Calcification in CKD: No Closer to the Cure
2008; Elsevier BV; Volume: 51; Issue: 6 Linguagem: Inglês
10.1053/j.ajkd.2008.04.004
ISSN1523-6838
Autores Tópico(s)Trace Elements in Health
ResumoRelated Article, p. 952Vascular calcification is highly prevalent in patients with end-stage renal disease (ESRD) and may be an important mechanism linking kidney failure with excess cardiovascular risk. Approximately 65% of incident and 85% of prevalent adult hemodialysis patients have calcification of the coronary arteries, as detected by electron beam computed tomography.1Block G.A. Raggi P. Bellasi A. Kooienga L. Spiegel D.M. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Crossref PubMed Scopus (667) Google Scholar, 2Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Abstract Full Text Full Text PDF PubMed Scopus (987) Google Scholar Pioneering basic science work has significantly advanced understanding of the mechanisms underlying dystrophic soft tissue calcification that occurs in chronic kidney disease (CKD).3Giachelli C.M. Vascular calcification: in vitro evidence for the role of inorganic phosphate.J Am Soc Nephrol. 2003; 14: S300-S304Crossref PubMed Google Scholar, 4Hruska K.A. Mathew S. Saab G. Bone morphogenetic proteins in vascular calcification.Circ Res. 2005; 97: 105-114Crossref PubMed Scopus (285) Google Scholar, 5Moe S.M. Duan D. Doehle B.P. O'Neill K.D. Chen N.X. Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels.Kidney Int. 2003; 63: 1003-1011Crossref PubMed Scopus (289) Google Scholar These studies have demonstrated arterial calcification to be a highly active process, analogous to bone formation, regulated by a growing list of promoters and inhibitors that are altered by kidney failure.While disturbances of normal mineral metabolism, particularly phosphate, are considered to be the primary cause of vascular calcification in ESRD patients, evidence suggests the possibility of an additional iatrogenic component: the administration of excessive dosages of calcium salts to control phosphate and parathyroid hormone levels.6Goodman 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 (2422) Google Scholar, 7Guerin A.P. London G.M. Marchais S.J. Metivier F. Arterial stiffening and vascular calcifications in end-stage renal disease.Nephrol Dial Transplant. 2000; 15: 1014-1021Crossref PubMed Scopus (882) Google Scholar ESRD represents a state of altered calcium homeostasis, in which skeletal mineralization is impaired and urinary calcium excretion absent.8Kurz P. Monier-Faugere M.C. Bognar B. et al.Evidence for abnormal calcium homeostasis in patients with adynamic bone disease.Kidney Int. 1994; 46: 855-861Crossref PubMed Scopus (299) Google Scholar Without a natural calcium reservoir or a means to remove excess calcium from the body, ESRD patients may incur significant positive calcium balance due to the intake of calcium-based binders and exposure to high calcium concentrations in the dialysate. Clinical studies of ESRD patients have reported an association of higher oral calcium dosage with greater coronary artery calcification scores.6Goodman 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 (2422) Google Scholar, 7Guerin A.P. London G.M. Marchais S.J. Metivier F. Arterial stiffening and vascular calcifications in end-stage renal disease.Nephrol Dial Transplant. 2000; 15: 1014-1021Crossref PubMed Scopus (882) Google Scholar Three clinical trials have found lesser progression of coronary artery calcification in kidney disease patients treated with sevelamer, a non–calcium-based phosphate binder, compared to those treated with a calcium-based binder.1Block G.A. Raggi P. Bellasi A. Kooienga L. Spiegel D.M. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Crossref PubMed Scopus (667) Google Scholar, 9Chertow G.M. Burke S.K. Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Crossref PubMed Scopus (1322) Google Scholar, 10Russo D. Corrao S. Miranda I. et al.Progression of coronary artery calcification in predialysis patients.Am J Nephrol. 2007; 27: 152-158Crossref PubMed Scopus (85) Google Scholar While not definitive evidence of harm, these findings motivated the recommendation of an upper limit of 1,500 mg of prescribed daily elemental calcium for patients with ESRD.11National Kidney FoundationK/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-S201Crossref PubMed Scopus (664) Google ScholarIn addition to binding phosphorus in the gastrointestinal tract, sevelamer also binds to dietary cholesterol and subsequently lowers low-density lipoprotein cholesterol (LDL-C) levels.12Chertow 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 (252) Google Scholar This non–mineral metabolism property of sevelamer motivated the clinical trial by Qunibi et al13Qunibi W. 