Sevelamer for hyperphosphataemia in kidney failure: controversy and perspective

Abstract

The term ‘chronic kidney disease–mineral and bone disorder’ (CKD–MBD), coined in 2006, was introduced in a position statement by the Kidney Disease: Improving Global Outcomes (KDIGO) organization. According to the KDIGO guidelines, CKD–MBD is a systemic disorder and patients with vascular or valvular calcifications should be included in the group with the greatest cardiovascular risk. Therefore, the presence or absence of calcification is a key factor in strategy decisions for such patients. In particular, it is recommended that the use of calcium-based phosphate binders should be restricted in patients with hypercalcaemia, vascular calcification, low levels of parathyroid hormone (PTH) or adynamic bone disease. In this respect, it should be underscored that treatment with phosphate-binding agents can normalise the levels of phosphate and PTH, but the use of calcium carbonate can favour the progression of vascular calcifications. There is evidence of reduced progression of vascular calcification in patients treated with sevelamer compared with high doses of calcium-based binders, but there is as yet no strong evidence regarding hard outcomes, such as mortality or hospitalization, to support the use of one treatment over another. Nevertheless, a number of experimental and observational findings seem to suggest that sevelamer should be preferred over calcium-based binders, in as much as these can increase cardiovascular mortality when used in high doses. A threshold dose below which calcium-based binders can be used safely in CKD patients with hyperphosphatemia has yet to be established.

Introduction

During the last decade, a growing body of evidence supported the role of hyperphosphataemia as a major player in promoting cardiovascular (CV) calcification and an important predictor of mortality in chronic kidney disease (CKD) patients. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines underlined the negative role of hyperphosphataemia in determining derangement of bone metabolism and of the CV system in CKD patients. The presence of strong associations between phosphate accumulation and diseases of the bone–vascular axis defined a new clinical syndrome: chronic kidney disease–mineral bone disorder (CKD–MBD) [CKD–MBD Work Group, 2009; Moe et al. 2006].

Inorganic phosphate (normal serum levels from 0.8 to 1.45 mmol/l) is involved in various physiological pathways, such as skeletal and mineral metabolism, cell membrane structure and signalling, platelet aggregation and mitochondrial metabolism. In healthy state, serum phosphate levels are maintained within the normal range by the combined interaction of dietary intake, bone formation and resorption, and renal excretion, as well as by equilibration with intracellular stores [Tonelli et al. 2010]. Normally, the estimated daily phosphate intake is 20 mg/kg of body weight per day, feeding the extracellular pool in continuous exchange with bone.

To maintain a neutral phosphate balance, two thirds of the intake is excreted by the kidney, while one third leaves the body through the faeces. When renal function decreases, two hormones, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23), prevent hyperphosphataemia by increasing renal fractional phosphorus excretion [Levin et al. 2007]. Through these mechanisms, the kidneys can maintain an adequate phosphate excretion until GFR (glomerular filtration rate) is 30 ml/min/1.73 m² [Kestenbaum et al. 2005].

Several studies have shown a relationship between hyperphosphataemia and mortality in dialysis patients. In 1998, Block and colleagues observed that hyperphosphataemia was an independent and powerful predictor of mortality in haemodialysis patients [Block et al. 1998]. This finding was subsequently confirmed in more than 40,000 patients from the US American Fresenius Medical Care database [Block et al. 2004] and from three additional registries [Young et al. 2005; Slinin et al. 2005; Kalantar-Zadeh et al. 2006]. Even if the optimal target level of serum phosphate is unknown, there is evidence that a positive phosphate balance is linked to a progression of vascular calcification [Tonelli et al. 2010]. KDIGO guidelines, updating the previous KDOQI guidelines published in 2003, recommend to reach phosphorus levels ‘toward the normal laboratory range’ [CKD–MBD Work Group, 2009].

