By Georges N. Nakhoul, MD, Stacey Jolly, MD, MAS, FACP, and Hernan Rincon-Choles, MD
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The balance between dietary intake and excretion of phosphorus can be impaired in patients with decreased renal function, leading to hyperphosphatemia. Many patients with end-stage renal disease on dialysis require phosphorus-binding drugs to control their serum phosphorus levels.
In previous posts, we discussed the pathophysiology and consequences of hyperphosphatemia in kidney disease. Here we discuss the different classes of phosphorus binders with respect to their availability, cost, side effects and scenarios in which one class of binder may be more beneficial than another.
Phosphorus binders reduce serum phosphorus levels by binding with ingested phosphorus in the gastrointestinal tract and forming insoluble complexes that are not absorbed. For this reason they are much more effective when taken with meals. Phosphorus binders come in different formulations: pills, capsules, chewable tablets, liquids and even powders that can be sprinkled on food.
The potency of each binder is quantified by its “phosphorus binder equivalent dose,” i.e., its binding capacity compared with that of calcium carbonate as a reference.
Phosphorus binders are broadly divided into those that contain calcium and those that do not.
The two most commonly used preparations are calcium carbonate (e.g., Tums) and calcium acetate (e.g., Phoslo). While these are relatively safe, some studies suggest that their use can lead to accelerated vascular calcification.
Calcium-containing binders should be avoided in hypercalcemia and adynamic bone disease. Additionally, the daily elemental calcium intake from binders should be limited to 1,500 mg, with a total daily intake that does not exceed 2,000 mg.
The elemental calcium content of calcium carbonate is about 40 percent of its weight (e.g., 200 mg of elemental calcium in a 500-mg tablet of Tums), while the elemental calcium content of calcium acetate is about 25 percent. Therefore, a patient who needs 6 g of calcium carbonate for efficacy will be ingesting 2.4 g of elemental calcium per day, and that exceeds the recommended daily maximum. The main advantage of calcium carbonate is its low cost and easy availability. Commonly reported side effects include nausea and constipation.
A less commonly used calcium-based binder is calcium citrate (e.g., Calcitrate). It should, however, be avoided in chronic kidney disease because of the risk of aluminum accumulation.
There are several calcium-free binders. Some are based on metals such as aluminum, magnesium, iron and lanthanum; others, such as sevelamer, are resin-based.
Aluminum- and magnesium-based binders are generally not used long-term in kidney disease because of the toxicity associated with aluminum and magnesium accumulation. However, aluminum hydroxide has an off-label use as a phosphorus binder in the acute setting, particularly when serum phosphorus levels are above 7 mg/dL. The dose is 300 to 600 mg three times daily with meals for a maximum of four weeks.
Sevelamer. Approved by the FDA in 1998, sevelamer acts by trapping phosphorus through ion exchange and hydrogen binding. It has the advantage of being calcium-free, which makes it particularly desirable in patients with hypercalcemia. Some studies (Renagel in New Dialysis, Treat-To-Goal, Calcium Acetate Renagel Evaluation, etc.) suggest that sevelamer may offer the advantage of decreasing vascular calcification, but the data are mixed and do not provide a solid answer. The main disadvantages of sevelamer are a high pill burden and side effects of nausea and dyspepsia.
Lanthanum, a metallic element, was approved as a phosphorus binder by the FDA in 2008. It comes as a chewable tablet and offers the advantage of requiring the patient to take fewer pills than sevelamer and calcium-based binders.
Lanthanum is minimally absorbed and is eliminated mainly by the hepatobiliary pathway. There were initial concerns regarding possible toxicity from accumulation. However, a study looking at ten-year data on lanthanum use showed no evidence of serious toxicity or accumulation. The most commonly reported side effects were nausea and diarrhea. A disadvantage of lanthanum is its relatively high cost.
Sucroferric oxyhydroxide comes as a chewable tablet. It has been shown to be noninferior to sevelamer. Advantages include a significantly lower pill burden. Disadvantages include gastrointestinal side effects such as diarrhea and nausea and the drug’s high cost.
One gram of ferric citrate delivers 210 mg of elemental iron. The main advantage of ferric citrate is its ability to increase iron markers. The phase 3 trial that demonstrated its efficacy as a binder showed an increase in ferritin compared with the active control. Disadvantages of ferric citrate include high pill burden, high cost and gastrointestinal side effects such as nausea and constipation.
Chitosan binds salivary phosphorus. It can potentially be used, but it is not approved, and its efficacy in lowering serum phosphorus remains unclear.
Choosing the appropriate phosphorus binder
The choice of phosphorus binder is based on the patient’s serum calcium level and iron stores and on the drug’s side effect profile, iron pill burden and cost. Involving patients in the choice after discussing potential side effects, pill burden and cost is important for shared decision-making and could play a role in improving adherence.
Phosphorus binders are a major portion of the pill burden in patients with end-stage renal disease, possibly affecting patient adherence. The cost of phosphorus binders is estimated at half a billion dollars annually, underlining the significant economic impact of phosphorus control.
Calcium-based binders should be the first choice when there is secondary hyperparathyroidism without hypercalcemia. There is no clear evidence regarding the benefit of correcting hypocalcemia, but KDIGO recommends keeping the serum calcium level within the reference range. KDIGO also recommends restricting calcium-based binders in persistent hypercalcemia, arterial calcification and adynamic bone disease. This recommendation is largely based on expert opinion.
Noncalcium-based binders, which in theory might prevent vascular calcification, should be considered for patients with at least one of the following:
- Complicated diabetes mellitus
- Vascular or valvular calcification
- Persistent inflammation
Noncalcium-based binders are also preferred in low bone-turnover states such as adynamic bone disease, as elevated calcium can inhibit parathyroid hormone.
However, the advantage of noncalcium-based binders regarding vascular calcification is largely theoretical and has not been proven clinically. Indeed, there are data comparing long-term outcomes of the different classes of phosphorus binders, but studies were limited by short follow-up, and individual studies have lacked power to detect statistical significance between two classes of binders on long-term outcomes. Meta-analyses have provided conflicting data, with some suggesting better outcomes with sevelamer than with calcium-based binders, and with others failing to show any difference.
Because iron deficiency is common in kidney disease, ferric citrate, which can improve iron markers, may be a suitable option, provided its cost is covered by insurance.
Future therapies may target FGF23 and other inflammatory markers that are upregulated in renal hyperparathyroidism. However, trials studying these markers are needed to provide a better understanding of their role in bone mineral and cardiovascular health and in overall long-term outcomes. Additionally, randomized controlled trials are needed to study long-term nonsurrogate outcomes such as reduction in cardiovascular disease and rates of overall mortality.
This abridged article was originally published in Cleveland Clinic Journal of Medicine.
Dr. Rincon-Choles is staff in the Department of Nephrology and Hypertension. Dr. Jolly is staff in the Department of Internal Medicine. Dr. Nakhoul is Director of the Center for Chronic Kidney Disease in the Department of Nephrology and Hypertension.