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Phosphate binders in chronic kidney disease

Hyperphosphataemia is common in the late stages of chronic kidney disease and use of intestinal phosphate binders is required

Corentin Gui MD
Pablo Ureña-Torres MD PhD
Ramsay Générale de Santé, Service de Néphrologie et Dialyse, Clinique du Landy; Department of Renal Physiology, Necker Hospital, University of Paris Descartes, Paris, France
The progression of chronic kidney disease (CKD) leads to the deterioration of numerous kidney functions and the development of different complications, including mineral and bone disorders (MBD), partly responsible for the increased risk of cardiovascular morbidity and mortality.1 If secondary hyperparathyroidism (SHPT) is an early and almost constant complication, hyperphosphataemia, directly toxic for the vascular endothelium and vessels wall, occurs late, and the two promote vascular calcifications and increase cardiovascular mortality.2,3
This is the case in patients suffering from CKD, but high serum phosphate levels even within normal limits is also associated with increased risk of mortality in the general population.4 Fibroblast growth factor 23 (FGF23) hormone, in the early stages of CKD, maintains the renal excretion of phosphate, despite the drop in glomerular filtration rate (GFR), but it also inhibits the 1α-hydroxylase activity and the conversion of 25(OH)D into active vitamin D or calcitriol.5
Hyperphosphataemia also stimulates parathyroid hormone (PTH), which also stimulates the urinary excretion of phosphate, but in contrast to FGF23, PTH stimulates calcitriol synthesis. The diminution of expression and renal production of klotho, the FGF23 co-factor receptor, renders the proximal renal tubule resistant to the phosphaturic action of FGF23.6
In the advanced stages of the CKD (stage 4–5), and especially in dialysis patients, hyperphosphatemia becomes a common complication. The traditional methods of dialysis do not make it sufficiently possible to eliminate all the daily phosphate provided by the diet. Nocturnal haemodialysis and daily haemodialysis, which are the most efficient methods, are poorly accessible. Therefore, the treatment of hyperphosphatemia in CKD essentially relies on two measures:  1) Restriction of daily phosphate intake, which is often inefficient and even very dangerous, and which may cause malnutrition. 
Indeed, the phosphorus content in foods significantly correlates with the protein content and a reduction of inputs of phosphorus at less than 40mmol/day (1000mg per day), is practically impossible without nutritional deficiency in proteins.7 2) Ingestion of intestinal phosphate binders.
Since 2009, the new Kidney Disease Improving Global Outcomes (KDIGO) International recommendations refer neither to target phosphate levels, nor to the degree of the circulating concentration of CaxP product, but recommend trying to get ‘serum phosphate levels approaching normality’.8
It is important to note here that the correction of the serum phosphate levels by dietary measures or intestinal phosphate binders could potentially improve the survival of dialysis patients. However, no randomised controlled trial has thus far demonstrated this. 
Types of phosphate binder
There are aluminium, calcium, magnesium and iron-based intestinal phosphate binders, as well binders without calcium and without aluminium. All of them are efficient and capable of significantly reducing phosphate levels (Table 1). Yet, no study has shown that a binder is more efficient than others in terms of control of the serum phosphate levels in CKD. By contrast, phosphate binders differ from one another to a certain extent, when it comes to their mode of action, just as they differ in their capacity to bind to the intestinal phosphate. 
Moreover, intestinal phosphate binders that do not contain calcium are associated with a reduction of mortality in the order of 22%, compared with those that do contain calcium as shown by a meta-analysis of over 4600 patients carried out at the Woman’s Hospital College of Toronto.9
Another meta-analysis, comprising 25 studies and 4770 patients (88% receiving dialysis and 12% suffering from stages 3–5 CKD has corroborated these results, showing a reduction of 46% of the risk of mortality of all causes, but not of cardiovascular mortality.10 However, these results are yet to be confirmed, because there was no control group placebo treated patients in the studies analysed. 
The first drugs in the history of intestinal phosphate binding to be used were high potency aluminium-based gels that are rarely used today due to their neurological, haematological and bone toxicities.11
Aluminium-based phosphate binders were followed by calcium salts (carbonate and acetate), which are the first-line intestinal phosphate binders, for reasons of cost, as well as for their beneficial action on a possible correction of mild hypocalcaemia. The mode of action consists in a selective phosphate binding in the digestive tract by dissociating in calcium and their respective anions. 
The calcium component and the dietary phosphate then form an insoluble phosphocalcic precipitate. Phosphate absorption is blocked as a result and faecal elimination facilitated. However, a certain quantity of calcium provided by these calcium-based salt binders can be absorbed and can result in a positive calcium balance. This is why they have been incriminated, rightly or wrongly, in the upsurge of cardiovascular calcifications. 
Furthermore, the calcium carbonate may not be very efficient in patients treated concurrently with proton pump inhibitors. In all cases, it is recommended not to administer the calcium salts at a dose greater than 1.5g of calcium component per day.8
Sevelamer (hydrochloride then carbonate) is the first polymer representative of non-calcium-based intestinal phosphate binders. It exchanges chloride ions for phosphate ions in a high pH medium, like the small intestine. The complex resulting from sevelamer–phosphate binding is insoluble and easily excreted via the faeces. It has an excellent affinity for phosphate, comparable to that of aluminium hydroxide and lanthanum carbonate. Its efficiency with regard to controlling serum phosphate levels has largely been demonstrated. 
