Control of hyperphosphatemia beyond phosphate
2007; Elsevier BV; Volume: 71; Issue: 5 Linguagem: Inglês
10.1038/sj.ki.5002138
ISSN1523-1755
Autores Tópico(s)Magnesium in Health and Disease
ResumoHyperphosphatemia is a prevalent condition in the dialysis population and is associated with bad outcome. Block et al. present data from a post hoc analysis indicating that sevelamer, a noncalcium-containing phosphate binder, may confer a survival benefit in incident hyperphosphatemic hemodialysis patients. This is the first intervention study in the field of mineral metabolism showing a beneficial effect on a hard end point. Hyperphosphatemia is a prevalent condition in the dialysis population and is associated with bad outcome. Block et al. present data from a post hoc analysis indicating that sevelamer, a noncalcium-containing phosphate binder, may confer a survival benefit in incident hyperphosphatemic hemodialysis patients. This is the first intervention study in the field of mineral metabolism showing a beneficial effect on a hard end point. Patients with chronic kidney disease (CKD) are at increased risk for cardiovascular morbidity and mortality.1.Foley R.N. Parfrey P.S. Sarnak M.J. Clinical epidemiology of cardiovascular disease in chronic renal disease.Am J Kidney Dis. 1998; 32: S112-S119Abstract Full Text PDF PubMed Scopus (2806) Google Scholar At present, the data support excessive atherosclerosis in CKD, and atherosclerotic lesions in CKD patients are more likely to be severely calcified than those in the general population.2.Moe S.M. Chen N.X. Pathophysiology of vascular calcification in chronic kidney disease.Circ Res. 2004; 95: 560-567Crossref PubMed Scopus (392) Google Scholar Furthermore, there is increasing stiffening of larger elastic arteries in CKD, with increased calcification.3.Guerin 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 (863) Google Scholar At least in non-uremic individuals, both the extent and the progression of cardiovascular calcification have been associated with a substantial increase in the risk of cardiovascular morbidity and mortality.4.Raggi P. Role of electron-beam computed tomography and nuclear stress testing in cardiovascular risk assessment.Am J Cardiol. 2005; 96: 20J-27JAbstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar This association is much less substantiated in the dialysis population. Baseline data from a study by Raggi et al.5.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 demonstrate that previous myocardial infarction, angina, and known coronary artery disease are all common in dialysis patients with higher calcification scores. In a 5- to 6-year follow-up study, Blacher et al.6.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 (1181) Google Scholar noted a strong association between the presence and severity of vascular calcifications and all-cause mortality in CKD stage 5D patients.6.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 (1181) Google Scholar Various noninvasive methods have been developed to detect and measure vascular and valvular calcification. The two most valuable methods are electron-beam computed tomography and multislice/helical computed tomography.4.Raggi P. Role of electron-beam computed tomography and nuclear stress testing in cardiovascular risk assessment.Am J Cardiol. 2005; 96: 20J-27JAbstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar,7.Floege J. Ketteler M. Vascular calcification in patients with end-stage renal disease.Nephrol Dial Transplant. 2004; 19: V59-V66Crossref PubMed Scopus (159) Google Scholar The availability of both techniques has triggered the increased awareness of cardiovascular calcifications in CKD. Important shortcomings of both computed tomography-based imaging methods are the lack of differentiation between calcifications of the vascular intima and media and that they cannot be used in patients with arrhythmia. Additional disadvantages include cost and radiation exposure.7.Floege J. Ketteler M. Vascular calcification in patients with end-stage renal disease.Nephrol Dial Transplant. 2004; 19: V59-V66Crossref PubMed Scopus (159) Google Scholar Bellasi et al.8.Bellasi A. Ferramosca E. Muntner P. et al.Correlation of simple imaging tests and coronary artery calcium measured by computed tomography in hemodialysis patients.Kidney Int. 2006; 70: 1623-1628Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar recently demonstrated that abdominal aorta calcification on plain X-ray films may accurately predict significant coronary calcification in the dialysis population and may thus represent a valid alternative in clinical practice.8.Bellasi A. Ferramosca E. Muntner P. et al.Correlation of simple imaging tests and coronary artery calcium measured by computed tomography in hemodialysis patients.Kidney Int. 2006; 70: 1623-1628Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar The pathogenesis of vascular calcification in CKD is not well understood and, like that in the general population, is almost certainly multifactorial.2.Moe S.M. Chen N.X. Pathophysiology of vascular calcification in chronic kidney disease.Circ Res. 2004; 95: 560-567Crossref PubMed Scopus (392) Google Scholar, 9.Shanahan C.M. Vascular calcification: a matter of damage limitation.Nephrol Dial Transplant. 