Phosphate binders, past – present – future. A critical appraisal.

‘Practice two things in your dealings with disease: either help or do not harm the patient’,[1] the great master said. And, this has been the cornerstone of medical practice. At the same time it represents our greatest burden, each and every morning we wake up, each and every night we stay awake during a night shift. Is the only doctor protected from mistakes the one who doesn’t do anything…? Of course it is not what Hippocrates meant, since it is questionable whether luck of action is always the equivalent of safety. Having these always in mind, for the past few decades we have been dedicated in the continuous battle of understanding and treating chronic kidney disease (CKD) and its complications; our results have been variable throughout this time.

It has been shown, and it is now generally accepted that chronic kidney disease mineral bone disorder (CKD-MBD) is one of the main determinants responsible for increased cardiovascular morbidity and mortality.[2] Cardiovascular calcification, impaired bone function, impaired cardiac function, electrolyte disorders (mainly calcium and phosphate), parathormone and FGF-23 secretion disorders and vitamin D deficiency are among the many characteristics of this syndrome. They have been even incriminated for the increased pain, poor sleep quality and diminished quality of life experienced by end-stage renal disease patients.[3] Fortunately, modern medicine has offered us the means to ameliorate and sometimes even improve the deleterious effects of this condition. Multiple targets have been designated; for the time being, in the present manuscript we try to approach treatment itinerary of hyperphosphatemia.

Phosphates represent one of the most common ingredients in modern world diet. As renal function deteriorates, human organism’s capability to excrete phosphate excess diminishes and becomes virtually inexistent in end-stage renal disease. Phosphate overloads leading to a permanent status of hyperphosphatemia in CKD patients, has been shown to be a strong and independent determinant of vascular calcification.[4,5] Inevitably, hyperphosphatemia has become, at least for the past 25 years, one of the major treatment targets in CKD patients. In the context of being preferable to prevent, rather than to treat, nephrologists all over the globe suggest dietary phosphate restriction. An absolute phosphate free diet represents for the moment an unattainable and unrealistic target. This is valid both because phosphate is a major constituent in most organic foods, rendering any attempt to completely eliminate it, to an inadequate diet (in the long-term), and because the majority of modern world patients are not willing to follow such a diet for an extended time period. Great master Hippocrates in his manuscript ‘Diseases’ ingeniously mentioned that medical art has three determinants: the disease, the patient and the doctor; the doctor and the patient should fight together and the doctor should be a servant of his art. That being said, we found out shortly in the course of chronic kidney disease that extreme diets are cumbersome and even when patients follow them faithfully, they might experience serious undesirable effects, as malnutrition. Besides doctors’ dietetic indications, anorexia is having an additive role in protein-energy malnutrition encountered in CKD patients.[6] Even though modern societies live in an era of over nutrition, malnutrition and protein-energy wasting have been recognized among the strongest risk factors for adverse outcomes in end-stage CKD patients and should be addressed.[7] On the other hand there is a small percent of end-stage renal disease patients, who are normo- even hypo-phosphatemics in spite of eating substantial amount of phosphate. This can usually be encountered in patients undergoing nocturnal hemodialysis[8] and occasionally after parathyroidectomy.[9]

The next best thing from preventing consumption of phosphates, is to prevent their absorption. And the use of phosphate binders rose. Actually, the first drugs used were already known for their effects since the 50’s and were used in the management of renal phosphatic calculi.[10] Probably following that knowledge, aluminum-based phosphate binders were the first binders used and the strongest so far. Fine then, problem solved; we had a cheap binder and extremely effective all the same. Well, not really; aluminum-based binders were ultimately proven harmful,[11] as they were absorbed and accumulated themselves, leading in serious central nervous system, bone toxicity and even microcytic anemia in CKD patients. Even though a few eminent doctors pointed out their observations regarding aluminum toxicity, it took us a couple of decades to finally accept it. Now, aluminum-based phosphate binders might be allowed only as a short course treatment for patients with elevated serum phosphate levels. In our institutions we avoid them at all costs.

Back to square zero. A replacement was urgently needed. In the mid 80’s, calcium containing phosphate binders started to make their appearance.[12] Two compounds have been extensively used since then, calcium carbonate and calcium acetate. Calcium-based phosphate binders (CCB) are well tolerated, reasonably effective and they have a low cost. Ok! Problem solved right? Well, not quite, increased doses of calcium containing binders have been incriminated for increased cardiovascular calcification.[13] Now it is not advisable to use doses over 1.5 g. Lower doses might not be that harmful, but they are less effective also. Their use in the presence of signs of vascular calcification should be considered very carefully and rather avoided. Nevertheless, they could be considered in a more limited number of cases. In everyday practice, we might come along a small number of patients presenting low calcium levels and borderline high phosphate levels, accompanied by relatively high intact parathormone levels. Administration of CCB in this subgroup of patients might be appropriate and effective.