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 (270) Google Scholar that appears in this issue of AJKD. The study hypothesis was that the relative protection of sevelamer on coronary calcification might have been due, in part, to its cholesterol-lowering effects, rather than procalcification properties of calcium-based binders. In the current study, 203 prevalent hemodialysis patients with known coronary calcification were randomly assigned to therapy with either calcium acetate or sevelamer as a phosphate binder, with the addition of atorvastatin to achieve similar target LDL-C levels.The rationale for the study design is questionable because there is limited evidence that LDL-C plays an important role in coronary calcification in populations with or without CKD. LDL-C concentrations are unrelated to coronary calcification scores in prevalent hemodialysis patients, and are unrelated to the progression of preexisting coronary calcification in more than 2,800 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) study.2Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Abstract Full Text Full Text PDF PubMed Scopus (987) Google Scholar, 14Kronmal R.A. McClelland R.L. Detrano R. et al.Risk factors for the progression of coronary artery calcification in asymptomatic subjects: results from the Multi-Ethnic Study of Atherosclerosis (MESA).Circulation. 2007; 115: 2722-2730Crossref PubMed Scopus (385) Google Scholar Intensive lipid lowering with atorvastatin had no effect on 1-year progression of coronary calcium scores in 471 participants without CKD with prevalent coronary calcification, and the 4D (Die Deutsche Diabetes Dialyse) trial demonstrated no effect of intensive LDL-C lowering on cardiovascular events in hemodialysis patients, yet coronary calcification is hypothesized to be a key surrogate of cardiovascular outcomes in this setting.15Schmermund A. Achenbach S. Budde T. et al.Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months: a multicenter, randomized, double-blind trial.Circulation. 2006; 113: 427-437Crossref PubMed Scopus (209) Google Scholar, 16Wanner C. Krane V. Marz W. et al.Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.N Engl J Med. 2005; 353: 238-248Crossref PubMed Scopus (2176) Google Scholar, 17Blacher J. Guerin A.P. Pannier B. Marchais S.J. London G.M. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Scopus (1227) Google Scholar In the current study, calcification progressed relentlessly in both treatment groups despite the substantial reduction of LDL-C levels to less than 70 mg/dL.Even if LDL-C were related to coronary calcification, it is difficult to interpret findings from a clinical trial that compares 1 treatment to 2 different treatments. Sevelamer and atorvastatin reduce cholesterol concentrations via completely different mechanisms, and statins possess many properties beyond their effects on LDL-C.18Jasinska M. Owczarek J. Orszulak-Michalak D. Statins: a new insight into their mechanisms of action and consequent pleiotropic effects.Pharmacol Rep. 2007; 59: 483-499PubMed Google Scholar The preferential addition of atorvastatin to 1 treatment arm for the sole purpose of equalizing LDL-C concentrations obscures the interpretation of any differences or similarities between the treatment groups in this study.In the current study, coronary calcification scores increased by 52% in the calcium acetate group and 57% in the sevelamer group after 1 year (P = 0.9). While it is tempting to conclude a lack of difference between the treatment groups, many other factors may have accounted for the observed similarity, including (1) loss of nearly half of the study participants during follow-up, (2) nontrivial measurement error in coronary calcification scores when scores are high,19Hokanson J.E. MacKenzie T. Kinney G. et al.Evaluating changes in coronary artery calcium: an analytic method that accounts for interscan variability.AJR Am J Roentgenol. 