2006; 21: 1166-1169Crossref PubMed Scopus (22) Google Scholar, 10.Goldsmith D. Ritz E. Covic A. Vascular calcification: a stiff challenge for the nephrologist. Does preventing bone disease cause arterial disease.Kidney Int. 2004; 66: 1315-1333Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar In CKD patients, several studies have found associations of both traditional and uremic-specific risk factors with calcification. However, these associations do not prove cause and effect, and prospective studies in humans or, at a minimum, experimental data are needed to definitely confirm the role of these factors. Although vascular calcification has traditionally been considered to be a physicochemical 'passive' precipitation in the tunica media of vessel walls, there are abundant animal and clinical data supporting the notion that more important than this passive process is an active ordered and regulated process. As has been elegantly demonstrated by Jono et al., high phosphate levels may change the phenotype of human aortic vascular smooth muscle cells in vitro from contractile to secretory in a fashion dependent on normal sodium–phosphate cotransport leading to upregulation of many genes associated with matrix mineralization.11.Jono S. McKee M.D. Murry C.E. et al.Phosphate regulation of vascular smooth muscle cell calcification.Circ Res. 2000; 87: E10-E17Crossref PubMed Google Scholar The recognition that hyperphosphatemia might be the primary culprit of accelerated calcification in CKD has led to a renewed interest in optimizing the treatment of hyperphosphatemia. Besides dietary restrictions, calcium-containing phosphate binders have been the mainstay to control hyperphosphatemia for more than two decades. In recent years, non-calcium-containing phosphate binders have become available, such as sevelamer.12.Burke S.K. Dillon M.A. Hemken D.E. et al.Meta-analysis of the effect of sevelamer on phosphorus, calcium, PTH, and serum lipids in dialysis patients.Adv Ren Replace Ther. 2003; 10: 133-145Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar As far as the control of hyperphosphatemia in dialysis patients is concerned, several studies apart from the Calcium Acetate Renagel Evaluation (CARE) trial13.Qunibi W.Y. Hootkins R.E. McDowell L.L. et al.Treatment of hyperphosphatemia in hemodialysis patients: the Calcium Acetate Renagel Evaluation (CARE Study).Kidney Int. 2004; 65: 1914-1926Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar have demonstrated comparable efficacy of sevelamer to calcium acetate.12.Burke S.K. Dillon M.A. Hemken D.E. et al.Meta-analysis of the effect of sevelamer on phosphorus, calcium, PTH, and serum lipids in dialysis patients.Adv Ren Replace Ther. 2003; 10: 133-145Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 14.Bleyer A.J. Burke S.K. Dillon M. et al.A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients.Am J Kidney Dis. 1999; 33: 694-701Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 15.Pieper A.K. Haffner D. Hoppe B. et al.A randomized crossover trial comparing sevelamer with calcium acetate in children with CKD.Am J Kidney Dis. 2006; 47: 625-635Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Despite an equal serum phosphorus control, sevelamer has been demonstrated to attenuate the progression of coronary calcification as compared with calcium acetate in both prevalent (Treat To Goal trial)16.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 and incident (Renagel in New Dialysis trial)17.Block 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 (692) Google Scholar hemodialysis patients. Whether cardiovascular calcifications are an independent predictor of mortality in dialysis patients and whether interventions that reduce cardiovascular calcifications lead to an improvement in mortality remained open questions so far. To answer these questions, Block et al.18.