Inevitably, the appearance and probably the fear of the afore mentioned complications have lead to the necessity of a new class of binders. Non-calcium and non-aluminum based phosphate binders emerged.[14] Sevelamer is the first representative of its class. Fortunately, sevelamer hydrochloride initially and carbonate latter, was proven to be an effective phosphate binder showing also additional favorable effects, as for example lowering low density lipoprotein cholesterol levels. Thus, it has been shown that sevelamer does not aggravate vascular calcification and in many instances it will reduce its formation.[15] Ok then, we have now a non-absorbable binder with additional favorable effects on vascular calcification. The only minor trouble is that a great number of sevelamer pills are needed daily in order to achieve the desirable serum phosphate levels and a few patients might experience, as with other phosphate binders, some gastrointestinal discomfort. Additionally, cost is another factor that might have limited its prescription in some countries. Although recently their retail price seems to have a decreasing tendency in some western countries and this will probably lead to even lower prices as we are looking at the end of patent protection.

Lanthanum carbonate, is the next non-calcium containing phosphate binder. It is a potent binder, usually needs fewer pills to achieve the desirable effect. This binder also has a favorable effect in reducing mortality risk. Similarly, for this binder, elevated cost is an issue. Furthermore, lanthanum carbonate pills are chewable, fact which because of its taste constitutes a major drawback for some patients, as like all phosphate binders, they should be consumed during meals.

Calcium–magnesium binders, also appeared relatively recently. Magnesium is known for its protective action against calcification and it is not a surprise that has a favorable effect on vascular calcification. Either alone,[16] or in combination with calcium, is an effective phosphate binder. Nevertheless, caution is needed to avoid prescribing increased doses in order to avoid calcium burden. Because of its low cost, it represents an appealing binder, at least in low income countries. Calcium and magnesium levels should be monitored carefully.

The future?

A newly introduced phosphate binding agent is colestilan. Colestilan has been already known since the early 2000 for its favorable effect on hypercholesterolemia, acting as a bile acid-binding resin. Similar to sevelamer, colestilan is a non-calcium containing, non-absorbable phosphate binder with additional favorable effect on low density lipoprotein levels.[17] The frequency and gravity of gastrointestinal side effects and the actual retail cost remains to be specified.

Iron-based phosphate binders. Ferric citrate and sucroferric oxhydroxide [18] belong to a new class of phosphate binders.[19] They are considered to be safe and effective, even though large scale studies are not completed yet. Beside the fact that they are both iron-based, they seem to have a distinctive difference, iron absorption. With ferric citrate, absorption of iron is significant, leading to reduced need for i.v. iron and epoetin. This effect should be taken into account both in patients in need for iron administration, as well as in those with already elevated ferritin/transferrin saturation levels. In the latter additional iron administration might not be desirable. Both binders present gastrointestinal side effects, but this time diarrhea seems to be leading cause of discomfort. Here also, retail price in not yet established for most western countries.

Among recent findings, the role of intestinal phosphate co-transporters is gaining importance. Thus, of increased importance seems the role of Npt2b as a therapeutic target in hyperphosphatemia [20]; and binders as nicotinamide might represent a future alternative. They also seem to have adverse events like diarrhea, flushing and nausea.

Expert opinion

All things considered, phosphate binders (Table 1) should be patient-tailored. It might be wise to start early during the course of CKD, immediately after serum phosphate levels are over laboratory normal values, in an attempt to delay vascular calcification and its deleterious consequences. Calcium burden, makes calcium-containing phosphate binders, mainly an adjuvant therapy, that has its place in cases of hypocalcemia, but should be carefully considered and even questioned when signs of vascular calcification are apparent. Newer phosphate binders, are for the time being a safe alternative. When extremely elevated doses of a binder are needed to reach suggested phosphate levels, a combination of different binders might be a safer alternative, in order to avoid piling up side effects that usually lead to non-compliant patients. Future binders could also constitute a useful alternative for some of our patients.

Table 1. Phosphate binders used to prevent intestinal phosphate absorption.

Intestinal phosphate binders
Aluminum hydroxide
Calcium carbonate
Calcium acetate
Calcium acetate and magnesium carbonate
Sevelamer hydrochloride
Sevelamer carbonate
Lanthanum carbonate
Colestilan
Nicotinamide
Ferric citrate
Sucroferric oxhydroxide

Practice two things in your dealings with disease: either help, or do not harm the patient.

Financial and competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.