Serum phosphate levels in CKD patients can be controlled by the reduction of oral phosphate intake, an adequate dialysis schedule, and the use of intestinal phosphate binders. Unfortunately, in the long term, patients rarely observe rigid dietary phosphate restriction. Moreover, the phosphate content of food may vary considerably, especially in industrially processed food [Kalantar-Zadeh et al. 2010]. With the exception of long, daily dialysis, intermittent haemodialysis is usually not sufficient to maintain normal serum phosphate levels. Therefore, phosphate binders appear to be essential to control phosphate overload and to improve outcomes in haemodialysis patients [Isakova et al. 2009].

Nowadays several effective phosphate binders are available [Tonelli et al. 2010]. Aluminium-based binders at high doses may induce aluminium accumulation and toxicity manifested as encephalopathy, osteomalacia and anaemia, while calcium-containing binders may contribute to causing CV calcification; thus, aluminium- and calcium-free phosphate binders may represent an advantageous therapeutic solution. On the other hand, calcium- and aluminium-free phosphate binders are more expensive than calcium salts, so that some authors do not recommend them for initial therapy [Tonelli et al. 2010].

In our opinion, the question of choosing the optimal phosphate binder is challenging for nephrologists, when they approach the problem of CV risk in dialysis patients. Effects of calcium- and aluminium-free phosphate binders strictly linked to their antiphosphataemic action, such as reduction of hypercalcaemia and vascular calcification, as well as pleiotropic effects such as lipid and inflammation control [Kwan et al. 2007], may support the indication of their use as first choice agents in a significant proportion of haemodialysis patients and possibly for primary prevention of vascular calcifications in early stages of CKD, despite their high cost [Cozzolino et al. 2011].

Sevelamer hydrochloride: the first calcium- and aluminium-free phosphate binder for dialysis patients

Sevelamer hydrochloride (HCl), which is an anion-exchange resin, has been the first calcium- and aluminium-free phosphate binder developed for hyperphosphataemia management in dialysis patients [Raggi et al. 2010]. Sevelamer is a nonabsorbable hydrogel that contains various amines separated by one carbon from the polymer backbone. These amines bind phosphorus and bile acids in the intestinal tract [Slatopolsky et al. 1999]. Initial studies showed a nonsignificant decrease in serum bicarbonate levels in haemodialysis patients receiving sevelamer. We evaluated the effects of sevelamer HCl versus calcium carbonate on acid–base balance in 16 haemodialysis patients, confirming the efficacy of sevelamer HCl in serum phosphate reduction but observing a significant decrease in serum bicarbonate levels at the third week after calcium carbonate withdrawal. Therefore, we concluded that reduction of serum bicarbonate levels might be dependent on the combination of discontinuing calcium carbonate and of a direct effect of sevelamer HCl administration, also suggesting a role of bone buffering in preventing further reduction of bicarbonate levels [Gallieni et al. 2000].

The Treat To Goal (TTG) study was an important trial that compared effectiveness and tolerability of sevelamer versus calcium carbonate. This study, conducted in 200 haemodialysis patients randomized to receive calcium-based binder or sevelamer, evaluated the efficacy of binders in reducing serum phosphate levels, hypercalcemic episode frequency (5% in the sevelamer versus 16% in calcium carbonate group, p = 0.04), and progression of coronary (6% versus 25%, p = 0.02) and aortic calcification (5% versus 28%, p = 0.02) [Chertow et al. 2002]. Further analysis also showed that patients treated with calcium-based binders had a reduction of thoracic-vertebral bone density in association with a concomitant increase of coronary calcification score [Raggi et al. 2005].

Data on the effects of sevelamer on bone turnover are limited. A bone biopsy study investigating adult haemodialysis patients for 1 year, 60% of whom had low-turnover bone disease, evaluated the effects of treatment with sevelamer versus calcium carbonate. Bone formation rate (BFR) increased from baseline in patients who were treated with sevelamer, whereas it remained unchanged in those who received calcium carbonate. These findings raise the possibility that sevelamer may increase BFR during the treatment of adynamic bone disease [Ferreira et al. 2008].

