Phosphorus binders: The new and the old, and how to choose
ABSTRACT
In caring for patients with chronic kidney disease, it is important to prevent and treat hyperphosphatemia with a combination of dietary restrictions and phosphorus binders. This review describes the pathophysiology and control of hyperphosphatemia and 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.
KEY POINTS
- Serum phosphorus is maintained within normal levels in a tightly regulated system involving interplay between organs, hormones, diet, and other factors.
- Dietary phosphorus comes mainly from protein, so restricting phosphorus without introducing protein deficiency is difficult. Food with a low phosphorus-to-protein ratio and plant-based sources of protein may be preferable.
- Although dialysis removes phosphorus, it usually does not remove enough, and many patients require phosphorus-binding drugs.
- Selection of an appropriate binder should consider serum calcium levels, pill burden, serum iron stores, and cost.
Calcium-free binders
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.28 The dose is 300 to 600 mg 3 times daily with meals for a maximum of 4 weeks.
Sevelamer. Approved by the US Food and Drug Administration (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.
The Renagel in New Dialysis25 and Treat-To-Goal29 studies were randomized controlled trials that looked at the effects of sevelamer vs calcium-based binders on the risk of vascular calcification. The primary end points were serum phosphorus and calcium levels, while the secondary end points were coronary artery calcification on computed tomography and thoracic vertebral bone density. Both studies demonstrated a higher risk of vascular calcification with the calcium-based binders.
Another possible benefit of sevelamer is an improvement in lipid profile. Sevelamer lowers total cholesterol and low-density lipoprotein cholesterol levels without affecting high-density lipoprotein cholesterol or triglyceride levels.30 This is likely due to its bile acid-binding effect.31 Sevelamer has also been shown to lower C-reactive protein levels.32 While the cardiovascular profile appears to be improved with the treatment, there are no convincing data to confirm that those properties translate to a proven independent survival benefit.
The Calcium Acetate Renagel Evaluation33 was a randomized controlled study comparing sevelamer and calcium acetate. The authors attempted to control for the lipid-lowering effects of sevelamer by giving atorvastatin to all patients in both groups who had a low-density lipoprotein level greater than 70 mg/dL. The study found sevelamer to be not inferior to calcium acetate in terms of mortality and coronary calcification.
Further studies such as the Brazilian Renagel and Calcium trial34 and the Dialysis Clinical Outcomes Revisited trial failed to show a significant long-term benefit of sevelamer over calcium-based binders. However, a secondary statistical analysis of the latter study showed possible benefit of sevelamer over calcium acetate among those age 65 and older.35
To understand how sevelamer could affect vascular calcification, Yilmaz et al36 compared the effects of sevelamer vs calcium acetate on FGF23 and fetuin A levels. Fetuin A is an important inhibitor of vascular calcification and is progressively diminished in kidney disease, leading to accelerated calcification.37 Patients on sevelamer had higher levels of fetuin A than their counterparts on calcium acetate.37 The authors proposed increased fetuin A levels as a mechanism for decreased vascular calcification.
In summary, some studies 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.
Sucroferric oxyhydroxide comes as a chewable tablet. It was approved by the FDA in 2013. Although each tablet contains 500 mg of iron, it has not been shown to improve iron markers. In terms of phosphorus-lowering ability, it has been shown to be noninferior to sevelamer.39 Advantages include a significantly lower pill burden. Disadvantages include gastrointestinal side effects such as diarrhea and nausea and the drug’s high cost.
Ferric citrate was approved by the FDA in 2014, and 1 g 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.40 The study also showed a decrease in the need to use intravenous iron and erythropoesis-stimulating agents. This was thought to be due to improved iron stores, leading to decreased erythropoietin resistance.41
The mean number of ferric citrate tablets needed to achieve the desired phosphorus-lowering effect was 8 per day, containing 1,680 mg of iron. In comparison, oral ferrous sulfate typically provides 210 mg of iron per day.42
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.43
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.11
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 1 of the following44:
- 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.45
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.
SPECIAL CIRCUMSTANCES FOR THE USE OF PHOSPHORUS BINDERS
Tumor lysis syndrome
Tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.46 Phosphorus binders in conjunction with intravenous hydration are used to treat hyperphosphatemia, but evidence about their efficacy in this setting is limited.
Hypocalcemia in tumor lysis syndrome is usually not treated unless symptomatic, as the calcium-phosphorus product can increase, leading to calcium phosphate crystallization. When the calcium-phosphorus product is greater than 60, there is a higher risk of calcium phosphate deposition in the renal tubules that can lead to acute renal failure in tumor lysis syndrome.47 To lower the risk of calcium phosphate crystallization, calcium-based binders should be avoided in tumor lysis syndrome.
Total parenteral nutrition
Since patients on total parenteral nutrition do not eat, phosphorus binders are considered ineffective; there are no concrete data showing that phosphorus binders are effective in these patients.48 In patients with kidney disease, the phosphorus content in the parenteral nutrition formulation must be reduced.
Pregnancy
Data on phosphorus binders in pregnancy are limited. Calcium can cross the placenta. Calcium carbonate can be used in pregnancy, and fetal harm is not expected if calcium concentrations are within normal limits.49 Calcium acetate, sevelamer, and lanthanum are considered pregnancy category C drugs. Patients with advanced chronic kidney disease and end-stage renal disease who become pregnant must receive specialized obstetric care for high-risk pregnancy.
FUTURE DIRECTIONS
Future therapies may target FGF23 and other inflammatory markers that are up-regulated 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.
