Portal de Periódicos da CAPES

Mineral Metabolism and Mortality in Patients with Chronic Kidney Disease

2007; Elsevier BV; Volume: 14; Issue: 1 Linguagem: Inglês

10.1053/j.ackd.2006.10.003

1548-5609

Eric W. Young,

Electrolyte and hormonal disorders

Chronic kidney disease is associated with profound alterations in mineral metabolism. A growing body of evidence, based largely on observational studies, indicates that patient mortality is associated with altered mineral metabolism. Evidence is reviewed concerning the association between mortality and high concentrations of serum phosphorus, calcium, calcium-phosphate product, and parathyroid hormone. In addition, mortality may be independently associated with dialysate calcium concentration, type of phosphate binder therapy, and use of vitamin D analogs. Practices related to management of altered mineral metabolism may prove to be a promising means of improving outcomes for patients with chronic kidney disease. Chronic kidney disease is associated with profound alterations in mineral metabolism. A growing body of evidence, based largely on observational studies, indicates that patient mortality is associated with altered mineral metabolism. Evidence is reviewed concerning the association between mortality and high concentrations of serum phosphorus, calcium, calcium-phosphate product, and parathyroid hormone. In addition, mortality may be independently associated with dialysate calcium concentration, type of phosphate binder therapy, and use of vitamin D analogs. Practices related to management of altered mineral metabolism may prove to be a promising means of improving outcomes for patients with chronic kidney disease. Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) exhibit well-known alterations in mineral metabolism.1Martin K.J. Olgaard K. Coburn J.W. et al.Diagnosis, assessment, and treatment of bone turnover abnormalities in renal osteodystrophy.Am J Kidney Dis. 2004; 43: 558-565Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar Although incompletely understood, these abnormalities are largely attributable to diminished renal excretory (phosphorus) and endocrine (calcitriol) functions. The resultant perturbations of intricate mineral homeostasis contribute to metabolic bone disease2Ho L.T. Sprague S.M. Renal osteodystrophy in chronic renal failure.Semin Nephrol. 2002; 22: 488-493Abstract Full Text PDF PubMed Scopus (42) Google Scholar and related extraskeletal manifestations.3Bardin T. Musculoskeletal manifestations of chronic renal failure.Curr Opin Rheumatol. 2003; 15: 48-54Crossref PubMed Scopus (64) Google Scholar More recently, a growing number of studies demonstrate that altered mineral metabolism is associated with mortality risk. This emerging knowledge carries several implications. Mortality information must be incorporated into clinical-guideline development, recognizing that mineral metabolism is no longer within the exclusive domain of bone health. The link with mortality provides new impetus to efforts to manage this difficult clinical problem. Efforts should be expended to understand the mechanistic link between mineral metabolism and mortality. This paper summarizes the described mortality associations with the major clinical markers of mineral metabolism: serum phosphorus, serum calcium, calcium-phosphorus product, and parathyroid hormone. Mineral metabolism is managed with a variety of therapeutic tools. The potentially independent association between mortality and mineral-treatment practices is also briefly reviewed. Several epidemiologic studies have found an association between mortality and serum-phosphorus concentrations above the “normal” range in patients with ESRD4Block G.A. Hulbert-Shearon T.E. Levin N.W. et al.Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: A national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2130) Google Scholar, 5Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1531) Google Scholar, 6Marco M.P. Craver L. Betriu A. et al.Higher impact of mineral metabolism on cardiovascular mortality in a European hemodialysis population.Kidney Int. 2003; 85: S111-S114Crossref Scopus (109) Google Scholar, 7Block 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 (2236) Google Scholar, 8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar, 9Slinin Y. Foley R.N. Collins A.J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: The USRDS waves 1, 3, and 4 study.J Am Soc Nephrol. 2005; 16: 1788-1793Crossref PubMed Scopus (368) Google Scholar, 10Stevens L.A. Djurdjev 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 (316) Google Scholar, 11Melamed M.L. Eustace J.A. Plantinga L. et al.Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: A longitudinal study.Kidney Int. 2006; 70: 351-357Crossref PubMed Scopus (305) Google Scholar and CKD.12Kestenbaum 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 (963) Google Scholar, 13Menon V. Greene T. Pereira A.A. et al.Relationship of phosphorus and calcium-phosphorus product with mortality in CKD.Am J Kidney Dis. 2005; 46: 455-463Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar These studies have helped expand the focus of altered mineral metabolism in kidney disease away from musculoskeletal health exclusively. The international Dialysis Outcomes and Practice Patterns Study (DOPPS) found that the association between mortality and phosphorus was consistent across seven countries,8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar notwithstanding claims of a steeper association in Europe.6Marco M.P. Craver L. Betriu A. et al.Higher impact of mineral metabolism on cardiovascular mortality in a European hemodialysis population.Kidney