In contrast, two other prospective studies (CARE-2 and BRiC) did not demonstrate a significant superiority of sevelamer versus calcium-based binders in reducing the progression of coronary and aortic calcification (CAC). In the Calcium Acetate Renagel Evaluation 2 (CARE-2) study, 203 prevalent haemodialysis patients with hyperphosphataemia were randomly assigned to calcium acetate or sevelamer. At the end of this 1-year study, the reduction in mean serum phosphorus levels was comparable in both treatment groups. Moreover, difference in progression of CAC score was not significant between two groups (35% with calcium acetate versus 39% with sevelamer). However, this trial cannot be compared with the TTG study because CARE-2 patients had a higher pre-existing CV risk [Qunibi et al. 2008]. In the Phosphate Binder Impact on Bone Remodeling and Coronary Calcification (BRiC) study, 101 Brazilian prevalent haemodialysis patients were randomized to sevelamer or calcium acetate: no significant difference was observed in CAC progression or bone remodelling between these two groups. This study also presented difficulties when compared with the TTG trial. In fact, the presence of aluminium bone disease and the use of a higher dialysate calcium concentration in sevelamer group may have blunted any differences between treatment groups [Barreto et al. 2008].

A few studies suggested that differences in mortality might be associated with the use of calcium-based binders and sevelamer [Block et al. 2005]. In the Renagel in New Dialysis (RIND) study [Block et al. 2007], the primary endpoint was to assess the progression of CAC scores by comparing treatment with sevelamer and calcium-based phosphate binders. The authors showed a significant reduction in vascular calcification (VC) progression among sevelamer-treated patients compared with calcium-based phosphate binders-treated patients, showing that treatment with sevelamer was associated with a significant survival benefit. Moreover, in subjects new to haemodialysis, baseline CAC score was a significant predictor of all-cause mortality. In fact, a secondary analysis about mortality data was performed: all-cause mortality after 4 years was higher in calcium-treated patients than sevelamer-treated patients (10.6 per 100 patient-years versus 5.3 per 100 patient-years respectively; p = 0.05). Improved survival for the sevelamer group was confirmed by multivariate analysis, after adjustment for confounding factors. The Dialysis Clinical Outcomes Revisited (DCOR) study, a large, prospective, randomized survival study, evaluated whether sevelamer administration was associated with a survival benefit in prevalent haemodialysis patients [Suki et al. 2007]. There were 2103 patients who were randomized to sevelamer hydrochloride or calcium-based phosphate binder treatment for up to 45 months. There were no differences in the two groups regarding both all-cause and cause-specific mortality rates (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.79–1.10; p = 0.40), probably due to the elevated drop-out rate during follow up. Nevertheless, a pre-set analysis showed a lower mortality rate in patients over 65 years of age treated with sevelamer (HR 0.77; 95% CI 0.61–0.96; p = 0.02). Furthermore, secondary analysis of the DCOR trial demonstrated that sevelamer compared with calcium-based binders administration reduced all-cause hospitalizations [St Peter et al. 2008].

Regarding peritoneal dialysis (PD), data from a multicentre, open-label study, randomizing 143 adult patients on PD with serum phosphorus >5.5 mg/dl to 12 weeks of treatment with sevelamer hydrochloride or calcium acetate, are available. At the end of the study, serum phosphorus and PTH levels were similarly and significantly reduced with both sevelamer hydrochloride and calcium acetate. In contrast, serum calcium levels increased in calcium acetate-treated patients compared with those receiving sevelamer (18% versus 2% respectively, p = 0.001). Both treatments were well tolerated and safety profiles were consistent with previous reports in haemodialysis patients [Evenepoel et al. 2009].

