The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer
2007; Elsevier BV; Volume: 72; Issue: 10 Linguagem: Inglês
10.1038/sj.ki.5002518
ISSN1523-1755
AutoresDomenico Russo, Iratxe Díez Miranda, Carolina Ruocco, Yuri Battaglia, Elisa Buonanno, Simona Manzi, Luigi Russo, Anna Scafarto, Vittorio E. Andreucci,
Tópico(s)Neurological and metabolic disorders
ResumoCoronary artery calcification is more prevalent in dialysis patients than in patients without kidney disease and this is associated with high serum phosphorus. In this study, we evaluate the effect of calcium carbonate or sevelamer treatments on the progression of calcification in 90 predialysis patients. Inclusion criteria were stable serum calcium, phosphorus, parathyroid hormone, and a similar baseline total calcium score (TCS). These patients were not treated by phosphate binder, vitamin D, or statin. They were given low-phosphorus diets without or with daily calcium carbonate or sevelamer throughout the study that averaged 2 years. Baseline demographic or clinical characteristics along with biochemical parameters were not different among the three groups. The TCS significantly increased in patients on the low-phosphorus diet alone, to a lesser extent in calcium carbonate-treated patients, and not at all in sevelamer-treated patients. The progression of coronary calcification paralleled that of the calcium score. Our study shows that sevelamer treatment should not be restricted to dialysis patients; however, a larger study should be undertaken to confirm these results. Coronary artery calcification is more prevalent in dialysis patients than in patients without kidney disease and this is associated with high serum phosphorus. In this study, we evaluate the effect of calcium carbonate or sevelamer treatments on the progression of calcification in 90 predialysis patients. Inclusion criteria were stable serum calcium, phosphorus, parathyroid hormone, and a similar baseline total calcium score (TCS). These patients were not treated by phosphate binder, vitamin D, or statin. They were given low-phosphorus diets without or with daily calcium carbonate or sevelamer throughout the study that averaged 2 years. Baseline demographic or clinical characteristics along with biochemical parameters were not different among the three groups. The TCS significantly increased in patients on the low-phosphorus diet alone, to a lesser extent in calcium carbonate-treated patients, and not at all in sevelamer-treated patients. The progression of coronary calcification paralleled that of the calcium score. Our study shows that sevelamer treatment should not be restricted to dialysis patients; however, a larger study should be undertaken to confirm these results. In patients on dialysis, the prevalence of vascular calcification is greater than in age- and sex-matched individuals without kidney disease;1.Braun J. Oldendorf M.M.W. Electron beam computed tomography in the evaluation of cardiac calcifications in chronic dialysis patients.Am J Kidney Dis. 1996; 27: 394-401Abstract Full Text PDF PubMed Scopus (703) Google Scholar for instance, coronary artery calcification (CAC) is more frequent in these patients than in individuals with established coronary artery disease but with normal kidney function.1.Braun J. Oldendorf M.M.W. Electron beam computed tomography in the evaluation of cardiac calcifications in chronic dialysis patients.Am J Kidney Dis. 1996; 27: 394-401Abstract Full Text PDF PubMed Scopus (703) Google Scholar,2.Block G.A. Spiegel D.M. Ehrlich J. et al.Effect of sevelamer and calcium on coronary artery calcifications in patients new to haemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar This finding together with the very high rate of cardiovascular events sustains the opinion that the presence of vascular calcification is the strongest predictor of cardiovascular morbidity and mortality in patients on dialysis.3.Blacher J. Guerin A.P. Pannier B. et al.Arterial calcifications, arterial stiffness, and cardiovascular risk in end stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Scopus (1180) Google Scholar Very recently, the severity of CAC at the time of entry in the hemodialysis has been confirmed as an important predictor of long-term survival.4.Block 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 (639) Google Scholar A harmful characteristic of CACs is its progression over the time that is regarded as further predictor of cardiac events. Among the several pathogenetic factors contributing to formation and progression of CAC, the serum concentration of phosphorus plays a major role.5.Stevens L.A. Djurdejev O. Cardew S. et al.Calcium, phosphate and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: Evidence for the complexity of the association between mineral metabolism and outcomes.J Am Soc Nephrol. 