda M. et al.Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro.J Clin Invest. 1996; 97: 2534-2540Crossref PubMed Scopus (466) Google Scholar The possibility that hyperphosphatemia contributes directly to hypocalcemia through interactions of calcium and phosphate ions and that there is an inherent inverse relationship between the two has also been considered. The inverse circadian rhythms of calcium and phosphate in humans7Jubiz W. Canterbury J.M. Reiss E. Tyler F.H. Circadian rhythm in serum parathyroid hormone concentration in human subjects: correlation with serum calcium, phosphate, albumin, and growth hormone levels.J Clin Invest. 1972; 51: 2040-2046Crossref PubMed Scopus (201) Google Scholar are consistent with this, but could also be hormonal. A decrease in ionized calcium occurs with acute phosphate administration in vivo11Calvo M.S. Heath H. Acute effects of oral phosphate-salt ingestion on serum phosphorus, serum ionized calcium, and parathyroid hormone in young adults.Am J Clin Nutr. 1988; 47: 1025-1029PubMed Google Scholar, 12Reiss E. Canterbury J.M. Bercovitz M.A. Kaplan E.L. The role of phosphate in the secretion of parathyroid hormone in man.J Clin Invest. 1970; 49: 2146-2149Crossref PubMed Scopus (179) Google Scholar, 13Silverberg S.J. Shane E. Clemens T.L. et al.The effect of oral phosphate administration on major indices of skeletal metabolism in normal subjects.J Bone Mineral Res. 1986; 1: 383-388Crossref PubMed Scopus (69) Google Scholar, 14Portale A.A. Halloran B.P. Murphy M.M. Morris R.C. Oral intake of phosphorus can determine the serum concentration of 1,25-dihydroxyvitamin D by determining its production rate in humans.J Clin Invest. 1986; 77: 7-12Crossref PubMed Scopus (214) Google Scholar, 15Hebert L.A. Lemann J. Petersen J.R. Lennon E.J. Studies of the mechanism by which phosphate infusion lowers serum calcium concentration.J Clin Invest. 1966; 45: 1886-1894Crossref PubMed Scopus (171) Google Scholar with an inverse relationship between serum phosphate and both total and ultrafilterable calcium.15Hebert L.A. Lemann J. Petersen J.R. Lennon E.J. Studies of the mechanism by which phosphate infusion lowers serum calcium concentration.J Clin Invest. 1966; 45: 1886-1894Crossref PubMed Scopus (171) Google Scholar Whether the decrease in calcium levels is directly related to an increase in circulating phosphate is unclear since it persists despite the return of phosphate levels toward baseline.11Calvo M.S. Heath H. Acute effects of oral phosphate-salt ingestion on serum phosphorus, serum ionized calcium, and parathyroid hormone in young adults.Am J Clin Nutr. 1988; 47: 1025-1029PubMed Google Scholar, 13Silverberg S.J. Shane E. Clemens T.L. et al.The effect of oral phosphate administration on major indices of skeletal metabolism in normal subjects.J Bone Mineral Res. 1986; 1: 383-388Crossref PubMed Scopus (69) Google Scholar Phosphate administration is also an effective therapy for hypercalcemia, but this occurs without an increase in serum phosphate.16Goldsmith R. Ingbar S.H. Inorganic phosphate treatment of hypercalcemia of diverse etiologies.N Engl J Med. 1966; 274: 1-7Crossref PubMed Scopus (124) Google Scholar Since phosphate concentration may not directly alter the sensitivity of parathyroid tissue to calcium,17Nielsen P.K. Feldt-Rasmussen U. Olgaard K. A direct effect in vitro of phosphate on PTH release from bovine parathyroid tissue slices but not from dispersed parathyroid cells.Nephrol Dial Transpl. 1996; 11: 1762-1768Crossref PubMed Scopus (143) Google Scholar any decrease in serum ionized calcium produced by an increase in serum phosphate concentration should be compensated by an increase in serum PTH. Accordingly, there is no relationship between serum calcium and phosphate levels in patients with acute renal failure,18Massry S.G. Arieff A.I. Coburn J.W. et al.Divalent ion metabolism in patients with acute renal failure: studies on the mechanism of hypocalcemia.Kidney Int. 1974; 5: 437-445Abstract Full Text PDF PubMed Scopus (86) Google Scholar and analysis of data derived from the general population (National Health and Nutrition Examination Survey; NHANES) revealed a positive rather than negative correlation between serum calcium and phosphate levels (Figure 1), consistent with complexation of calcium and phosphate without a change in ionized calcium. In summary, there is no convincing evidence for a direct inverse relationship between circulating calcium and phosphate levels. Management of altered mineral metabolism in CKD and ESRD has focused primarily on the control and prevention of sHPT and subsequent renal osteodystrophy. Initially this was accomplished with aluminum-containing antacids to reduce intestinal phosphate absorption and a high dialysate calcium concentration to counter the hypocalcemia. The switch to calcium-based phosphate binders had the additional benefit of increasing intestinal calcium absorption. Initial concerns about the potential detrimental effects of positive calcium balance19Slatopolsky E. Weerts C. Lopez-Hilker S. et al.Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing dialysis.N Engl J Med. 1986; 315: 157-161Crossref PubMed Scopus (311) Google Scholar went unheeded. However, control of sHPT was incomplete on this regimen, and many patients developed hypercalcemia. The discovery that calcitriol has direct effects on the parathyroid gland eventually led to the use of active vitamin D compounds to effectively control sHPT.20Slatopolsky E. Weerts C. Thielan J. et al.Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients.J Clin Invest. 1984; 74: 2136-2143Crossref PubMed Scopus (641) Google Scholar This necessitated a lowering of dialysate calcium concentration as well as the dosage of oral calcium to prevent hypercalcemia, but despite this, dialysis patients are still in positive calcium balance.21Hill K.M. Martin B.R. Wastney M.E. et al.Oral calcium carbonate affects calcium but not phosphorus balance in stage 3–4 chronic kidney disease.Kidney Int. 2013; 83: 959-966Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 22Spiegel D.M. Brady K. Calcium balance in normal individuals and in patients with chronic kidney disease on low- and high-calcium diets.Kidney Int. 2012; 81: 1116-1122Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 23Moe S.M. Chertow G.M. The case against calcium-based phosphate binders.Clin J Am Soc Nephrol. 2006; 1: 697-703Crossref PubMed Scopus (91) Google Scholar It appears, then, that maintaining normal serum calcium levels requires a positive calcium balance in most ESRD patients, likely contributing to extensive vascular calcification24Goodman 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 (2436) Google Scholar and raising the question of whether the target for serum calcium should be lower. This illustrates the important point that serum calcium does not indicate or correlate with calcium balance. A normal serum calcium is associated with positive calcium balance in ESRD but a negative balance in most cases of osteoporosis. Likewise, calcium balance is positive in hypercalcemia due to vitamin D toxicity but negative in primary hyperparathyroidism. In hypocalcemia, balance is positive or neutral in hypoparathyroidism but negative in vitamin D deficiency. Epidemiologic data support a lower calcium target. Serum calcium levels in the higher range of normal and greater have consistently been associated with greater vascular calcification and higher relative risks of death from all causes and from cardiovascular disease.25Young E.W. Albert J.M. Satayathum S. et al.Predictors and consequences of altered mineral metabolism: the Dialysis Outcomes and Practice Patterns Study.Kidney Int. 2005; 67: 1179-1187Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar, 26Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2208) Google Scholar, 27Tentori F. Blayney M.J. Albert J.M. et al.Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2008; 52: 519-530Abstract Full Text Full Text PDF PubMed Scopus (812) Google Scholar Serum calcium levels below normal were initially linked with increased mortality in ESRD patients, but subsequent multicenter studies with appropriate adjustment for albumin levels and other factors have shown either no increased risk27Tentori F. Blayney M.J. Albert J.M. et al.Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2008; 52: 519-530Abstract Full Text Full Text PDF PubMed Scopus (812) Google Scholar or risk reductions as great as 34%.25Young E.W. Albert J.M. Satayathum S. et al.Predictors and consequences of altered mineral metabolism: the Dialysis Outcomes and Practice Patterns Study.Kidney Int. 2005; 67: 1179-1187Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar, 26Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2208) Google Scholar Although suggestive, these data do not necessarily indicate that lowering serum calcium below the normal range is beneficial. While the role of serum calcium in patient outcomes has not been directly tested in prospective studies, reductions in serum calcium were a consequence of most outcome trials involving calcium-free phosphate binders and calcimimetics in ESRD and CKD.28Chertow G.M. Burke S.K. Raggi P. 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 (1327) Google Scholar, 29Braun J. Asmus H.-G. Holzer H. et al.Long-term comparison of a calcium-free phosphate binder and calcium-carbonate—phosphorus metabolism and cardiovascular calcification.Clin Nephrol. 2004; 62: 104-115Crossref PubMed Google Scholar, 30Block G.A. Spiegel D.M. Ehrlich J. et al.Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar, 31Asmus H.G. Braun J. Krause R. et al.Two year comparison of sevelamer and calcium carbonate effects on cardiovascular calcification and bone density.Nephrol Dial Transplant. 2005; 20: 1653-1661Crossref PubMed Scopus (157) Google Scholar, 32Russo D. Miranda I. Ruocco C. et al.The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer.Kidney Int. 2007; 72: 1255-1261Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 33Barreto D.V. Barreto F.C. de Carvalho A.B. et al.Phosphate binder impact on bone remodeling and coronary calcification—results from the BRiC study.Nephron Clin Pract. 2008; 110: c273-c283Crossref PubMed Scopus (133) Google Scholar, 34Qunibi W.Y. Moustafa M. Muenz L.R. et al.A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: The Calcium Acetate Renagel Evaluation-2 (CARE-2) study.Am J Kidney Dis. 2008; 51: 952-965Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar, 35Raggi P. Chertow G.M. Torres P.U. et al.The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis.Nephrol Dial Transpl. 2011; 26: 1327-1339Crossref PubMed Scopus (419) Google Scholar, 36Block G.A. Wheeler D.C. Persky M.S. et al.Effects of phosphate binders in moderate CKD.J Am Soc Nephrol. 2012; 23: 1407-1415Crossref PubMed Scopus (420) Google Scholar, 37Di Iorio B. Bellasi A. Russo D. Mortality in kidney disease patients treated with phosphate binders: a randomized study.Clin J Am Soc Nephrol. 2012; 7: 487-493Crossref PubMed Scopus (185) Google Scholar, 38Kakuta T. Tanaka R. Hyodo T. et al.Effect of sevelamer and calcium-based phosphate binders on coronary artery calcification and accumulation of circulating advanced glycation end products in hemodialysis patients.Am J Kidney Dis. 2011; 57: 422-431Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Unfortunately, these reductions were minimized by study designs that aimed to maintain serum calcium in the normal range and overlooked the transient but prolonged potential increases after ingestion of calcium salts.39Bristow S.M. Gamble G.D. Stewart A. et al.Acute and 3-month effects of microcrystalline hydroxyapatite, calcium citrate and calcium carbonate on serum calcium and markers of bone turnover: a randomised controlled trial in postmenopausal women.Br J Nutr. 2014; 112: 1611-1620Crossref PubMed Scopus (39) Google Scholar These changes in serum calcium have largely been ignored in the extensive and often lively discussion of the effectiveness of these therapies. However, a decrease in serum calcium occurred in every study comparing sevelamer to calcium salts as oral phosphate binders and was associated with less progression of coronary artery calcification in all but one.34Qunibi W.Y. Moustafa M. Muenz L.R. et al.A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: The Calcium Acetate Renagel Evaluation-2 (CARE-2) study.Am J Kidney Dis. 2008; 51: 952-965Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar This was true even in a recent study showing a surprisingly greater progression of coronary artery calcification in CKD patients taking phosphate binders (calcium carbonate, lanthanum, or sevelamer) compared to placebo, where the serum calcium was lower in the placebo group.36Block G.A. Wheeler D.C. Persky M.S. et al.Effects of phosphate binders in moderate CKD.J Am Soc Nephrol. 2012; 23: 1407-1415Crossref PubMed Scopus (420) Google Scholar Within this study, both coronary artery calcification and serum calcium were greatest in patients receiving calcium carbonate. Cinacalcet also results in a lower serum calcium and less vascular calcification.35Raggi P. Chertow G.M. Torres P.U. et al.The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis.Nephrol Dial Transpl. 2011; 26: 1327-1339Crossref PubMed Scopus (419) Google Scholar However, this is often mitigated by concomitant measures to maintain serum calcium in the normal range. Data from all of the interventional studies (listed in Table 1) are presented graphically in Figure 2, where the differences in serum calcium concentration are compared to the differences in the progression of coronary artery calcification in patients treated with sevelamer or cinacalcet compared to calcium salts (or placebo in the case of cinacalcet). While the changes in serum calcium were not significant in many of the studies, together they show a consistent, direct relationship with the progression of coronary artery calcification, with only 1 study showing a slight inverse relationship. In studies that also examined aortic calcification, the results were similar.28Chertow G.M. Burke S.K. Raggi P. 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 (1327) Google Scholar, 29Braun J. Asmus H.