Furthermore, this binder has a beneficial effect on the lipid profile and can reduce the circulating concentration of total cholesterol and LDL. It also reduces markers of inflammation, such as the C-reactive protein (CRP), uric acid and glycosylated haemoglobin. Moreover, it has been demonstrated that it does not aggravate vascular calcifications.12–14 Better yet, it can alleviate their formation and progression. Nevertheless, taking several sevelamer pills is necessary to achieve the desired outcome. 
According to Curtin et al.,15 this is how 70% of haemodialysis patients do not often comply with their treatment by phosphate binder. Gastrointestinal disorders, metabolic acidosis (for sevelamer hydrochloride) and reduction of lipid-soluble vitamins (A, D, E, K), have been observed in a CKD patients.16 The cost of sevelamer remains high and is a limiting factor to its use.
Lanthanum carbonate separates in the upper part of the digestive tract (acidic medium) where its trivalent cations bind to the dietary phosphorus to form the insoluble and non-absorbable lanthanum phosphate complexes, which are eliminated in the faeces. 
The binding and elimination of lanthanum occur independently from the pH, which is the probable explanation of its great power as a phosphate binder compared with the two calcium binders. This binder is also believed to have a favourable effect on the risk of mortality in dialysis patients. The number of pills and their taste has a negative impact on compliance; this is especially the case for chewable tablets. The powder form seems to be better tolerated. 
A documented adverse reaction with lanthanum carbonate is peripheral oedema. Lanthanum is a trivalent cation often wrongly compared to other heavy metals such as aluminium. This suggested that it could accumulate in tissues, like the bone and the brain, as does aluminium. 
However Behets et al.17 showed that lanthanum does not accumulate in these organs and intestinal absorption of lanthanum is minimal (0.00089% in humans versus 0.01% to 0.1% for aluminium). Like sevelamer, the cost of this intestinal phosphate binder remains high and limits its use in a number of countries. 
Dialysis patients tend to have low serum concentrations of magnesium. This is associated with an increased risk of mortality. A phosphate binder combining calcium carbonate with magnesium carbonate has therefore been proposed. Intakes of magnesium would, on the one hand, protect against cardiovascular calcifications and, on the other, reduce the negative effects of the calcium carbonate. The magnesium would also facilitate PTH control by acting as an agonist of the parathyroid calcium-sensing receptor. It would also have anti-arrhythmic effect at the cardiac level. 
Several comparative studies have shown the hypophosphataemia effect of magnesium-based binders.16 However, its potentially beneficial effects on morbi-mortality in dialysis patients still remain to be demonstrated through randomised studies. These products have a major asset: their low cost, which makes them suitable for developing countries.
Colestilan, a new resin, has demonstrated a chelating ability similar to sevelamer.16 Compared with placebo, this medication significantly reduces the levels of blood phosphate. Moreover, similar to sevelamer, it also has a favourable effect on the reduction of total cholesterol, LDL, HbA1c, and uric acid. The frequency and severity of gastrointestinal side effects must be notified, because they limit its use. Although cheaper than sevelamer, it is still quite costly. 
The newcomers in the arsenal of intestinal phosphate binders are iron based.18 They exist in two pharmaceutical forms: ferric citrate and ferric oxyhydroxide. They are presented as efficient and safe, in the absence of proper evaluation. Ferric citrate acts by trapping dietary phosphate with the iron molecules, thereby reducing its intestinal absorption and increasing excretion in the faeces. 
Ferric oxyhydroxide uses ligand exchange between dietary phosphates and hydroxyl groups and/or the water contained in its molecule. It is worth pointing out that the iron absorption with the ferric citrate is significant. This can lead to a reduction of iron requirements and erythropoietin in patients receiving intravenous iron rather than those whose ferritin count/saturation in transferrin is high. 
In short, the administration of intravenous iron may prove useless with ferric citrate. The side effects related to these two medicines are predominantly gastrointestinal in nature, aside from the risk of iron overload, which may be induced by ferric citrate. There is a drug interaction between ferric oxyhydroxide and levothyroxine (Table 2). The cost of iron-based binders is between that of calcium-based binders, sevelamer and lanthanum. 
Thus, a therapeutic regimen for the taking of intestinal phosphate binders can be proposed: start with a calcium-based binder if serum calcium levels, PTH and the absence of cardiovascular calcification allow it, without exceeding 1.5g of calcium component per day. 
In case of low efficiency, one should, either add a non-calcium-containing phosphate binder to the calcic binder, or substitute the calcic binder with a non-calcic binder. It certainly remains open to the prescriber to first offer the binder of his/her choice, because there are no clear guidelines on this matter. 
For these intestinal phosphate binders to be as efficient as possible, they must always be taking during a meal or with a snack and preferably in the middle of the meal or snack. 
Finally, the intestinal phosphate binder must be adapted to the patient, and the best binder is, and remains, that which the patient actually takes.
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