2004; 15: 770-779Crossref PubMed Scopus (293) Google Scholar, 6.Block 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 (2080) Google Scholar, 7.Giachelli C.M. Vascular calcification mechanisms.J Am Soc Nephrol. 2004; 15: 2959-2964Crossref PubMed Scopus (419) Google Scholar The relationship between concentration of phosphorus, CAC, and cardiovascular events is likely more complex than previously thought.7.Giachelli C.M. Vascular calcification mechanisms.J Am Soc Nephrol. 2004; 15: 2959-2964Crossref PubMed Scopus (419) Google Scholar, 8.Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (869) Google Scholar, 9.Tomiyama C. Higa A. Dalboni M.A. et al.The impact of traditional and not-traditional factors on coronary calcification in pre-dialysis patients.Nephrol Dial Transplant. 2006; 21: 2464-2471Crossref PubMed Scopus (103) Google Scholar Phosphorus may accelerate the development and progression of CAC through both passive precipitation and cell-mediated process, the latter being more important than the former.7.Giachelli C.M. Vascular calcification mechanisms.J Am Soc Nephrol. 2004; 15: 2959-2964Crossref PubMed Scopus (419) Google Scholar Association between higher phosphate levels and mortality risk has been reported among pre-dialysis patients with absolute serum phosphate levels in the high–normal range but not among patients with lower serum phosphate levels; it has been hypothesized that phosphorus might contribute to mortality by increasing vascular calcifications.8.Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (869) Google Scholar In addition, severe CACs were found in pre-dialysis patients despite the fact that majority of them had concentration of serum phosphorus within the normal range.9.Tomiyama C. Higa A. Dalboni M.A. et al.The impact of traditional and not-traditional factors on coronary calcification in pre-dialysis patients.Nephrol Dial Transplant. 2006; 21: 2464-2471Crossref PubMed Scopus (103) Google Scholar Not only hyperphosphatemia but even its treatment may promote the calcification process and enhance the progression of CAC. The use of calcium-based phosphate binders is, in fact, strongly associated with development and progression of CAC due to the large amount of calcium ingested and the consequent hypercalcemia. Thus, therapeutic approaches such as limiting the use of calcium-based phosphate binders and implementing the use of sevelamer, a non-calcium-based phosphate binder, have been undertaken to modify the development or progression of CAC. Sevelamer halted or significantly reduced the progression of CAC in prevalent and incident patients on dialysis.2.Block G.A. Spiegel D.M. Ehrlich J. et al.Effect of sevelamer and calcium on coronary artery calcifications in patients new to haemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar,10.Chertow 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 (1269) Google Scholar However, there is no unanimous agreement on abandoning the calcium-based phosphate binders for the treatment of hyperphosphatemia; the trials forming the case against calcium are regarded as flawed,11.Friedman E.A. Calcium-based phosphate binders are appropriate in chronic renal failure.Clin J Am Soc Nephrol. 2006; 1: 704-709Crossref PubMed Scopus (30) Google Scholar and the cost–benefit analysis indicates that in absence of hypercalcemia, calcium acetate should remain the treatment of choice for hyperphosphatemia in hemodialysis patients.12.Quinibi W.Y. Hootkins R.E. Mc Dowell L.L. et al.Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (The CARE Study).Kidney Int. 2004; 65: 1912-1926Google Scholar We have demonstrated that both prevalence and progression of CAC are greater in pre-dialysis patients than in subjects with normal renal function.13.Russo D. Palmiero G. De Blasio A.P. et al.Coronary artery calcification in patients with CRF not undergoing dialysis.Am J Kidney Dis. 2004; 44: 1024-1030Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar In addition, although derangement of mineral metabolism does not predict the prevalence of CAC, values of serum phosphorus at the upper limit of normal range are associated with faster progression of CAC.13.Russo D. Palmiero G. De Blasio A.P. et al.Coronary artery calcification in patients with CRF not undergoing dialysis.Am J Kidney Dis. 2004; 44: 1024-1030Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar,14.Russo D. Corrao S. Miranda I. et al.Progression of coronary artery calcification in pre-dialysis patients.Am J Nephrol. 