NDT Advance Access originally published online on April 9, 2008
Nephrology Dialysis Transplantation 2008 23(6):2101-2102; doi:10.1093/ndt/gfn165
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Reply
Correspondence and offprint requests to: E-mail: suetoniapalmer{at}clear.net.nzCalcium salts reduce alimental phosphorus uptake in chronic kidney disease although treatment-related decreases in serum phosphorus (associated with reduced survival) are often opposed by an increasing serum calcium (with the potential risk for increased mortality) [1]. The search for an alternative agent that combines effective phosphorus sequestration without hypercalcaemia in chronic kidney disease has been ongoing, both to reduce the risk of vascular calcification, and because existing aluminium-based agents (the first such ‘ideal’ agents) were associated with significant and important cerebral toxicity [2]. Searching for alternatives to calcium- and aluminium-containing phosphate binders has resulted in the improvement of sevelamer (hydrochloride or carbonate) [3] and lanthanum carbonate [4].
The argument that sevelamer and lanthanum are superior to calcium-based agents (and indeed newer vitamin D compounds and calcimimetic agents) rests on the ability of such compounds to lower both calcium and phosphorus levels, and thereby potentially improve event free survival. These potential benefits of newer agents, including sevelamer, and other anion-exchange resins, as discussed by Drs Wrong and Harland [5], are supported, only in part, by very large-scale observational studies, where lower levels of serum calcium, phosphorus, and less so parathyroid hormone, are associated with improved survival for people with chronic kidney disease [1,6]. As we have previously discussed extensively, this is not enough [7–9]. What remains important is that the direct relationship between modification of calcium, phosphorus or PTH with improved survival and cardiovascular outcomes in randomized, controlled trials is still far from proven. This is despite the largest trial in this area, the Dialysis Clinical Outcomes Revisited (DCOR) trial enrolling over 2100 patients to either sevelamer or calcium salts, which showed no difference for mortality between treatment arms [10] and the meta-analyses of phosphate binders [11], calcimimetics [9] and vitamin D compounds [8].
The ongoing search for efficacious and cost-effective agents, such as anion exchange resins, is laudable. Therefore, the suggestion of Wrong and Harland that colestipol, or other cheaper alternatives, could be promoted in preference to the more expensive sevelamer, is appealing. However, while these and other measures may be temporarily supported, the real priority for resources in this area should be directed at understanding the effects of the treatment for altered mineral metabolism on patient centred outcomes, including bone pain, cardiovascular events and mortality in chronic kidney disease. Do any of these drugs, which can control phosphorus levels, really have any effect on reducing the excess mortality which is attributable to high serum phosphorus levels in chronic kidney disease? Certainly there are numerous resins that can be used to absorb intestinal phosphorus, but just as well there are now numerous data to support that adequately powered, randomized trials investigating either pharmaceutical agents or the serum targets of calcium, phosphorus and parathyroid hormone levels should be developed.
Conflict of interest statement. None declared.
1 Department of Medicine University of Otago Christchurch Christchurch New Zealand and 2 Mario Negri Sud Consortium S. Maria Imbaro, Italy
References
- Block GA, Klassen PS, Lazarus JM, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol (2004) 15:2208–2218.
[Abstract/Free Full Text] - Alfrey AC, LeGendre GR, Kaehny WD. The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med (1976) 294:184–188.[Abstract]
- Delmez J, Block G, Robertson J, et al. A randomized, double-blind, crossover design study of sevelamer hydrochloride and sevelamer carbonate in patients on hemodialysis. Clin Nephrol (2007) 68:386–391.[Web of Science][Medline]
- Hutchison AJ, Maes B, Vanwalleghem J, et al. Long-term efficacy and tolerability of lanthanum carbonate: results from a 3-year study. Nephron Clin Pract (2006) 102:c61–c71.[CrossRef][Medline]
- Wrong O, Harland C. Sevelamer and other anion-exchange resins in the prevention and treatment of hyperphosphataemia in chronic renal failure. Nephron Physiol (2007) 107:p17–p33.[CrossRef][Medline]
- Ganesh SK, Stack AG, Levin NW, et al. Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol (2001) 12:2131–2138.
[Abstract/Free Full Text] - Palmer SC, Craig JC, Strippoli GF. Sevelamer: a promising but unproven drug. Nephrol Dial Transplant (2007) 22:2742–2745.
[Free Full Text] - Palmer SC, McGregor DO, Macaskill P, et al. Vitamin D compounds in chronic kidney disease: a meta-analysis. Ann Intern Med (2007) 147:840–853.
[Abstract/Free Full Text] - Strippoli GFM, Palmer SC, Tong A, et al. Meta-analysis of biochemical and patient-level effects of calcimimetic therapy. Am J Kidney Dis (2006) 47:715–726.[CrossRef][Web of Science][Medline]
- Suki WN, Zabaneh R, Cangiano JL, et al. Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int (2007) 72:1130–1137.[CrossRef][Web of Science][Medline]
- Tonelli M, Wiebe N, Culleton B, et al. Systematic review of the clinical efficacy and safety of sevelamer in dialysis patients. Nephrol Dial Transplant (2007) 22:2856–2866.
[Abstract/Free Full Text]
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