Control of Hyperphosphataemia
Magnesium has been described as an important link between multiple cardiovascular risk factors.75,76
A series of clinical studies over the
past 15 years, ranging in size from seven to 390 patients, has shown significant associations between higher serum magnesium beyond the normal range and reduced prevalence and/or progression of arterial calcification. Parameters determined include coronary artery calcification,72
calcification of the hand arteries,79 progression/regression.81
intima-media thickness of the carotid artery,77,78 mitral annular thickness80
and
The link between higher magnesium levels and inhibition of calcification has been elucidated in bovine vascular smooth muscle cells.82
associated with the lowest mortality. Higher magnesium levels and those at the upper end of the normal range were associated with a lower risk of mortality. Further randomised prospective studies are required to confirm this protective effect and examine its implications.
These
cells were incubated in β-glycerophosphate and physiological levels of magnesium (2.6 mg/dL [1.1 mmol/L]) for seven to 21 days, inducing marked calcification. Increasing the magnesium concentration to 4.9 mg/dL (2 mmol/L) reduced calcification and magnesium levels of 7.3 mg/dL (3 mmol/L) reduced it still further to control levels indicating a dose-dependent effect. Increased magnesium also increased the secretion of matrix Gla protein that is known to inhibit cellular calcification, and reduced the genetic expression of core binding factor-alpha, a transcription protein typical for calcified smooth muscle cells. These findings provide a possible mechanism for the protective role of magnesium against vascular calcification in clinical situations.
The association between serum magnesium levels and mortality has also been investigated using information from the EuCliD® database that has gathered information on the HD treatment of over 30,000 patients in 20 countries. An analysis of records of 953 patients from six European countries showed that, after adjusting for patient demographic factors, as serum magnesium levels decreased, the mortality risk increased.83
It was notable that
even patients within the normal range for serum magnesium were at an increased risk of death that reached borderline significance.
A recent observational analysis of magnesium data from a large population of patients receiving HD treatment in North America (n=27,544) was presented at the ERA–EDTA meeting in Prague 2011 and showed a significant association between lower serum magnesium levels of less than 2.6 mEq/L (<1.3 mmol/L or <3.2 mg/dL) and risk of death.84 Peer review and publication of these data are awaited. Magnesium concentrations higher than 2.6 mEq/L (3.2 mg/dL [1.30 mmol/L]) were
1. KDIGO, Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD–MBD), Kidney Int, 2009;76 (S113):S50–S69.
2. Schucker JJ, Ward KE, Hyperphosphatemia and phosphate binders, Am J Health Syst Pharm, 2005;62:2355–61.
3. Block GA, Hulbert-Shearon TE, Levin NW, et al., Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study, Am J Kidney Dis, 1998;31:607–17.
4. Dhingra R, Sullivan LM, Fox CS, et al., Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community, Arch Intern Med, 2007;167:879–85.
5. Kestenbaum B, Sampson JN, Rudser KD, et al., Serum phosphate levels and mortality risk among people with chronic kidney disease, J Am Soc Nephrol, 2005;16:520–8.
6. Rodriguez-Benot A, Martin-Malo A, Alvarez-Lara MA, et al., Mild hyperphosphatemia and mortality in hemodialysis patients, Am J Kidney Dis, 2005;46:68–77.
7. Tonelli M, Sacks F, Pfeffer M, et al., Relation between serum phosphate level and cardiovascular event rate in people with coronary disease, Circulation, 2005;112:2627–33.
8. Roussanne MC, Lieberherr M, Souberbielle JC, et al., Human parathyroid cell proliferation in response to calcium, NPS R-467, calcitriol and phosphate, Eur J Clin Invest, 2001;31:610–6.
Early data from small studies therefore indicate that magnesium-based phosphate binders have a variety of interesting potential benefits that include reducing the risk of cardiovascular disease, particularly arterial calcification, as well as cardiovascular death and bone demineralisation, which are frequent consequences of CKD. Larger prospective trials are required to substantiate these findings and validate these claimed advantages in dialysis patients.