2007; 27: 152-158Crossref PubMed Scopus (79) Google Scholar On the basis of the previous observations and lack of data on phosphate binders and progression of CAC in pre-dialysis patients, we have undertaken this study to assess the efficacy of calcium carbonate and sevelamer in reducing the progression of CAC in pre-dialysis patients. Study design and final number of patients available for analysis are reported in Figure 1. At the start of the study, 90 patients were randomly assigned to one of the following regimens: low-phosphate diet alone (controls; n=30), low-phosphate diet+calcium carbonate (n=30), low-phosphate diet+sevelamer (n=30). Six patients were lost during the follow-up: one was assigned to low-phosphate diet suffered acute myocardial infarction, two assigned to calcium carbonate withdrew their consent, three assigned to sevelamer could not bear the cost of the drug any longer. All dropped-out patients had baseline CAC. Thus, 84 patients completed the study. Baseline demographic and clinical characteristics of patients who completed the study are reported in Table 1. There was no statistically significant difference among the groups apart from higher body mass index and shorter duration of hypertension in patients assigned to sevelamer.Table 1Baseline demographic clinical characteristics of patientsControls (n=29)Calcium carbonate (n=28)Sevelamer (n=27)Gender (M/F)25/423/524/3Age (years)54.4 (13.7)55.2 (12.0)54.4 (12.9)Body mass index (kg/m2)24.8 (2.3)24.5 (2.9)26.1 (4.1)*Traditional risk factor (n)5.3 (1.4)5.3 (1.2)5.6 (1.4)Systolic blood pressure (mm Hg)134.4 (13.9)136.8 (7.6)135.5 (9.7)Diastolic blood pressure (mm Hg)82.2 (5.6)84.8 (5)80.5 (3.7)Mean blood pressure (mm Hg)99.4 (7.9)102 (3.7)98.8 (3.9)Pulse pressure (mm Hg)51.4 (9.7)52.0 (10.2)55.0 (10.7)Duration HTN (months)90 (89)133 (73)*60 (52)Antihypertensive drugs (n)2.1 (0.6)2.3 (0.7)2.5 (1.1)Calcium channel blockers use (%)444845Without CAC (n)555CAC, coronary artery calcification; F, female; HTN, hypertension; M, male.Numbers are mean s.d.*P<0.01 vs other groups. Open table in a new tab CAC, coronary artery calcification; F, female; HTN, hypertension; M, male. Numbers are mean s.d. *P<0.01 vs other groups. Baseline (initial) and end of the study (final) biochemical variables are reported in Table 2. Initial values were not significantly different across the groups. On the contrary, significant changes were observed in some final values. For instance, glomerular filtration rate and serum concentration of calcium, alkaline phosphatase, and fibrinogen were significantly changed in the sevelamer group. Phosphaturia increased in controls. As expected, there was a significant decrease in urinary phosphorus excretion with both binders and particularly with sevelamer. Absolute mean serum concentration of lipids did not change. However, in sevelamer groups, median concentration of total cholesterol decreased by 7% (from 170 to 158 mg/dl), triglycerides by 18% (from 107 to 88 mg/dl), and low-density lipoprotein cholesterol by 11% (from 106 to 94 mg/dl); median values remained unchanged in the other two groups.Table 2Initial and final biochemical variablesControlsCalciumSevelamerVariablesInitialFinalInitialFinalInitialFinalGFR (ml/min)33.4 (20.2)33.6 (25.0)26.2 (8.3)25.9 (5.3)26.3 (15.6)24.1* (14.7)PTH (pg/ml)140.7 (73.2)146.9 (77.4)172.1 (73.8)176.1 (54.8)136.5 (101.7)134.9 (72.7)Serum calcium (mg/dl)9.2 (0.6)9.3 (0.5)9.0 (0.7)9.1 (0.8)9.2 (0.2)9.0* (0.3)Serum phosphorus (mg/dl)3.9 (0.7)3.9 (0.9)4.6 (1.5)4.7 (1.5)4.5 (0.7)4.8 (0.9)Calcium × P product (mg2 × dl2)35.8 (7.0)36.0 (7.8)42.3 (8.0)40.3 (11.8)41.7 (6.9)43.1 (8.4)Alkaline phosphatase (mg/dl)113.7 (62.2)85.1* (25.1)148.0 (83.2)143.0 (93.2)134.2 (67.1)103.4** (47.6)Total serum proteins (mg/dl)7.2 (0.8)7.5 (0.8)6.9 (1.0)7.2 (1.2)7.2 (0.7)7.2 (0.7)Serum albumin (mg/dl)3.9 (0.52)4.2 (0.5)3.8 (0.7)3.9 (0.8)3.9 (0.4)4.2 (0.2)Carbonate (mEq/l)23.4 (3.8)24.3 (3.5)21.6 (5.3)23.2 (4.2)22.3 (3.1)21.2 (2.3)Homocysteine (μmol/l)29.8 (18.7)27.2 (14.6)38.0 (14.5)38.0 (14.5)31.5 (10.5)33.5 (19.7)Fibrinogen (mg/dl)342.6 (124.5)385.5 (99.5)401.3 (96.7)397.3 (85.7)424 (222)332** (57)Total cholesterol (mg/dl)189.0 (36.3)188.6 (38.8)184.9 (32.5)184.0 (23.5)173.0 (50.5)181.3 (53.1)Triglycerides (mg/dl)137.7 (101.8)131.9 (94.4)119.2 (50.3)139.2 (50.3)141.4 (92.3)131.6 (109.7)HDL cholesterol (mg/dl)59.8 (44.1)48.9 (13.1)46.8 (10.2)46.7 (10.2)48.8 (10.7)49.9 (11.8)LDL cholesterol (mg/dl)115.9 (32.1)118.0 (47.5)121.0 (47.4)101.0 (33.2)113.9 (55.1)107.3 (39.1)C-reactive protein (mg/dl)0.98 (2.38)0.34 (0.08)1.1 (2.7)0.33 (0.09)0.50 (0.27)0.73 (0.99)Phosphorus intake (mg/day)682 (480)788 (470)694 (492)658 (478)690 (398)784 (385)Phosphaturia (mg/24 h)367 (389)514* (285)496 (125)413* (126)490 (128)410** (130)GFR, glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PTH, parathyroid hormone.Numbers are mean and s.d.