2004; 182: 1327-1332Crossref PubMed Scopus (154) Google Scholar (3) potential for partial or nonadherence to assigned therapies, (4) relatively short duration of follow-up, and (5) small number of participants. In fact, many common errors in clinical studies produce bias toward the null and potential for type II error, in which no difference between treatment groups is observed when in fact a true difference exists. Even in the setting of a very large clinical trial, a proven treatment standard with large effect size, and precisely measured end points, it remains difficult to prove noninferiority.20Fleming T.R. Current issues in non-inferiority trials.Stat Med. 2008; 27: 317-332Crossref PubMed Scopus (152) Google Scholar It is not appropriate to apply the term noninferiority to this study, which is simply a small negative study with many possible reasons for the negative findings, not proof that the 2 treatments are equal. In all fairness, coronary calcification progressed substantially in both treatment groups at rates similar to the natural history of the disease; it is likely that a placebo group would have been statistically noninferior to both treatment groups under these study conditions.These findings contrast those of 3 previous clinical trials that demonstrated lesser progression of coronary calcification with sevelamer compared to calcium binders. In the Treat-to-Goal study, 200 prevalent hemodialysis patients were randomly assigned to sevelamer versus a calcium-based phosphate binder.9Chertow G.M. Burke S.K. Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Crossref PubMed Scopus (1322) Google Scholar After 1 year, mean changes in coronary calcification scores were −46 Agatston units in the sevelamer group versus +151 Agatston units in the calcium group. The RIND (Renagel in New Dialysis) trial randomly assigned 129 incident hemodialysis patients to sevelamer or calcium for 18 months; mean increases in coronary calcification scores were +138 Agatston units in the sevelamer group versus +338 Agatston units in the calcium group.1Block G.A. Raggi P. Bellasi A. Kooienga L. Spiegel D.M. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Crossref PubMed Scopus (667) Google Scholar Finally, Russo et al assigned 90 predialysis patients with stages 3 to 5 CKD and no clinical diabetes or coronary heart disease to a low-phosphorus diet plus either sevelamer, calcium carbonate, or placebo for 24 months.21Russo 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: 1255-1261Crossref PubMed Scopus (287) Google Scholar Mean changes in coronary artery calcification scores were +178 Agatston units in the placebo group, +133 Agatston units in the calcium carbonate group, and +38 Agatston units in the sevelamer group. The current study by Qunibi et al most closely relates to the Treat-to-Goal study of prevalent dialysis patients; however, progression of calcification was substantially greater in the current study, possibly due to a higher proportion of diabetic patients. Control of calcium and phosphate concentrations was similar in the 2 studies, though parathyroid hormone was somewhat better controlled in Treat-to-Goal study. Disparate findings from these relatively small clinical trials emphasize the role of sampling variation and the variability of coronary artery calcium measurements.There is currently no effective treatment available for vascular calcification. From bench to bedside, novel therapies are needed to inhibit aberrant smooth muscle mineralization and to enhance deposition of calcium and phosphate in the skeleton, where these minerals belong. In the meantime, the current study does little to change clinical practice standards or current national guidelines. Nephrologists should continue to control serum phosphorus levels while recognizing the potential for dystrophic calcification that may result from excessive calcium loading, as well as from other agents that can increase serum calcium and phosphate levels. Particular caution is advised for patients with known calcification, or those with calcification risk factors, such as diabetes and higher serum phosphate and calcium concentrations. Related Article, p. 952 Related Article, p. 952 Related Article, p. 952 Vascular calcification is highly prevalent in patients with end-stage renal disease (ESRD) and may be an important mechanism linking kidney failure with excess cardiovascular risk. Approximately 65% of incident and 85% of prevalent adult hemodialysis patients have calcification of the coronary arteries, as detected by electron beam computed tomography.1Block G.A. Raggi P. Bellasi A. Kooienga L. Spiegel D.M. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Crossref PubMed Scopus (667) Google Scholar, 2Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Abstract Full Text Full Text PDF PubMed Scopus (987) Google Scholar Pioneering basic science work has significantly advanced understanding of the mechanisms underlying dystrophic soft tissue calcification that occurs in chronic kidney disease (CKD).3Giachelli C.M. Vascular calcification: in vitro evidence for the role of inorganic phosphate.J Am Soc Nephrol. 