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 (640) Google Scholar (this issue) performed a post hoc survival analysis of patients included in the aforementioned RIND trial. This study provides evidence that, as in non-uremics, the presence of coronary artery calcification in patients with CKD stage 5D is associated with a worse outcome. Even more fascinating is the observation of a significant survival benefit in patients assigned to treatment with sevelamer as compared with calcium acetate. This observation contrasts with the findings of the Dialysis Clinical Outcomes Revisited (DCOR) study, which failed to show a significant difference in mortality.19.Suki W. Zabaneh R. Cangiano J. et al.A prospective, randomized trial assessing the impact on outcomes of sevelamer in dialysis patients. The DCOR trial.Nephrol Dial Transplant. 2006; 21: 145-146PubMed Google Scholar The apparent contradiction between the present study by Block et al.18.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 (640) Google Scholar and the DCOR trial may be explained at least partly by differences in case mix (for example, incident versus prevalent hemodialysis patients) and duration of follow-up (44 versus 20 months). At present, however, it is too early to generally advocate sevelamer as a first-line phosphate binder. The design of the study, a post hoc analysis with its inherent limitations, the small size and the specificities of the study cohort (young age, high prevalence of diabetes, incident patients) necessitate additional investigations for confirmation. Besides efficacy, the budgetary impact of a medication has also to be considered, as health-care resources are under continuous pressure. Although specific data on this point are lacking, it is unlikely that at present the reduction of expensive cardiovascular complications by sevelamer will outweigh its overall extra cost.20.Manns B. Stevens L. Miskulin D. et al.A systematic review of sevelamer in ESRD and an analysis of its potential economic impact in Canada and the United States.Kidney Int. 2004; 66: 1239-1247Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar It is therefore of utmost importance to identify subgroups that will benefit most from treatment with sevelamer. The parent RIND study17.Block 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 (692) Google Scholar as well as this post hoc analysis18.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 (640) Google Scholar suggests that treatment with sevelamer will be especially of benefit in incident calcified hemodialysis patients. Undoubtedly, the study by Block et al.18.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 (640) Google Scholar will fuel the ongoing controversy on the potential role of calcium loading resulting from the use of calcium-containing phosphate binder in the pathogenesis of cardiovascular calcification.21.Coladonato J.A. Szczech L.A. Friedman E.A. Owen Jr., W.F. Does calcium kill ESRD patients—the skeptic's perspective.Nephrol Dial Transplant. 2002; 17: 229-232Crossref PubMed Scopus (26) Google Scholar, 22.Canavese C. Bergamo D. Dib H. et al.Calcium on trial: beyond a reasonable doubt.Kidney Int. 2003; 63: 381-382Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 23.Qunibi W.Y. Nolan C.A. Ayus J.C. Cardiovascular calcification in patients with end-stage renal disease: a century-old phenomenon.Kidney Int Suppl. 2002; : 73-80Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar This controversy was initiated by observations made by two independent research groups in the late 1990s.3.Guerin 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 (863) Google Scholar,24.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 Both observed an independent association between the extent of vascular calcification and the prescribed daily dose of calcium-containing phosphate binder. Opposite to the Treat To Goal study,16.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 RIND study17.Block 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 (692) Google Scholar provides detailed information on dialysate calcium content, vitamin D usage, and nocturnal calcium supplements. Calcium dialysate was fixed in all patients at 1.25 mmol, only two patients allocated to sevelamer were receiving nocturnal calcium supplements, and vitamin D usage was similar in both groups. It is therefore most likely that the higher serum calcium levels and higher prevalence of episodes of hypercalcemia in the calcium acetate group are due to the extra calcium loading related to phosphate binder usage. The pathophysiological role of elevated serum calcium levels has been made evident by recent in vitro data supporting a model whereby elevations of calcium, in addition to elevating the Ca × PO4 product, enhance and accelerate human smooth muscle cell mineralization via increased sodium-dependent phosphate cotransporter level.25.Reynolds J.L. Joannides A.J. Skepper J.N. et al.Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD.J Am Soc Nephrol. 2004; 15: 2857-2867Crossref PubMed Scopus (692) Google Scholar,26.Yang H. Curinga G. Giachelli C.M. Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro.Kidney Int. 2004; 66: 2293-2299Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar Neither the Treat to Goal study16.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 nor the RIND study,17.Block 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 (692) Google Scholar including the current post hoc analysis,18.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 (640) Google Scholar can inform us solely about the role of calcium ingestion in the pathogenesis of cardiovascular calcification. This is because the comparator drugs (sevelamer and calcium acetate/carbonate) differed not only in their 'calcium loading' but also in their lipid-lowering capacities. Sevelamer, overall, causes a 35% reduction in low-density lipoprotein cholesterol levels.16.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,17.Block 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 (692) Google Scholar In the parent study,17.Block 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 (692) Google Scholar the mean cholesterol level significantly correlated with change in total coronary artery calcification score. It should be stressed, however, that not all studies have suggested an important influence of low-density lipoprotein cholesterol levels on the progression of coronary artery calcification. For example, Schmermund et al.27.Schmermund 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 (202) Google Scholar failed to observe a relationship between on-treatment low-density lipoprotein cholesterol levels and the progression of calcified coronary atherosclerosis in non-uremics. Moreover, the results of the 4D study, comparing the effects of atorvastatin versus placebo on cardiovascular outcomes in 1255 type 2 diabetic patients on maintenance hemodialysis, were essentially negative.28.Wanner 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 (2047) Google Scholar Besides its well-known lipid-lowering effect, sevelamer has been shown to reduce inflammation, serum uric acid levels, and oxidative stress, to improve bone health, and to increase serum fetuin-A levels (Figure 1).29.Ferramosca E. Burke S. Chasan-Taber S. et al.Potential antiatherogenic and anti-inflammatory properties of sevelamer in maintenance hemodialysis patients.Am Heart J. 2005; 149: 820-825Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 30.Garg J.P. Chasan-Taber S. Blair A. et al.Effects of sevelamer and calcium-based phosphate binders on uric acid concentrations in patients undergoing hemodialysis: a randomized clinical trial.Arthritis Rheum. 2005; 52: 290-295Crossref PubMed Scopus (99) Google Scholar, 31.Ferreira A. Frazao J.M. Faugere M.C. et al.Effects of sevelamer and calcium carbonate on bone mineralisation and turnover in chronic maintenance haemodialysis patients.Nephrol Dial Transplant. 2006; 21: 293Google Scholar Any or all of these alternative mechanisms may contribute to the abolition of progression of vascular calcification and/or the survival benefit. Additional studies are required to explore the impact of these individual mechanisms. The CARE-2 trial (ClinicalTrials.gov Identifier: NCT00211939) will test the hypothesis that if low-density lipoprotein levels are lowered to a similar level in calcium acetate- and sevelamer-treated patients, there will be no difference in the progression of cardiovascular calcification. Inclusion in this study has been completed, and results may be expected in the near future. In addition, it is important to compare other non-calcium phosphate binders (such as lanthanum carbonate or ferric chloride) with calcium acetate in the same way. In conclusion, there is convincing evidence that sevelamer attenuates the progression of cardiovascular calcification, a condition with bad prognostic implications for outcome. Block et al.18.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 (640) Google Scholar provide data supporting this line of reasoning. However, considering the limitations of the study and the drug-related extra cost, additional well-designed and adequately powered outcome studies are required before sevelamer can be advocated as the first option in the treatment of hyperphosphatemia in all dialysis patients. The further elucidation of the underlying pathophysiological mechanisms, though a challenge for the researcher, is of less relevance for the clinician. The author thanks K. Claes, D. Kuypers, and Y. Vanrenterghem for their useful comments and advice.
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