*P<0.05, **P<0.01 vs own initial. Open table in a new tab GFR, glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PTH, parathyroid hormone. Numbers are mean and s.d. *P<0.05, **P<0.01 vs own initial. At the end of the study, there were no statistically significant differences in systolic, diastolic, mean blood pressure, and pulse pressure across the groups. Mean absolute and annualized absolute changes of total calcium score (TCS) are reported in Figure 2 and 3. The final TCS was significantly greater than the initial TCS in controls (369±115 (mean±s.e.) vs 547±175; P<0.001) and in calcium-treated subjects (340±38 vs 473±69; P<0.001); in contrast, the final TCS was not significantly different from the initial TCS among subjects receiving sevelamer (415±153 vs 453±127; NS). Annualized progression of TCS was 205±82 in controls, 178±40 in calcium carbonate patients, and 36±32 in sevelamer patients. No significant between-group change was found in mean absolute and annualized absolute values of TCS.Figure 3Annualized progression of TCS in controls (n=29) and in patients assigned to calcium carbonate (n=28) and sevelamer (n=27). Numbers are mean and s.e.View Large Image Figure ViewerDownload (PPT) Fifteen patients without baseline CAC remained 'not calcified' at the end of the study. In a recent study, we have demonstrated progression of CAC in pre-dialysis patients by an extent nearly similar to that reported in patients on dialysis and in subjects with symptomatic coronary artery disease.14.Russo D. Corrao S. Miranda I. et al.Progression of coronary artery calcification in pre-dialysis patients.Am J Nephrol. 2007; 27: 152-158Crossref PubMed Scopus (79) Google Scholar In addition, our study has shown that higher serum concentration of phosphorus was significantly associated to greater progression of CAC, despite that the majority of patients had normal serum concentration of ion. Finally, fatal and not fatal cardiac events were more frequent in patients whose CAC progressed. These findings motivated the present study, which aimed to evaluate whether the administration of two distinctive phosphate binders, calcium carbonate and sevelamer, could modify the progression of CAC in pre-dialysis patients. Some relevant findings were attained in this study. First, treatment with calcium carbonate in pre-dialysis patients did not enhance the progression of CAC as it has been observed in patients on dialysis. Second, sevelamer reduced progression of CAC in a more consistent manner than calcium carbonate. Third, progression was observed only in patients with CAC, whereas those without baseline CAC remained 'non-calcified' at the end of the study. It is worth noting that high-risk patients were enrolled; in fact, several traditional risk factors were associated with high baseline calcium score. Apart from traditional risk factors, high calcium score is regarded as a strong predictor of cardiovascular events in patients on dialysis.4.Block 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 (639) Google Scholar, 10.Chertow 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 (1269) Google Scholar, 15.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, 16.Raggi 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 (951) Google Scholar Without treatment with phosphate binders CAC progressed more severely. This finding is clinically relevant. A similar rate of progression in non-uremic individuals has been associated with very high risk for myocardial infarction.17.Raggi P. Callister T.Q. Budoff M.J. Shaw L.J. Progression of coronary artery calcium and risk of first myocardial infarction in patients receiving cholesterol lowering therapy.Arterioscler Thromb Vasc Biol. 2004; 24: 1272-1277Crossref PubMed Scopus (248) Google Scholar,18.Raggi P. Cooil B. Shaw L.J. et al.Progression of coronary calcification on serial electron beam tomography scanning is greater in patients with future myocardial infarction.Am J Cardiol. 