2003; 14: S300-S304Crossref PubMed Google Scholar, 4Hruska K.A. Mathew S. Saab G. Bone morphogenetic proteins in vascular calcification.Circ Res. 2005; 97: 105-114Crossref PubMed Scopus (285) Google Scholar, 5Moe S.M. Duan D. Doehle B.P. O'Neill K.D. Chen N.X. Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels.Kidney Int. 2003; 63: 1003-1011Crossref PubMed Scopus (289) Google Scholar These studies have demonstrated arterial calcification to be a highly active process, analogous to bone formation, regulated by a growing list of promoters and inhibitors that are altered by kidney failure. While disturbances of normal mineral metabolism, particularly phosphate, are considered to be the primary cause of vascular calcification in ESRD patients, evidence suggests the possibility of an additional iatrogenic component: the administration of excessive dosages of calcium salts to control phosphate and parathyroid hormone levels.6Goodman 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 (2422) Google Scholar, 7Guerin A.P. London G.M. Marchais S.J. Metivier F. Arterial stiffening and vascular calcifications in end-stage renal disease.Nephrol Dial Transplant. 2000; 15: 1014-1021Crossref PubMed Scopus (882) Google Scholar ESRD represents a state of altered calcium homeostasis, in which skeletal mineralization is impaired and urinary calcium excretion absent.8Kurz P. Monier-Faugere M.C. Bognar B. et al.Evidence for abnormal calcium homeostasis in patients with adynamic bone disease.Kidney Int. 1994; 46: 855-861Crossref PubMed Scopus (299) Google Scholar Without a natural calcium reservoir or a means to remove excess calcium from the body, ESRD patients may incur significant positive calcium balance due to the intake of calcium-based binders and exposure to high calcium concentrations in the dialysate. Clinical studies of ESRD patients have reported an association of higher oral calcium dosage with greater coronary artery calcification scores.6Goodman 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 (2422) Google Scholar, 7Guerin A.P. London G.M. Marchais S.J. Metivier F. Arterial stiffening and vascular calcifications in end-stage renal disease.Nephrol Dial Transplant. 2000; 15: 1014-1021Crossref PubMed Scopus (882) Google Scholar Three clinical trials have found lesser progression of coronary artery calcification in kidney disease patients treated with sevelamer, a non–calcium-based phosphate binder, compared to those treated with a calcium-based binder.1Block G.A. Raggi P. Bellasi A. Kooienga L. Spiegel D.M. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Crossref PubMed Scopus (667) Google Scholar, 9Chertow G.M. Burke S.K. Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Crossref PubMed Scopus (1322) Google Scholar, 10Russo D. Corrao S. Miranda I. et al.Progression of coronary artery calcification in predialysis patients.Am J Nephrol. 2007; 27: 152-158Crossref PubMed Scopus (85) Google Scholar While not definitive evidence of harm, these findings motivated the recommendation of an upper limit of 1,500 mg of prescribed daily elemental calcium for patients with ESRD.11National Kidney FoundationK/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-S201Crossref PubMed Scopus (664) Google Scholar In addition to binding phosphorus in the gastrointestinal tract, sevelamer also binds to dietary cholesterol and subsequently lowers low-density lipoprotein cholesterol (LDL-C) levels.12Chertow 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 (252) Google Scholar This non–mineral metabolism property of sevelamer motivated the clinical trial by Qunibi et al13Qunibi W. 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 (270) Google Scholar that appears in this issue of AJKD. The study hypothesis was that the relative protection of sevelamer on coronary calcification might have been due, in part, to its cholesterol-lowering effects, rather than procalcification properties of calcium-based binders. In the current study, 203 prevalent hemodialysis patients with known coronary calcification were randomly assigned to therapy with either calcium acetate or sevelamer as a phosphate binder, with the addition of atorvastatin to achieve similar target LDL-C levels. The rationale for the study design is questionable because there is limited evidence that LDL-C plays an important role in coronary calcification in populations with or without CKD. LDL-C concentrations are unrelated to coronary calcification scores in prevalent hemodialysis patients, and are unrelated to the progression of preexisting coronary calcification in more than 2,800 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) study.2Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Abstract Full Text Full Text PDF PubMed Scopus (987) Google Scholar, 14Kronmal R.A. McClelland R.L. Detrano R. et al.Risk factors for the progression of coronary artery calcification in asymptomatic subjects: results from the Multi-Ethnic Study of Atherosclerosis (MESA).Circulation. 