Primer on Phosphate Binders
All patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD) will require management of phosphorus levels. Dietary therapy may provide control in some patients, but most will require drugs to reduce the amount of this material absorbed from the diet.
What is phosphorus?
First, phosphorus is important, something our bodies can’t live without. Inorganic phosphorus participates in intracellular signal transduction, cell membranes, and energy storage and production. Most phosphorus resides in bone and teeth, with significant amounts within the cells that make up the body’s tissues. A relatively small portion circulates in the blood as various phosphates.
In the US, adults typically ingest 1200 mg of phosphate each day. Dairy products, meats, and whole grains are the most important sources. Between 2/3 and 3/4 of the ingested load is absorbed by the gut. This same amount must be excreted by the kidneys to maintain a steady-state.
Because so many foods contain phosphorus, dietary efforts alone cannot usually normalize serum phosphate levels with kidney disease. Very restricted diets can compromise nutritional status, increasing risks as much as high phosphate levels do. Since the beginning of treatment of CKD, a variety of drugs have been used to bind phosphorus in the gut so it cannot be absorbed.
A brief history of binders
Through the mid-1980s aluminum was the binder of choice. This element was effective, but not the tastiest medication. It could be baked into pastries, though, and Amphojel cookies were on the formulary during my medical school nephrology rotation in 1984. Unfortunately, with no renal route to clear aluminum, this metal proved to be more toxic than the phosphorus. Encephalopathy, dementia, osteomalacia, and anemia led to the abandonment of aluminum.
Calcium preparations became the dominant binder by the time I started my nephrology training in 1988. Calcium carbonate and calcium acetate, both used as antacids and supplements, proved to reduce phosphorus effectively and apparently safely. Some patients had gastrointestinal complaints, but overall it looked like a win-win situation. Some patients did get high blood calcium levels, even though their phosphorus levels remained high; then what should we do? Also, calcium interacted with other medications and prevented their absorption. Patients had to take some medications at the beginning of meals and others afterwards. Complicated regimens do not improve treatment adherence.
We needed calcium-free binders. Still.
In 1998 Sevelamer (Renagel) received FDA approval. This anion-exchange resin bound phosphorus effectively but had few interactions with other medications. It had no taste or odor. It was expensive, but it gave us another option. Sevelamer also produced some gastrointestinal side effects, and it had a tendency to bind bicarbonate. The latter issue led to FDA-approval of Sevelamer Carbonate in 2007. This new formulation provided another important option: a non-tablet formulation. Packets of powdered Renvela could be added to food or liquids. The downside of these agents? Cost- Renagel runs 4- to 8-times the cost of calcium based agents, with Renvela 5- to 10-fold higher.
The newest binder is Lanthanum carbonate (Fosrenol), a chewable tablet that received FDA approval in 2004. This element is #57 in the periodic table, found in the upper row of elements beneath the main table. It avidly binds phosphorus with minimal, if any, systemic absorption. Long-term effects are unknown.
Other agents of interest are under development. Magnesium has traditionally been avoided in CKD patients because it can accumulate and cause neurotoxicity; however, magnesium is an excellent phosphorus binder. New preparations may allow it to be used without significant absorption. Colestilan, another anion-exchange resin, has reduced serum phosphate in short-term clinical trials. Niacin and nicotinamide can also reduce levels, perhaps by inhibiting sodium-dependent transport in the gut. They could also produce a once-a-day drug to reduce phosphate absorption. Another recent development takes advantage of the markedly elevated salivary phosphate concentration in CKD patients. A chewing gum binder has proven effective in small, short-term studies.
Why do we need new binders?
No single agent can be tolerated by all patients, so we need therapeutic choices. The most pressing reason for non-calcium binders though is the recognition of the role of vascular calcification in morbidity and mortality in CKD patients. Could calcium in binders raise the risk of vascular calcification? If so, non-calcium binders could present an advantage, especially in adult patients. No study to date has conclusively shown an advantage to non-calcium binders in cardiovascular endpoints. Yet.
How do we prescribe binders currently?
Most nephrologists start with calcium carbonate or calcium acetate, as long as blood calcium levels are normal. Doses are increased until the patient has normal phosphate levels, hypercalcemia, or cannot tolerate the side effects. At that point, either a Sevelamer preparation or Lanthanum is added and advanced using the same criteria. In some patients all 3 binders may eventually be used.
Nutritional consultation also must be performed. While dietary phosphorus reduction helps, the dietitian needs to assure adequate nutritional intake as well.