2003; 92: 827-829Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Therefore, a potential association between progression of CAC and cardiac outcome should be taken into account for pre-dialysis patients. All available studies comparing the effects of sevelamer and calcium-based phosphate binders on progression of calcification have been undertaken in patients on dialysis with deranged mineral metabolism. Thus, the achievement of lower or normal serum concentration of phosphorus, calcium, parathyroid hormone (PTH), and calcium × phosphorus product has been regarded as crucial determinant for slowing down the progression of calcification. In this study, patients without baseline alteration of mineral metabolism were studied. Nevertheless, given that progression of CAC was reduced only in patients treated with phosphorus binders, we can hypothesize that serum phosphorus might have been involved despite that its serum concentration remained within normal range. This hypothesis seems supported by two studies in patients not yet on dialysis. In the first study,8.Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (869) Google Scholar increased mortality risk was not observed among people with lower serum phosphate levels whereas an association between phosphate and mortality risk was found among people with serum phosphate levels in high–normal range. Serum phosphorus of 3.5 mg/dl was associated with a significantly increased risk for death, and mortality risk increased linearly with each subsequent 0.5 mg/dl rise of serum phosphorus level. Vascular calcifications were claimed as the potential determinant of the increased mortality risk. In the second study,9.Tomiyama C. Higa A. Dalboni M.A. et al.The impact of traditional and not-traditional factors on coronary calcification in pre-dialysis patients.Nephrol Dial Transplant. 2006; 21: 2464-2471Crossref PubMed Scopus (103) Google Scholar a significant correlation was found between severe CAC and phosphorus despite that the majority of patients had normal serum concentration of the ion. It is commonly recognized that development and progression of CAC in patients on dialysis is dependent on hyperphosphatemia on the one hand and on calcium ingested as phosphate binder on the other hand. To our knowledge, no clinical studies have evaluated the development and progression of CAC in untreated and treated patients on dialysis with calcium-based phosphate binders. Likewise, no study has been carried out in pre-dialysis patients. In this study, CAC progressed by a minor extent in patients treated with calcium carbonate than in controls. Therefore, in pre-dialysis patients, the progression of CAC should not be unequivocally ascribed to the calcium ingested as phosphate binder as it occurs in patients on dialysis. Otherwise, the progression of CAC should have been greater in patients treated with calcium carbonate than in controls, because a significant progression has been reported in patients on dialysis with doses of elemental calcium as small as 1.1 g/day.10.Chertow 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 (1269) Google Scholar It is likely that exogenous calcium load from phosphate binder may have fewer effects on the calcification process, since the function of renal tubuli is not completely lost in CKD patients. It is worth noting that baseline levels of serum phosphorus and TCS were higher (although not significantly different) in patients assigned to sevelamer than in controls; nonetheless, sevelamer patients did not experience significant progression of CAC and three of them had regression of the process. It has been reported that progression is more severe when baseline plaque burden is greater.10.Chertow 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 (1269) Google Scholar The least severe progression of CAC with sevelamer is in keeping with that found by others in prevalent and incident patients on dialysis.2.Block G.A. Spiegel D.M. Ehrlich J. et al.Effect of sevelamer and calcium on coronary artery calcifications in patients new to haemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar,10.Chertow 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 (1269) Google Scholar Calcium scores were, in fact, significantly lower in patients treated with sevelamer compared to patients treated with calcium-based phosphate binders, despite a similar control of mineral metabolism. Fewer episodes of hypercalcemia and favorable effects on lipid profile were potential determinants of the greater efficacy of sevelamer in slowing down the progression of coronary and cardiac valve calcification.2.Block G.A. Spiegel D.M. Ehrlich J. et al.Effect of sevelamer and calcium on coronary artery calcifications in patients new to haemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar,10.Chertow 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 (1269) Google Scholar In fact, hypercalcemic episodes were less frequent in sevelamer subjects even if an increase in serum calcium was observed.10.Chertow 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 (1269) Google Scholar,19.Chertow G.M. Slowing the progression of vascular calcification in hemodialysis.J Am Soc Nephrol. 