NDT Advance Access originally published online on November 26, 2007
Nephrology Dialysis Transplantation 2008 23(1):17-19; doi:10.1093/ndt/gfm801
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
After several years of witchhunting, can calcium-based phosphate binding be released on probation?
Department of Nephrology, Klinikum Coburg, Coburg, Germany
Correspondence and offprint requests to: Prof. Markus Ketteler, III. Medizinische Klinik (Nephrologie), Klinikum Coburg, Ketschendorfer Str. 33, 96450 Coburg, Germany. Tel: +49-9561-249611; Fax: +49-9561-249612; E-mail: markus.ketteler{at}klinikum-coburg.de
Keywords: atherosclerosis; calcification; calcium; phosphate; sevelamer
 |
Introduction |
|---|
 Top Introduction References |
|---|
The experimental model of uraemic ApoE-deficient mice has become increasingly used to investigate treatment options in the setting of chronic renal failure (CRF) created by 5/6-nephrectomy or other surgical methods, in combination with severe atherosclerotic plaque disease. Although the pathologic changes associated with this model are not immediately comparable to the development of CRF and atherosclerosis in humans, the phenotypic features of both vascular damage and biochemical abnormalities appear quite similar to what is observed in patients with progressive chronic kidney disease (CKD).
Phosphate binders and experimental atherosclerosis
In 2005, Phan et al. first published a study demonstrating that the phosphate binder sevelamer ameliorated not only vascular calcification, but also plaque progression in uraemic ApoE-deficient mice [1]. In addition to effective phosphate lowering, suppression of oxidative stress within the vessel wall was suggested as a mechanism preventing enhanced vascular damage. Subsequently, this experimental setting has now been repeated by the same group of investigators using calcium carbonate instead of sevelamer in order to evaluate the respective roles of phosphate binding and of calcium load in the same context [2]. Treatment with calcium carbonate did not influence plaque progression, but clearly attenuated plaque and media calcification in this model. Given the current clinical paradigm that high calcium load (mostly by administration of high doses of calcium-containing phosphate binders) is a key culprit in the progression of vascular calcification, and possibly in cardiovascular morbidity and mortality as well, this finding was unexpected.
Calcium-based phosphate binding: effective and an innocent bystander?
What do these experimental results suggest? First, they probably point to the key role of phosphate in the process of calcification initiation and progression. This assumption is supported by several experimental observations. In vitro studies demonstrated a strong and linear relationship between phosphate exposure and hydroxyapatite deposition, in contrast to a more attenuated relationship between calcium exposure and calcification [3–5]. Moreover, in vivo studies in experimental animals also pointed to a predominant, if not exclusive, role of phosphate in the calcification process [6,7]. Accordingly, epidemiological data repeatedly demonstrated a strong relationship between hyperphosphataemia and cardiovascular mortality, which was significantly less pronounced with regard to hypercalcaemia [8,9]. Notably, calcium levels are under tighter control than phosphate levels, and serum calcium concentration only insufficiently reflects calcium balance. Second, the data may emphasise the fact that intact calcium-regulatory systems efficiently modify sensitivity towards extraosseous calcification. In this study, it was demonstrated that in parallel with decreased vascular calcification, increases of local osteopontin and osteoprotegerin were observed within the vessel wall—this upregulation of protective factors may have been potentially induced by high calcium. Third, but unfortunately based on an incomplete data set, calcium-based phosphate binding was found to be associated with a marked downregulation of PTH levels. In line with current clinical assumptions, it could be hypothesized that effective suppression of high-turnover bone disease was beneficial in ameliorating vascular and soft-tissue calcification, even when achieved by some degree of calcium load.
From bench to bedside: the good and the bad news
Can we now extrapolate that the use of calcium-based phosphate binders is safe in the clinical setting? First of all, it must be emphasized that we are dealing with an animal model that is in some respects artificial in comparison to the human situation (i.e. serum lipid levels are unresponsive to statin and to sevelamer treatment, respectively, in ApoE-deficient mice). Further, in this particular study, the CRF mice did not have elevated phosphate levels when compared to the non-CRF mice on a standard diet, while calcium carbonate-treated CRF mice developed a 25% decrease in serum phosphate compared to the other two groups.
Nevertheless, it is quite possible that there are a number of scenarios in which calcium-based phosphate binding is an effective and at the same time completely harmless treatment option of hyperphosphataemia; but, as always, there is good and bad news. As simple as it sounds, the good news is, at least in our interpretation of this study, that the crucial part of phosphate-binding strategies in general is to lower phosphate below a certain threshold. The bad news is that we do not exactly know where this individual threshold lies and that this ‘safety margin’ most certainly differs amongst patients with CKD.
In the same context, the good news is that it is probably true that CKD patients with intact defense mechanisms against extraosseous calcification (e.g. sufficient levels of calcification inhibitors including osteopontin or fetuin-A) additionally benefit from any kind of phosphate binding, with no particular harm associated with the use of calcium-containing compounds. However, the bad news here is that we do not yet have sufficiently reliable and validated biomarkers at hand to firmly identify low- from high-risk individuals.