The acid–base status when using sevelamer HCl in PD patients was evaluated by a study of 89 patients, 12 of whom were taking sevelamer. Results showed no evidence of acidosis in both groups. The authors thought that constant exposure to PD solutions with high lactate or bicarbonate content might prevent any effect on the acid–base status [Pagé and Knoll, 2005].

Finally, an observational study with 90 CKD patients not on dialysis was performed to compare differences in CAC score progression using a low-phosphate diet, calcium carbonate or sevelamer for 2 years. This study showed a possible benefit with sevelamer administration in predialysis patients, but these data have to be confirmed with randomized studies [Russo et al. 2007].

Few data are also available concerning economic issues of sevelamer treatment in haemodialysis. The analysis performed in a simulated cohort of North American dialysis patients suggested that the cost per quality-adjusted life year (QALY) gained with sevelamer is not an attractive therapeutic solution when compared with calcium carbonate treatment [Manns et al. 2007]. Nevertheless, an economic evaluation by Taylor and colleagues suggested that treatment with sevelamer could confer clinical benefits with a modest investment of additional economic resources. In particular, sevelamer-treated patients may be expected to experience higher quality of life than calcium carbonate-treated patients [Taylor et al. 2008]. These authors showed that sevelamer is cost-effective, but final conclusions are not possible because strong data on mortality are not available. Finally, we want to underline the importance of compliance in the management of hyperphosphataemia, as phosphate binders represent up to half of the pills taken by dialysis patients [Chiu et al. 2009]. Differential effects of phosphate binders in chronic kidney disease patients are shown in Table 1.

Table 1.

Differential effects of phosphate binders in patients with chronic kidney disease.

	Sevelamer HCl and Sevelamer carbonate	Calcium carbonate and calcium acetate
Adverse effects	Gastrointestinal effects:	Gastrointestinal effects:
	• Nausea	• Nausea
	• Vomiting	• Vomiting
	• Abdominal pain	• Abdominal pain
	• Bloating	• Bloating
	• Diarrhoea	• Diarrhoea
	• Constipation	• Constipation
	Peritonitis	Peritonitis
	Metabolic acidosis (only with sevelamer	Pruritus
	HCl)	Xerostomia
		Hypercalcaemia
		Muscle cramping
Advantages	Effective	Effective
	Does not contain calcium	Inexpensive
	Lower risk of metabolic acidosis (sevelamer carbonate)	Lower risk of metabolic acidosis
	Nonclassical effects:
	• Reduces low-density lipoprotein cholesterol
	• Reduces serum uric acid levels
	• Reduces serum FGF-23 levels
	• Increases serum Fetuin-A levels
	• Bacteria lipopolysaccharide binding properties in the intestinal tract
Disadvantages	Expensive	Promote vascular calcification
	Nonclassical effects:
	• Potential interference with vitamin D and vitamin K intestinal absorption

FGF, fibroblast growth factor.

Sevelamer carbonate to improve hyperphosphataemia management for CKD patients

Sevelamer carbonate is an anion exchange resin developed as an improved, buffered form derived by sevelamer HCl, where carbonate replaces chloride as the anion. Sevelamer carbonate has been found to have the same safety and efficacy profile as sevelamer HCl in haemodialysis patients [Delmez et al. 2007]. Although the majority of trials have involved sevelamer HCl, it is reasonable to assume that the results of earlier studies also apply to sevelamer carbonate, considering that the two products have similar phosphate-binding effects [Biggar and Ketteler, 2010]. Sevelamer carbonate is also significantly better tolerated than sevelamer HCl. In fact, in a double-blind, randomized, crossover study evaluating 79 haemodialysis patients for 16 weeks, frequency of gastrointestinal adverse events, including abdominal bloating, diarrhoea and constipation, was approximately halved on sevelamer carbonate compared with sevelamer HCl [Delmez et al. 2007].

