Managing Phosphate Burden in Patients Receiving Dialysis: Beyond Phosphate Binders and Diet

Abstract

Most patients receiving dialysis rely on dietary restriction and phosphate binders to minimize the risk of hyperphosphatemia, which is associated with increased mortality. However, dietary restriction is difficult because of hidden phosphate additives in processed foods and medications. Restriction of dietary phosphate sources such as protein may increase the risk of malnutrition. Phosphate binders, the only pharmacologic option for phosphate management since aluminum salts were introduced several decades ago, are often insufficient for binding the 1400-2500 mg of phosphate potentially consumed daily. Over the last decade, serum phosphate levels in the United States have risen, and >69% of patients receiving dialysis exhibited a most recent phosphate level >4.5 mg/dl (above the normal range), indicating an urgent need for new, more effective therapies to manage phosphate burden. Novel, nonbinder therapies such as transcellular and paracellular phosphate absorption inhibitors may be used for phosphate management, and future studies should examine whether they allow fewer dietary restrictions for patients receiving dialysis, potentially improving patient quality of life and nutritional status. It is imperative that we collaborate to move beyond the restrictive approaches available today and provide patients and clinicians with an array of strategies so that they may choose the most appropriate patient-centered therapy.

Figure 1

Timeline of phosphate management strategies. Over the last 50 years, minor changes in the phosphate binder drug class have been introduced through use of different active ingredients.

Figure 2

Phosphate binders are insufficient to match daily dietary phosphate intake.^–, The binding capacity of phosphate binders is too low to account for daily phosphate intake, particularly for diets high in hidden phosphates.

Figure 3

Reasons for phosphate binder discontinuation. Approximately half of patients who discontinued phosphate binders cited gastrointestinal (GI) upset as the reason for discontinuation.

Figure 4

Intestinal phosphate absorption pathways. (A) Intestinal phosphate absorption occurs through the transcellular and paracellular pathways. Absorption through the secondary transcellular pathway is facilitated by the sodium-dependent phosphate transporter NaPi2b. In the primary paracellular pathway, phosphate is absorbed passively along the concentration gradient through tight junctions. (B) Tenapanor reduces permeability of tight junctions to phosphate, reducing paracellular phosphate absorption. NaPi2b, sodium-dependent phosphate transporter 2b; NHE3, sodium/hydrogen exchanger isoform 3.

Figure 5

Phosphate absorption inhibitor trials. Two new classes of phosphate management drugs, transcellular and paracellular phosphate absorption inhibitors, are in development.