-G. Holzer H. et al.Long-term comparison of a calcium-free phosphate binder and calcium-carbonate—phosphorus metabolism and cardiovascular calcification.Clin Nephrol. 2004; 62: 104-115Crossref PubMed Google Scholar, 31Asmus H.G. Braun J. Krause R. et al.Two year comparison of sevelamer and calcium carbonate effects on cardiovascular calcification and bone density.Nephrol Dial Transplant. 2005; 20: 1653-1661Crossref PubMed Scopus (157) Google Scholar, 35Raggi P. Chertow G.M. Torres P.U. et al.The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis.Nephrol Dial Transpl. 2011; 26: 1327-1339Crossref PubMed Scopus (419) Google Scholar, 36Block G.A. Wheeler D.C. Persky M.S. et al.Effects of phosphate binders in moderate CKD.J Am Soc Nephrol. 2012; 23: 1407-1415Crossref PubMed Scopus (420) Google Scholar The clinical benefit of reducing vascular calcification is not likely to be immediate and may require a number of years. However, 4 studies examined mortality or cardiovascular events in patients treated with sevelamer37Di Iorio B. Bellasi A. Russo D. Mortality in kidney disease patients treated with phosphate binders: a randomized study.Clin J Am Soc Nephrol. 2012; 7: 487-493Crossref PubMed Scopus (185) Google Scholar, 40Suki W. Zabaneh R. Cangiano J.L. et al.Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients.Kidney Int. 2007; 72: 1130-1137Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar, 41Block G.A. Raggi P. Bellasi A. et al.Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Abstract Full Text Full Text PDF PubMed Scopus (672) Google Scholar or cinacalcet,42EVOLVE Trial InvestigatorsEffect of cinacalcet on cardiovascular disease in patients undergoing dialysis.N Engl J Med. 2012; 367: 2482-2494Crossref PubMed Scopus (686) Google Scholar and in each case a reduction in death or cardiovascular events in the treated patients was accompanied by a decrease in serum calcium.Table 1Interventional studies examining coronary artery calcification that are depicted in Figure 2StudyComparisonCAC parameterSymbol in Figure 2Chertow et al. 200228Chertow G.M. Burke S.K. Raggi P. 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 (1327) Google ScholarSevelamer vs. CaCO3 or calcium acetateMean absolute change , 1 yrABraun et al. 200429Braun J. Asmus H.-G. Holzer H. et al.Long-term comparison of a calcium-free phosphate binder and calcium-carbonate—phosphorus metabolism and cardiovascular calcification.Clin Nephrol. 2004; 62: 104-115Crossref PubMed Google ScholarSevelamer vs. CaCO3Mean absolute change, 1 yrBBlock et al. 200530Block G.A. Spiegel D.M. Ehrlich J. et al.Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (718) Google ScholarSevelamer vs. CaCO3 or calcium acetateMean absolute change, 1.5 yrCRusso et al. 200732Russo D. Miranda I. Ruocco C. et al.The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer.Kidney Int. 2007; 72: 1255-1261Abstract Full Text Full Text PDF PubMed Scopus (287) Google ScholarSevelamer vs. CaCO3Mean absolute change, 2 yrDRusso et al. 200732Russo D. Miranda I. Ruocco C. et al.The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer.Kidney Int. 2007; 72: 1255-1261Abstract Full Text Full Text PDF PubMed Scopus (287) Google ScholarDiet alone vs. CaCO3Mean absolute change, 2 yrEBarreto et al. 200833Barreto D.V. Barreto F.C. de Carvalho A.B. et al.Phosphate binder impact on bone remodeling and coronary calcification—results from the BRiC study.Nephron Clin Pract. 2008; 110: c273-c283Crossref PubMed Scopus (133) Google ScholarSevelamer vs. calcium acetateMean absolute change, 1 yrFQunibi et al. 200834Qunibi W.Y. Moustafa M. Muenz L.R. et al.A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: The Calcium Acetate Renagel Evaluation-2 (CARE-2) study.Am J Kidney Dis. 2008; 51: 952-965Abstract Full Text Full Text PDF PubMed Scopus (272) Google ScholarSevelamer vs. calcium acetateMean absolute change, 1 yrGRaggi et al. 201135Raggi P. Chertow G.M. Torres P.U. et al.The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis.Nephrol Dial Transpl. 2011; 26: 1327-1339Crossref PubMed Scopus (419) Google ScholarCinacalcet vs. no cinacalcetMedian % change, 1 yrHKakuta et al. 201138Kakuta T. Tanaka R. Hyodo T. et al.Effect of sevelamer and calcium-based phosphate binders on coronary artery calcification and accumulation of circulating advanced glycation end products in hemodialysis patients.Am J Kidney Dis. 2011; 57: 422-431Abstract Full Text Full Text PDF PubMed Scopus (113) Google ScholarSevelamer vs. CaCO3Mean absolute change, 1 yrIBlock et al. 201236Block G.A. Wheeler D.C. Persky M.S. et al.Effects of phosphate binders in moderate CKD.J Am Soc Nephrol. 2012; 23: 1407-1415Crossref PubMed Scopus (420) Google ScholarPlacebo vs. calcium acetate% change in median, 1 yrJBlock et al. 201236Block G.A. Wheeler D.C. Persky M.S. et al.Effects of phosphate