A study of 46 patients not on dialysis conducted by Ketteler and colleagues showed that sevelamer carbonate significantly decreased mean serum phosphate levels. The authors also found that sevelamer carbonate reduced total and low-density lipoprotein (LDL) cholesterol and increased serum bicarbonate levels (from 16.6 to 18.2 mEq/l), showing a better control of metabolic acidosis and optimal tolerance [Ketteler et al. 2008].

In contrast with sevelamer HCl, sevelamer carbonate is available in two different formulations: tablets and powder. The powder formulation may be beneficial especially for the elderly and paediatric populations. It may also be preferable in patients treated with a large number of other tablet or capsule medications. A multicentre, open-label, randomized, crossover design study by Fan and colleagues compared the safety and efficacy of sevelamer carbonate powder with sevelamer HCl tablets in CKD patients on haemodialysis. Sevelamer carbonate powder and sevelamer HCl tablets were found to be equivalent in reducing serum phosphate levels and they were well tolerated, while bicarbonate levels improved only with sevelamer carbonate treatment [Fan et al. 2009]. Nevertheless, another similar randomized, parallel, open-label study showed that once-daily administration of sevelamer carbonate powder was not as effective in decreasing serum phosphate levels compared to thrice-daily administration of sevelamer HCl tablets, although sevelamer carbonate powder also decreased serum phosphate levels significantly, reaching the KDOQI phosphate target in the majority of patients. Probably, the once-daily dose may not adequately match the variable intestinal phosphate content which is present after meals [Fishbane et al. 2010].

A review by Pai and colleagues compared characteristics of sevelamer HCl and sevelamer carbonate to evaluate the roles of these two drugs in the management of the hyperphosphataemia [Pai and Shepler, 2009]. This review underscores that in patients with CKD and hyperphosphataemia who received haemodialysis or PD, serum bicarbonate concentration decreases with the use of sevelamer HCl, whereas sevelamer carbonate does not have this negative effect. Both agents appear to have the same action in lowering serum phosphate levels. These authors concluded that as sevelamer carbonate permitted a better management of serum bicarbonate levels, it may be more appropriate for patients at risk for metabolic acidosis who require phosphate binders that do not contain calcium or aluminium [Pai and Shepler, 2009].

‘Non-classical’, pleiotropic effects of sevelamer in CKD

Several studies have documented relevant pleiotropic effects of sevelamer, emphasizing the role for an aluminium- and calcium-free phosphate binder in CV risk prevention. Nowadays, the new endpoint of therapy is focused not only on hyperphosphataemia management, but also in a more wide control of metabolic disorders, including dyslipidemia, hyperuricaemia, inflammation and other factors involving in vascular calcification. According to recent data, sevelamer seems to satisfy these new efficacy standards.

Regarding dyslipidemia, sevelamer hydrochloride was associated with decreases in total cholesterol, LDL cholesterol, and uric acid, with a parallel increase in bone-specific alkaline phosphatase [Evenepoel et al. 2009]. Other studies showed significant reductions in total cholesterol and LDL cholesterol with sevelamer, which is likely due to inhibition of cholesterol absorption from the intestine [Wilkes, 1998]. In another randomized study, 108 haemodialysis patients showed advantageous modifications in lipids and inflammatory markers with potentially useful antiatherogenic effects when treated with sevelamer in contrast with calcium acetate [Ferramosca et al. 2005]. Moreover, Chertow and colleagues studied the effect of calcium acetate on progression of VC and demonstrated that, in haemodialysis patients, calcium acetate led to a significant increase in coronary arteries and aorta calcification. These changes were similar for calcium carbonate, while there were no significant changes in calcification among sevelamer-treated subjects [Chertow et al. 2003].