Int. 2003; 85: S111-S114Crossref Scopus (109) Google ScholarFigure 1 displays the association between mortality and serum phosphorus from the DOPPS study. The occasional small, negative study6Marco M.P. Craver L. Betriu A. et al.Higher impact of mineral metabolism on cardiovascular mortality in a European hemodialysis population.Kidney Int. 2003; 85: S111-S114Crossref Scopus (109) Google Scholar should serve as a reminder of the aversion to publication of negative findings on the part of both investigators and journals. However, on balance, the finding seems robust and reproducible in multiple large studies. Epidemiologic associations alone do not establish causality. The observed association between mortality and serum phosphorous (or other baseline variables) could also be explained by confounding variables that are associated with the measured variable. For example, patients with a high phosphorus concentration may also tend to have higher comorbidity or lower compliance behavior than do patients with normal phosphorus levels. The association with mortality could be causally related to comorbidity or compliance rather than to serum phosphorus. Although this possibility is a serious concern, several factors suggest that the association is true and causal. First, the result has now been replicated in several large studies based on different populations, study designs, and investigators. Also, each of these studies used multivariate-regression techniques to adjust for potential confounding variables such as age, sex, race, comorbid conditions, other laboratory values, and dialysis dose. Multivariate approaches allow exploration of specific associations with phosphorus, while in statistical terms, holding constant other mineral metabolism variables such as calcium and PTH. Finally, the epidemiologic data are consistent with other observational and experimental data that suggest plausible biologic mechanisms. At this time, a causal link between serum-phosphorus concentration and mortality of ESRD and CKD patients seems likely. As noted, mortality risk increases at serum-phosphorus concentrations above the normal range established for patients without kidney disease. Delineation of the concentration associated with increased risk is important for clinical practice and guideline development. Ascertainment of the risk threshold value is highly dependent on study methodology. Precise estimation of the threshold concentration depends on two conflicting study attributes: the width (range) of groups defined by serum-phosphate concentration for categorical analysis and the sample size of each category. Currently available studies found a significant risk elevation at serum-phosphorus concentrations of 3.5 to 4.0 mg/dL (CKD),12Kestenbaum 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 (963) Google Scholar 5.0 to 5.5 mg/dL,7Block 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 (2236) Google Scholar 6.0 to 7.0 mg/dL,10Stevens L.A. Djurdjev 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 (316) Google Scholar greater than 6.0 mg/dL,11Melamed M.L. Eustace J.A. Plantinga L. et al.Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: A longitudinal study.Kidney Int. 2006; 70: 351-357Crossref PubMed Scopus (305) Google Scholar 6.4 to 7.5 mg/dL,9Slinin Y. Foley R.N. Collins A.J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: The USRDS waves 1, 3, and 4 study.J Am Soc Nephrol. 2005; 16: 1788-1793Crossref PubMed Scopus (368) Google Scholar 6.5 to 7.0 mg/dL,8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar and greater than 6.5 mg/dL.4Block G.A. Hulbert-Shearon T.E. Levin N.W. et al.Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: A national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2130) Google Scholar, 5Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1531) Google Scholar Studies often reveal a mortality trend at serum-phosphorus concentrations below those that reach statistical significance. Variability in the threshold phosphorus concentration across studies is probably attributable to sample size and adjustment differences. Some element of increased risk seems likely associated with even modest elevations of the serum-phosphorus concentration. Current guidelines that recommend a serum-phosphorus concentration below 5.5 mg/dL seem defensible in terms of bone health and survival. The magnitude of the increased mortality risk is difficult to summarize across studies because of differences in group and reference definitions and potential nonlinearity of the effect. When analyzed as a continuous variable (which minimizes the apparent impact at higher phosphorus concentrations), a 1 mg/dL increment in the serum-phosphorus concentration was associated with 4%,8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar 6%,4Block G.A. Hulbert-Shearon T.E. Levin N.W. et al.Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: A national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2130) Google Scholar and 9%5Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1531) Google Scholar higher mortality risk. Categorical analyses generally yield higher risk estimates, as shown by selected illustrative examples:10% higher risk at phosphorus concentrations of 6.4 to 7.5 mg/dL9Slinin Y. Foley R.N. Collins A.J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: The USRDS waves 1, 3, and 4 study.J Am Soc Nephrol. 2005; 16: 1788-1793Crossref PubMed Scopus (368) Google Scholar18% higher risk at phosphorus concentration of 6.6 to 7.8 mg/dL4Block G.A. Hulbert-Shearon T.E. Levin N.W. et al.Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: A national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2130) Google Scholar25% higher risk at phosphorus concentrations of 6.0 to 7.0 mg/dL7Block 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 (2236) Google Scholar28% higher risk at phosphorus concentrations of 6.5 to 7.0 mg/dL8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar53% higher risk at phosphorus concentrations of 6.0 to 7.0 mg/dL10Stevens L.A. Djurdjev 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 (316) Google Scholar54% higher risk at phosphorus concentrations greater than 6.0 mg/dL11Melamed M.L. Eustace J.A. Plantinga L. et al.Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: A longitudinal study.Kidney Int. 2006; 70: 351-357Crossref PubMed Scopus (305) Google Scholar 83% higher risk in CKD patients with P concentrations of 4.5 to 4.9 mg/dL.12Kestenbaum 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 (963) Google Scholar Variability in risk estimates across studies probably represents measurement error and different degrees of adjustment. Block et al7Block 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 (2236) Google Scholar estimated the population-attributable risk at 17.5% for disorders of mineral metabolism, largely because of hyperphosphatemia. Port et al14Port F.K. Pisoni R.L. Bragg-Gresham J.L. et al.DOPPS estimates of patient life years attributable to modifiable hemodialysis practices in the United States.Blood Purif. 2004; 22: 175-180Crossref PubMed Scopus (93) Google Scholar estimated that correction of hyperphosphatemia could save 33,793 patient life-years in the United States over a 5-year period. On balance, serum phosphorus potentially accounts for an important portion of the excess mortality of patients with ESRD and CKD. As noted, all-cause mortality is associated with higher concentrations of serum phosphorus. Several studies found an even stronger association between cardiovascular mortality (and or morbidity) and serum phosphorus (Fig 1), which gives credence to a vascular mechanism of action.5Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1531) Google Scholar, 8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar, 9Slinin Y. Foley R.N. Collins A.J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: The USRDS waves 1, 3, and 4 study.J Am Soc Nephrol. 2005; 16: 1788-1793Crossref PubMed Scopus (368) Google Scholar An emerging body of evidence suggests a link between mineral metabolism and disease pathways such as immune function, infection, and neoplastic potential.15Peterlik M. Cross H.S. Vitamin D and calcium deficits predispose for multiple chronic diseases.Eur J Clin Invest. 2005; 35: 290-304Crossref PubMed Scopus (287) Google Scholar, 16Nagpal S. Na S. Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands.Endocr Rev. 2005; 26: 662-687Crossref PubMed Scopus (790) Google Scholar, 17Yee Y.K. Chintalacharuvu S.R. Lu J. et al.Vitamin D receptor modulators for inflammation and cancer.Mini Rev Med Chem. 2005; 5: 761-778Crossref PubMed Scopus (71) Google Scholar However, a dominant vascular etiology seems most compelling at this time.18Reslerova M. Moe S.M. Vascular calcification in dialysis patients: Pathogenesis and consequences.Am J Kidney Dis. 2003; 41: S96-S99Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar In addition to the robust association with high serum phosphorus, several studies found that mortality is also associated with low serum concentration of phosphorus below the usual “normal” range. In various studies, mortality risk rises at phosphorus concentrations below approximately 3 mg/dL.7Block 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 (2236) Google Scholar, 8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar The increase in mortality associated with low serum-phosphorus concentration is most commonly ascribed to malnutrition. However, the relation remains, even after adjustment for putative nutritional indicators such as serum-albumin concentration and body mass index. The increased mortality risk at low phosphorus concentrations may be explained by case-mix adjustment.7Block 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 (2236) Google Scholar Mortality risk at low phosphorus concentrations is not selectively skewed toward cardiovascular causes. At this time, the possibility of a direct mortality risk from low phosphorus has not been excluded. In addition to mortality, other important clinical outcomes are also associated with the serum-phosphorus concentration, including all-cause hospitalization,7Block 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 (2236) Google Scholar cardiovascular hospitalization,7Block 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 (2236) Google Scholar fracture-related hospitalization,7Block 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 (2236) Google Scholar and parathyroidectomy.8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar Several epidemiologic studies also report an association between mortality risk and higher concentrations of serum calcium, independent of the serum-phosphorus concentration (Figure 2 shows DOPPS results).7Block 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 (2236) Google Scholar, 8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar, 9Slinin Y. Foley R.N. Collins A.J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: The USRDS waves 1, 3, and 4 study.J Am Soc Nephrol. 2005; 16: 1788-1793Crossref PubMed Scopus (368) Google Scholar On the other hand, other studies found no such significant association.4Block G.A. Hulbert-Shearon T.E. Levin N.W. et al.Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: A national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2130) Google Scholar, 10Stevens L.A. Djurdjev 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 (316) Google Scholar Melamed et al11Melamed M.L. Eustace J.A. Plantinga L. et al.Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: A longitudinal study.Kidney Int. 2006; 70: 351-357Crossref PubMed Scopus (305) Google Scholar found that mortality was associated with serum-calcium concentration in a time-dependent model only. Multivariate-regression techniques were used by all studies, which minimize (but do not eliminate) the possibility of confounding. In particular, mortality is associated with the serum-calcium concentration independent of other mineral metabolism variables such as serum phosphorus and PTH. In studies that found a significant association, the threshold value is highly influenced by sample size and categorization. In studies that reported on threshold concentrations, a significant increase in adjusted mortality risk was found at serum-calcium concentrations (generally corrected for serum albumin) of 9.7 to 10.2 mg/dL,9Slinin Y. Foley R.N. Collins A.J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: The USRDS waves 1, 3, and 4 study.J Am Soc Nephrol. 2005; 16: 1788-1793Crossref PubMed Scopus (368) Google Scholar greater than 9.73 mg/dL (time dependent)11Melamed M.L. Eustace J.A. Plantinga L. et al.Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: A longitudinal study.Kidney Int. 2006; 70: 351-357Crossref PubMed Scopus (305) Google Scholar and greater than 11.4 mg/dL.8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar As for phosphorus, cardiovascular risk exceeded all-cause risk at higher serum-calcium concentrations.8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar, 9Slinin Y. Foley R.N. Collins A.J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: The USRDS waves 1, 3, and 4 study.J Am Soc Nephrol. 2005; 16: 1788-1793Crossref PubMed Scopus (368) Google Scholar The current ESRD treatment guidelines for serum calcium seem suitable for optimizing both bone health and patient survival. The magnitude of the risk is difficult to summarize across studies because of variation in calcium-concentration group categories and potential nonlinearity. In continuous-variable models, every 1 mg/dL increase in the serum-calcium concentration was associated with an average 10% higher all-cause mortality and 14% higher cardiovascular mortality.8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar Some illustrative examples of risk at specific levels of serum calcium include an 11% higher risk at calcium concentrations of 9.7 to 10.2 mg/dL,9Slinin Y. Foley R.N. Collins A.J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: The USRDS waves 1, 3, and 4 study.J Am Soc Nephrol. 2005; 16: 1788-1793Crossref PubMed Scopus (368) Google Scholar a 22% higher risk associated with calcium concentrations greater than 11.4 mg/dL,8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar and a 52% higher risk time-dependently associated with calcium concentrations greater than 9.73 mg/dL.11Melamed M.L. Eustace J.A. Plantinga L. et al.Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: A longitudinal study.Kidney Int. 2006; 70: 351-357Crossref PubMed Scopus (305) Google Scholar Variation in the risk estimate across studies is likely the result of measurement error and degree of adjustment for other factors. The association between mortality and serum-calcium concentration is not as robust as the association with serum phosphorus, which raises questions about causality and confounding. If the association turns out to be causal, it independently accounts for an important component of mortality of patients with ESRD/CKD. At lower levels of serum calcium, some studies found lower mortality risk,8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar, 9Slinin Y. Foley R.N. Collins A.J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: The USRDS waves 1, 3, and 4 study.J Am Soc Nephrol. 2005; 16: 1788-1793Crossref PubMed Scopus (368) Google Scholar whereas others report stable or even markedly increased7Block 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 (2236) Google Scholar, 19Foley R.N. Parfrey P.S. Harnett J.D. et al.Hypocalcemia, morbidity, and mortality in end-stage renal disease.Am J Nephrol. 1996; 16: 386-393Crossref PubMed Scopus (82) Google Scholar mortality risk. In their very large study of more than 40,000 ESRD patients, Block et al7Block 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 (2236) Google Scholar found that the elevated mortality risk associated with lower calcium concentrations was explained by other factors, particularly serum-albumin concentration. Although more information would be helpful, the current weight of evidence suggests that risk is not substantially elevated at low levels of serum calcium. Other clinically important outcomes have been significantly associated with the serum-calcium concentration, including all-cause hospitalization7Block 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 (2236) Google Scholar and parathyroidectomy.8Young 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: 1179-1187Crossref PubMed Scopus (666) Google Scholar Given the above described associations between mortality and the serum concentrations of both phosphorus and calcium, a similar strong association consistently found between mortality and the calcium-phosphorus product (Ca-P) is not surprising (Figure 3 shows DOPPS results).4Block G.A. Hulbert-Shearon T.E. Levin N.W. et al.Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: A national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2130) Google Scholar, 5Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elev