2007; 115: 2722-2730Crossref PubMed Scopus (385) Google Scholar Intensive lipid lowering with atorvastatin had no effect on 1-year progression of coronary calcium scores in 471 participants without CKD with prevalent coronary calcification, and the 4D (Die Deutsche Diabetes Dialyse) trial demonstrated no effect of intensive LDL-C lowering on cardiovascular events in hemodialysis patients, yet coronary calcification is hypothesized to be a key surrogate of cardiovascular outcomes in this setting.15Schmermund A. Achenbach S. Budde T. et al.Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months: a multicenter, randomized, double-blind trial.Circulation. 2006; 113: 427-437Crossref PubMed Scopus (209) Google Scholar, 16Wanner C. Krane V. Marz W. et al.Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.N Engl J Med. 2005; 353: 238-248Crossref PubMed Scopus (2176) Google Scholar, 17Blacher J. Guerin A.P. Pannier B. Marchais S.J. London G.M. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Scopus (1227) Google Scholar In the current study, calcification progressed relentlessly in both treatment groups despite the substantial reduction of LDL-C levels to less than 70 mg/dL. Even if LDL-C were related to coronary calcification, it is difficult to interpret findings from a clinical trial that compares 1 treatment to 2 different treatments. Sevelamer and atorvastatin reduce cholesterol concentrations via completely different mechanisms, and statins possess many properties beyond their effects on LDL-C.18Jasinska M. Owczarek J. Orszulak-Michalak D. Statins: a new insight into their mechanisms of action and consequent pleiotropic effects.Pharmacol Rep. 2007; 59: 483-499PubMed Google Scholar The preferential addition of atorvastatin to 1 treatment arm for the sole purpose of equalizing LDL-C concentrations obscures the interpretation of any differences or similarities between the treatment groups in this study. In the current study, coronary calcification scores increased by 52% in the calcium acetate group and 57% in the sevelamer group after 1 year (P = 0.9). While it is tempting to conclude a lack of difference between the treatment groups, many other factors may have accounted for the observed similarity, including (1) loss of nearly half of the study participants during follow-up, (2) nontrivial measurement error in coronary calcification scores when scores are high,19Hokanson J.E. MacKenzie T. Kinney G. et al.Evaluating changes in coronary artery calcium: an analytic method that accounts for interscan variability.AJR Am J Roentgenol. 2004; 182: 1327-1332Crossref PubMed Scopus (154) Google Scholar (3) potential for partial or nonadherence to assigned therapies, (4) relatively short duration of follow-up, and (5) small number of participants. In fact, many common errors in clinical studies produce bias toward the null and potential for type II error, in which no difference between treatment groups is observed when in fact a true difference exists. Even in the setting of a very large clinical trial, a proven treatment standard with large effect size, and precisely measured end points, it remains difficult to prove noninferiority.20Fleming T.R. Current issues in non-inferiority trials.Stat Med. 2008; 27: 317-332Crossref PubMed Scopus (152) Google Scholar It is not appropriate to apply the term noninferiority to this study, which is simply a small negative study with many possible reasons for the negative findings, not proof that the 2 treatments are equal. In all fairness, coronary calcification progressed substantially in both treatment groups at rates similar to the natural history of the disease; it is likely that a placebo group would have been statistically noninferior to both treatment groups under these study conditions. These findings contrast those of 3 previous clinical trials that demonstrated lesser progression of coronary calcification with sevelamer compared to calcium binders. In the Treat-to-Goal study, 200 prevalent hemodialysis patients were randomly assigned to sevelamer versus a calcium-based phosphate binder.9Chertow G.M. Burke S.K. Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Crossref PubMed Scopus (1322) Google Scholar After 1 year, mean changes in coronary calcification scores were −46 Agatston units in the sevelamer group versus +151 Agatston units in the calcium group. The RIND (Renagel in New Dialysis) trial randomly assigned 129 incident hemodialysis patients to sevelamer or calcium for 18 months; mean increases in coronary calcification scores were +138 Agatston units in the sevelamer group versus +338 Agatston units in the calcium group.1Block G.A. Raggi P. Bellasi A. Kooienga L. Spiegel D.M. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Crossref PubMed Scopus (667) Google Scholar Finally, Russo et al assigned 90 predialysis patients with stages 3 to 5 CKD and no clinical diabetes or coronary heart disease to a low-phosphorus diet plus either sevelamer, calcium carbonate, or placebo for 24 months.21Russo 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: 1255-1261Crossref PubMed Scopus (287) Google Scholar Mean changes in coronary artery calcification scores were +178 Agatston units in the placebo group, +133 Agatston units in the calcium carbonate group, and +38 Agatston units in the sevelamer group. The current study by Qunibi et al most closely relates to the Treat-to-Goal study of prevalent dialysis patients; however, progression of calcification was substantially greater in the current study, possibly due to a higher proportion of diabetic patients. Control of calcium and phosphate concentrations was similar in the 2 studies, though parathyroid hormone was somewhat better controlled in Treat-to-Goal study. Disparate findings from these relatively small clinical trials emphasize the role of sampling variation and the variability of coronary artery calcium measurements. There is currently no effective treatment available for vascular calcification. From bench to bedside, novel therapies are needed to inhibit aberrant smooth muscle mineralization and to enhance deposition of calcium and phosphate in the skeleton, where these minerals belong. In the meantime, the current study does little to change clinical practice standards or current national guidelines. Nephrologists should continue to control serum phosphorus levels while recognizing the potential for dystrophic calcification that may result from excessive calcium loading, as well as from other agents that can increase serum calcium and phosphate levels. Particular caution is advised for patients with known calcification, or those with calcification risk factors, such as diabetes and higher serum phosphate and calcium concentrations. Support: None. Financial Disclosure: Dr Kestenbaum has received grant support from Amgen, and has also received consulting fees from Abbott Inc and Shire Inc. 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) StudyAmerican Journal of Kidney DiseasesVol. 51Issue 6PreviewPrevious clinical trials showed that progression of coronary artery calcification (CAC) may be slower in hemodialysis patients treated with sevelamer than those treated with calcium-based phosphate binders. Because sevelamer decreases low-density lipoprotein cholesterol (LDL-C) levels, we hypothesized that intensive lowering of LDL-C levels with atorvastatin in hemodialysis patients treated with calcium acetate would result in CAC progression rates similar to those in sevelamer-treated patients. Full-Text PDF Progression of Calcification in the Calcium Acetate Renagel Evaluation-2 (CARE-2) StudyAmerican Journal of Kidney DiseasesVol. 52Issue 5PreviewWe write in response to the comments by Kestenbaum1 on our Calcium Acetate Renagel Evaluation-2 (CARE-2) Study.2 He takes issue with our hypothesis on the role of low-density lipoprotein cholesterol (LDL-C), as well as with our noninferiority study design. First, regarding our hypothesis, it was unfortunate that the trials he cited3-6 have allowed significant difference in LDL-C levels between sevelamer-treated patients and those treated with calcium-based phosphate binders (CBPB). Although we acknowledge that the effect of decreasing LDL-C levels on progression of coronary artery calcification (CAC) has not been consistent, it is difficult to understand Dr Kestenbaum's opposition to controlling LDL-C levels in trials examining progression of calcification, a surrogate marker of atherosclerosis. Full-Text PDF
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