People with advanced CKD have more frequently hyperuricaemia that may increase the risk of CV disease [Alderman, 2002]. Moreover, gout affects a large fraction of CKD patients. Data from short-term and open-label studies suggest that sevelamer might lower the concentration of uric acid. In particular, a long-term, randomized, clinical trial evaluating 200 subjects undergoing maintenance haemodialysis, comparing sevelamer with calcium salts, confirmed that sevelamer reduces serum uric acid concentration compared with calcium salts (–0.64 mg/dl versus –0.26 mg/dl; p = 0.03 from baseline to the end of the study) [Garg et al. 2005]. However, the clinical significance of reducing serum uric acid in CKD patients without gout is still questionable, using either allopurinol or alternative products such as sevelamer.

In CKD, various biomarkers have been used to investigate CV progression. Despite classical risk factors, these include markers of inflammation such as C-reactive protein (CRP). CRP is often elevated in CKD and it has been associated with CV death in haemodialysis patients [Wanner and Metzger, 2002]. A reduction in serum CRP after sevelamer treatment has been demonstrated, but not after calcium salts administration [Ferramosca et al. 2005]. These data were recently confirmed by Navarro and colleagues who demonstrated that use of sevelamer in haemodialysis patients is associated with significant decrease in hs-CRP, interleukin (IL)-6 and sCD14 concentrations. Moreover, sevelamer was also able to reduce serum endotoxin levels: it seems to have the property of dampening the effects of exposure to soluble bacterial products that are responsible for activation of inflammation [Navarro-González et al. 2011]. Fetuin-A is a negative acute phase protein involved in bone remodelling in the foetus, having an inhibitory function of calcium phosphate deposition. Fetuin-A deficiency may be responsible for accelerated atherosclerosis in uraemia. In fact, serum fetuin-A concentration is significantly lower in patients on haemodialysis than in healthy controls, showing an impaired ex vivo capacity to inhibit calcium phosphorus precipitation [Ketteler et al. 2003]. Moreover, decreased serum levels of Fetuin-A have been associated with progression of vascular calcification and an increased mortality risk in haemodialysis patients [Cozzolino et al. 2006]. A randomized prospective study conducted on 50 nondiabetic stage 4 CKD patients with hyperphosphataemia evaluated for 8 weeks the effect of short-term sevelamer versus calcium acetate treatment on both serum fetuin-A concentrations and endothelial dysfunction. Results showed that use of sevelamer led to a significant increase in the fetuin-A concentration with improvement in flow-mediated dilation, whereas no significant difference was observed in the calcium acetate group [Caglar et al. 2008].

Another evidence of potential anticalcification mechanisms by sevelamer was found by Brandenburg and colleagues in haemodialysis patients [Brandenburg et al. 2010]. The treatment with sevelamer over 8 weeks, compared with calcium acetate, was associated with a delayed yet long-lasting increase in serum fetuin-A levels, even if the exact mechanism remains unknown.

Administration of calcium-free phosphate binders has found wide application in CKD patient undergoing dialysis, but only few studies demonstrated their potential clinical advantages in early stages of CKD. Recent works indicate that FGF-23, a fibroblast growth factor (FGF) family member produced by osteocytes, may be involved in early CKD–MBD. In response to phosphate overload, FGF-23 acts on the kidney to downregulate the production of 1,25-vitamin D₃ (by suppression of 1-α-hydroxylase) and the expression of the 2a and 2c sodium phosphate cotransporters maintaining serum phosphate level within the normal range. Blunting the increase of serum FGF23 levels in CKD patients may prevent the premature decrease in serum 1,25-vitamin D₃ and the subsequent increase in serum PTH. Potential beneficial effects of lowering FGF-23 levels are suggested by the correlation between FGF-23, vascular calcification, CKD progression, and mortality, although a lower FGF-23 levels could be simply obtained by a better control of phosphate overload. A study in clinically stable CKD stages 3 or 4 patients evaluated whether the administration of two different phosphate binders (calcium acetate or sevelamer hydrochloride) could modify serum PTH and FGF-23. Final data showed that treatment with both phosphate binders reduced serum PTH and urinary phosphate, without changing in serum calcium or serum phosphate. Instead, significant changes were observed in FGF-23 levels only in sevelamer-treated patients [Oliveira et al. 2010].