2003; 14: S310-S314Crossref PubMed Google Scholar On the contrary, in this study, a small but significant decrease in final serum calcium (9.2±0.2 vs 9.0±0.2 mg/dl; P<0.05) was observed in patients assigned to sevelamer; this decrease was, in our opinion, of minimal clinical significance. In the same way, final calcium was not increased in patients assigned to calcium carbonate. Both the findings may be likely due to the fact that in our patients the renal function was not completely lost and that they were not treated with vitamin D. Sevelamer is the unique phosphate binder that consistently decreases low-density lipoprotein cholesterol and increases high-density lipoprotein cholesterol in patients on dialysis.2.Block G.A. Spiegel D.M. Ehrlich J. et al.Effect of sevelamer and calcium on coronary artery calcifications in patients new to haemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar, 10.Chertow 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 (1269) Google Scholar, 19.Chertow G.M. Slowing the progression of vascular calcification in hemodialysis.J Am Soc Nephrol. 2003; 14: S310-S314Crossref PubMed Google Scholar We cannot determine whether the greater reduction of progression was due to the effect of sevelamer on lipids. In fact, no significant differences were found in the markers of lipid metabolism at the end of the study. Nevertheless, sevelamer decreased the absolute concentration of cholesterol and, by a greater extent, the median value of low-density lipoprotein cholesterol; likewise, it increased high-density lipoprotein cholesterol. More marked effects on lipid profile observed in patients on dialysis may be due to larger prescribed doses of sevelamer.2.Block G.A. Spiegel D.M. Ehrlich J. et al.Effect of sevelamer and calcium on coronary artery calcifications in patients new to haemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar,10.Chertow 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 (1269) Google Scholar Markers of inflammation have been associated with mortality and coronary calcification in patients on dialysis because they may activate arterial calcium deposition.20.Yeun J.Y. Levine R.A. Mantadilok V. Kaysen G.A. C-reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients.Am J Kidney Dis. 2000; 35: 469-476Abstract Full Text Full Text PDF PubMed Scopus (765) Google Scholar, 21.Goldsmith D. Ritz E. Covic A. Vascular calcification: a stiff challenge for the nephrologists.Kidney Int. 2004; 66: 1315-1333Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 22.Krasniak A. Drozdz M. Pasowicz M. et al.Factors involved in vascular calcification and atherosclerosis in maintenance haemodialysis patients.Nephrol Dial Transplant. 2007; 22: 515-521Crossref PubMed Scopus (104) Google Scholar Distinctive effects of sevelamer on inflammation are regarded as capable of slowing down the progression of CAC.10.Chertow 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 (1269) Google Scholar,19.Chertow G.M. Slowing the progression of vascular calcification in hemodialysis.J Am Soc Nephrol. 2003; 14: S310-S314Crossref PubMed Google Scholar In this study, patients assigned to sevelamer showed no changes in the concentration of C-reactive protein and homocysteine but showed a significant decrease in fibrinogen. In a previous study, the markers of inflammation were not predictive factors of either prevalence or progression of CAC in pre-dialysis patients.13.Russo D. Palmiero G. De Blasio A.P. et al.Coronary artery calcification in patients with CRF not undergoing dialysis.Am J Kidney Dis. 2004; 44: 1024-1030Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar,14.Russo D. Corrao S. Miranda I. et al.Progression of coronary artery calcification in pre-dialysis patients.Am J Nephrol. 2007; 27: 152-158Crossref PubMed Scopus (79) Google Scholar Clinical studies have shown that sevelamer reduces plasma concentration of bicarbonate, worsening metabolic acidosis in patients on dialysis.10.Chertow 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 (1269) Google Scholar, 12.Quinibi W.Y. Hootkins R.E. Mc Dowell L.L. et al.Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (The CARE Study).Kidney Int. 2004; 65: 1912-1926Google Scholar, 23.Gallieni M. Cozzolino M. Brancaccio D. Transient decrease of serum bicarbonate levels with sevelamer hydrochloride as the phosphate binder (Letter).Kidney Int. 2000; 57: 1776-1777Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar In this study, the reduction of carbonate in patients assigned to sevelamer was negligible, likely due to, on the one hand, to a small amount of the binder, and on the other hand, to still preserved renal function. However, acid–base balance should be closely monitored during treatment with higher doses of sevelamer. The duration of hypertension was shorter in patients treated with sevelamer than in other groups; however, this difference had, in our opinion, no relevant implication as the duration of hypertension was not a predictive factor of progression in previous larger studies in pre-dialysis patients.13.Russo D. Palmiero G. De Blasio A.P. et al.Coronary artery calcification in patients with CRF not undergoing dialysis.Am J Kidney Dis. 2004; 44: 1024-1030Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar,14.Russo D. Corrao S. Miranda I. et al.Progression of coronary artery calcification in pre-dialysis patients.Am J Nephrol. 2007; 27: 152-158Crossref PubMed Scopus (79) Google Scholar A further relevant finding of this study is that patients without baseline CAC remained free from CAC at the end of the study despite similar 'uremic' environment and exogenous promoting factors. Persisting 'non-calcified' patients were, in fact, found in all groups. This finding might suggest that use of phosphate binders is not required in pre-dialysis patients without CAC, the progression being a natural process that occurs only in the presence of CAC. It should be of clinical relevance to identify demographic, biochemical, and/or genetic characteristics that protect pre-dialysis patients against development of CAC. The 'non-calcified' status is, however, not permanent; in fact, CAC has not been found in 47% of pre-dialysis patients, in 36% of those entering dialysis treatment, and in 11 and 7% of those on hemodialysis for an average of 39 and 65 months, respectively.2.Block G.A. Spiegel D.M. Ehrlich J. et al.Effect of sevelamer and calcium on coronary artery calcifications in patients new to haemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar, 3.Blacher J. Guerin A.P. Pannier B. et al.Arterial calcifications, arterial stiffness, and cardiovascular risk in end stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Scopus (1180) Google Scholar, 13.Russo D. Palmiero G. De Blasio A.P. et al.Coronary artery calcification in patients with CRF not undergoing dialysis.Am J Kidney Dis. 2004; 44: 1024-1030Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar, 16.Raggi 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 (951) Google Scholar These data may indicate that distinctive pathogenetic factors are involved in the process leading to development and progression of CAC among pre-dialysis patients and those on dialysis. Main limitation of this study is the small number of patients. This was mainly due to the fact that prescription of sevelamer is authorized only for patients on dialysis. The dosing of binders was not adjusted to reach a targeted serum concentration of phosphorus. Nonetheless, calcium carbonate and sevelamer were clearly effective in reducing CAC progression. Owing to small cohort of patients, on the one hand, and to a large variation in the values of TCS, on the other hand, no significant between-group change was found. No significant between-group difference has been reported in a recent larger study evaluating the effects of sevelamer on progression of CAC in incident patients on dialysis.2.Block G.A. Spiegel D.M. Ehrlich J. et al.Effect of sevelamer and calcium on coronary artery calcifications in patients new to haemodialysis.Kidney Int. 2005; 68: 1815-1824Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar The exclusion of patients with diabetes might have made the study not representative of 'the real-life'. But patients with diabetes would have influenced the results since diabetes 'per se' accelerates the progression of CAC. Progression of CAC is severe in pre-dialysis patients not treated with phosphate binders. Treatment with calcium carbonate appears to be safe in pre-dialysis patients given that the binder does not worsen the progression of CAC as it does in patients on dialysis. The progression of CAC may be more markedly hampered by sevelamer. Nevertheless, the relatively small number of patients does not allow drawing a definitive conclusion on both issues. Larger prospective study should be undertaken in pre-dialysis patients to confirm these results. In this case, the use of sevelamer should be not restricted to patients on dialysis. Finally, it would be clinically relevant to identify demographic, biochemical, and/or genetic characteristics that protect some pre-dialysis patients against the development of CAC.
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