Finally, calcium-based phosphate binding may be particularly reasonable in patients with high-turnover bone disease because by lowering PTH levels, the efflux of calcium (and phosphate) from bone may be reversed, and the net effect could be stable or decreased extraosseous mineral availabaility, even in the presence of elevated calcium intake. This idea is supported by the PTH data in Table 1 of the report by Phan et al. [2], but hampered by the fact that successful PTH measurements could only be performed in three mice of this group. However, very severe or unresponsive high-turnover bone disease may again render a high calcium load deleterious.
Support from clinical studies: calcium and calcification progression in pre-dialysis patients
While these experimental data partly direct us to a new (or back to an old) view about calcium-based phosphate binding, the recent clinical study by Russo et al. lends support to the observed lack of calcification induction by oral calcium loading, and to potentially vasculoprotective properties of calcium-based phosphate binding [10]. These authors examined the progression of coronary artery calcification scores in patients with stages CKD 3–5. The patients were treated with low-phosphate diet alone, calcium carbonate or sevelamer, respectively. Mean serum phosphate levels were normal to high normal, with no significant differences between groups. While calcification progression was lowest in the sevelamer-treated group, treatment with calcium carbonate was slightly superior to the sole prescription of a low-phosphate diet. Calcium carbonate was clearly not, as perhaps expected, an additional progression factor. The superiority of sevelamer could be due either to the absence of a concomitant calcium overload or to some pleiotropic effects, as experimentally demonstrated by the combination of antioxidant and antiatherosclerotic effects of sevelamer treatment reported by Phan et al. [1].
What do we learn?
It may not be appropriate to build a strong case against calcium-based phosphate binder use in clinical practice, given this new, interesting experimental and also limited clinical evidence [2,10]. However, some caution is still advised, because the extrapolation of such animal model results into clinical routine does not always work in a linear fashion. The trouble is that we do not know tolerable phosphate thresholds and degrees of additional calcification protection in individual patients. Combinations of phosphate binders, including a balanced use of calcium-based phosphate binders, may be an important option, since phosphate lowering appears to be the central, mechanistically most important goal to protect from progressive vascular calcification. The prescription of very high doses of calcium-containing phosphate binders, such as those given in the recent past, should not still be advocated.
Conflict of interest statement. M.K. received grant support and honoraria (lecture fees, advisory tasks) from Genzyme, Fresenius Medical Care and Shire.
Conflict of interest statement. M.K. received grant support and honoraria (lecture fees, advisory tasks) from Genzyme, Fresenius Medical Care and Shire.
(See related article by Phan et al. Effect of oral calcium carbonate on aortic calcification in apolipoprotein E-deficient (apoE–/–) mice with chronic renal failure. Nephrol Dial Transplant 2008; 23: 82–90.)
|
References |
|---|
|
TopIntroductionReferences |
|---|
- Phan O, Ivanovski O, Nguyen-Khoa T, et al. Sevelamer prevents uremia-enhanced atherosclerosis progression in apolipoprotein E deficient (apoE-/-) mice. Circulation (2005) 112:2875–2882.
[Abstract/Free Full Text] - Phan O, Ivanovski O, Nikolov IG, et al. Effect of oral calciumcarbonate on aortic calcification in apolipoprotein E deficient (apoE-/-) mice with chronic renal failure. Nephrol Dial Transplant (2007) in press.
- Jono S, McKee MD, Murry CE, et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res (2000) 87:E10–E17.[Web of Science][Medline]
- Yang H, Curinga G, Giachelli CM. Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro. Kidney Int (2004) 66:2293–2299.[CrossRef][Web of Science][Medline]
- Reynolds JL, Joannides AJ, Skepper JN, 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) 15:2857–2867.
[Abstract/Free Full Text] - Murshed M, Harmey D, Millan JL, et al. Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. Genes Dev (2005) 19:1093–1104.
[Abstract/Free Full Text] - Stubbs JR, Liu S, Tang W, et al. Role of hyperphosphatemia and 1,25-dihydroxyvitamin d in vascular calcification and mortality in fibroblastic growth factor 23 null mice. J Am Soc Nephrol (2007) 18:2116–2124.
[Abstract/Free Full Text] - 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] - Kalantar-Zadeh K, Kuwae N, Regidor DL, et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int (2006) 70:771–780.[CrossRef][Web of Science][Medline]
- 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) Epub ahead of print.
Accepted in revised form: 15.10.07
CiteULike 
Connotea 
Del.icio.us What's this?
Related articles in NDT:
- Effect of oral calcium carbonate on aortic calcification in apolipoprotein E-deficient (apoE–/–) mice with chronic renal failure
- Olivier Phan, Ognen Ivanovski, Igor G. Nikolov, Nobuhiko Joki, Julien Maizel, Loïc Louvet, Maud Chasseraud, Thao Nguyen-Khoa, Bernard Lacour, Tilman B. Drüeke, and Ziad A. Massy
NDT 2008 23: 82-90.[Abstract] [FREE Full Text] - In this issue ...
NDT 2008 23: i.[Extract] [FREE Full Text]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||