In contrast, sevelamer may reduce adsorption of vitamin K. An in vitro study conducted to determine the vitamins (B6, B12, C, K and folic acid) adsorption profile of sevelamer HCl and colestilan/colestimide showed that sevelamer HCl had almost complete adsorption of vitamin C, vitamin K and folic acid, but weak adsorption of vitamin B6, and no adsorption of vitamin B12 [Takagi et al. 2010]. Moreover, potential drug interactions between warfarin and sevelamer were studied. In particular, a study showed that sevelamer does not interfere with the absorption or excretion of warfarin [Burke et al. 2001]. The importance of these findings should be underscored, considering that administration of vitamin K antagonists for long-term oral anticoagulation appears to promote vascular calcification by interfering with an important calcification inhibitor, matrix GLA protein [Cozzolino and Brandenburg, 2010]. Therefore, a patient treated by warfarin is probably not a good candidate for any avoidable calcium intake, since an important anticalcification system is already impaired by warfarin administration.

Vitamin D insufficiency and deficiency are common in CKD patients and exogenous vitamin D administration is often required. In healthy volunteers, sevelamer carbonate was found to significantly reduce serum concentrations of calcitriol when administered at the same time with oral calcitriol. In fact, as sevelamer binds bile salts, it may impair the absorption of fat-soluble molecules, such as vitamin D and the already mentioned vitamin K. No specific studies about the interaction between calcitriol and sevelamer HCl have been reported in humans, whereas this finding was observed in beagle dogs. Instead, regarding sevelamer carbonate, a study with 41 volunteers receiving a single dose of calcitriol alone, a single dose of calcitriol plus three doses of lanthanum carbonate or a single dose of calcitriol plus three doses of sevelamer carbonate, demonstrated that sevelamer carbonate, but not lanthanum carbonate, significantly reduces serum levels of exogenous calcitriol when co-administered with oral calcitriol [Pierce et al. 2011]. Figure 1 summarizes the nonclassical effects of sevelamer in CKD.

Figure 1.

Nonclassical effects of sevelamer. Potentially positive effects are in white boxes while negative ones are in grey boxes. FGF, fibroblast growth factor.

Conclusions and perspectives

The abnormalities in bone metabolism commonly found in patients with CKD are associated with an unfavourable prognosis. In fact, there is mounting evidence supporting the association between CKD–MBD and CV risk. In particular, hyperphosphataemia represents one of the most important risk factors, even with minimal variations of phosphate serum levels. In this regard, the matter of calcium intake is the subject of increasing attention in CKD patients. The intake of calcium recommended for healthy elderly people is high, similar to the intake recommended for children and adolescents during growth, in order to remedy the reduction in bone mass seen in this population. Nevertheless, the prevalence of vascular calcification also increases with age, suggesting the adoption of opposite strategies. Some evidence is now questioning the indiscriminate use of calcium supplementation in non-CKD patients. In fact, a study from Bolland and colleagues [Bolland et al. 2008], evaluating non-CKD postmenopausal women, demonstrated that calcium supplementation was associated with upward trends in CV event rate. These data were also confirmed by a meta-analysis [Bolland et al. 2010] showing an association between calcium supplements (without co-administration of vitamin D) and increased risk of myocardial infarction. However, it is not clear by how much the dosage of calcium-based phosphate binders ought to be reduced and which patients at risk of vascular calcification should undergo screening. It is important to reiterate that sevelamer carbonate is a calcium-free phosphate binder that reduces the impact of calcium overload in CKD. Moreover, sevelamer carbonate may ameliorate the CV prognosis in this population by its nonclassical effects. Therefore, it is important to identify new early markers (FGF-23, fetuin-A) of abnormal phosphate homeostasis (even if we cannot suggest to measure them in all CKD patients) so that patients with maximum vascular calcification risk may be identified promptly and treated appropriately.