Conclusions
There is now a wide range of effective oral phosphate binders available to patients, which facilitate adherence to the KDIGO guidelines. A Cochrane analysis suggests that sevelamer-HCL may not be significantly more effective than calcium-based therapies and is associated with a range of adverse events particularly gastrointestinal symptoms. Sevelamer-HCL and lanthanum carbonate may be more appropriate in patients with hypercalcaemia and may be preferred by some patients especially those who cannot tolerate particular calcium-based binders. In addition, lanthanum carbonate has the potential benefit of reducing total pill burden. However, these binders are expensive and this currently precludes their widespread use in many territories and healthcare organisations. High-quality trials to demonstrate both benefit and cost-effectiveness are needed to justify the use of any oral phosphate binders, but particularly the more expensive ones, in CKD. However, using combinations of calcium-free phosphate binders with calcium, or using calcium with magnesium, are useful means of controlling serum phosphate effectively while restricting calcium intake at a reasonable cost.
The KDIGO guidelines provide valuable assistance to physicians as they try to make sense of the current literature and optimise patient outcomes. They also rightly highlight the lack of high-quality trials to inform future guidelines and to demonstrate effective strategies to minimise risks of vascular calcification and early death. Best practice is therefore largely opinion based and requires a co-ordinated multidisciplinary approach from physicians, nurses, dieticians, pharmacists and patients utilising all the available dietary, pharmacological and dialytic techniques to achieve this. n
9. Silver J, Naveh-Many T, Phosphate and the parathyroid, Kidney Int, 2009;75:898–905.
10. Estepa JC, Aguilera-Tejero E, Lopez I, et al., Effect of phosphate on parathyroid hormone secretion in vivo, J Bone Miner Res, 1999;14:1848–54.
11. Qunibi WY, Hootkins RE, McDowell LL, et al., Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study), Kidney Int, 2004;65:1914–26.
12. de Francisco AL, Leidig M, Covic AC, et al., Evaluation of calcium acetate/magnesium carbonate as a phosphate binder compared with sevelamer hydrochloride in haemodialysis patients: a controlled randomized study (CALMAG study) assessing efficacy and tolerability, Nephrol Dial Transplant, 2010;25:3707–17.
13. Wohrle S, Bonny O, Beluch N, et al., FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone, J Bone Miner Res, 2011;26:2486–97.
14. Tentori F, Blayney MJ, Albert JM, et al., Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS), Am J Kidney Dis, 2008;52:519–30.
15. Noordzij M, Korevaar JC, Boeschoten EW, et al., The Kidney Disease Outcomes Quality Initiative (K/DOQI) Guideline for Bone Metabolism and Disease in CKD: association with mortality in dialysis patients, Am J Kidney Dis, 2005;46:925–32.
16. Foley RN, Chronic kidney disease: Levels of phosphorus and patient outcomes, Nat Rev Nephrol, 2011;7:428–30.
17. Palmer SC, Hayen A, Macaskill P, et al., Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis, JAMA, 2011;305:1119–27.
18. USDA National Nutrient Database for Standard Reference, Release 21 Content of Selected Foods per Common Measure, Phosphorus, P (mg) sorted by nutrient content, 2009. Available at:
www.nal.usda.gov/fnic/foodcomp/Data/ SR21/nutrlist/sr21w305.pdf (accessed 3 August 2011).
19. Russo D, Miranda I, Ruocco C, et al., The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer, Kidney Int, 2007;72:1255–61.
20. Culleton BF, Walsh M, Klarenbach SW, et al., Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial, JAMA, 2007;298:1291–9.
21. Achinger SG, Ayus JC, The role of daily dialysis in the control of hyperphosphatemia, Kidney Int Suppl, 2005;28–32.
22. Oates T, Pinney JH, Davenport A, Haemodiafiltration versus high-flux haemodialysis: Effects on phosphate control and erythropoietin response, Am J Nephrol, 2011;33:70–5.
23. Block GA, Klassen PS, Lazarus JM, et al., Mineral metabolism, mortality, and morbidity in maintenance hemodialysis, J Am Soc Nephrol, 2004;15:2208–18.
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