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 due to “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 1,400-2,500 mg of phosphate potentially consumed daily. Over the last decade, serum phosphate levels in the US 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, non-binder 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.

Hyperphosphatemia in Chronic Kidney Disease: The Search for New Treatment Paradigms and the Role of Tenapanor

“…It has been observed that the limited intracellular proton retention induced by NHE3 inhibitors leads to a pH-related conformational change in specific tight junction proteins, named claudins, with resulting reduction in the transepithelial permeability to phosphate and then decrease in phosphate absorption. 59,60 Based on these mechanisms, growing evidence is accruing on promising pharmacological agents able to interfere with phosphate absorption, targeting one of the two described pathways rather than bind dietary phosphate in the gastrointestinal tract.…”

“…Active transcellular transport is mediated by specific transporters such as the sodium-dependent phosphate 2b transport protein (NaPi2b), whose expression is regulated by serum phosphorus values through modifications in activated vitamin D3 levels, or type-III inorganic phosphate (Pi) transporters PiT-1 and PiT-2. 58 , 59 Conversely, passive paracellular transport occurs through tight junction complexes along the concentration gradient and involves the sodium/hydrogen exchanger isoform 3 (NHE3). This isoform is largely expressed at the gastrointestinal level where it transports sodium ions into cells in exchange for hydrogen ions, in this way playing a crucial role in maintaining water and acid-base balance homeostasis.…”

“…It has been observed that the limited intracellular proton retention induced by NHE3 inhibitors leads to a pH-related conformational change in specific tight junction proteins, named claudins, with resulting reduction in the transepithelial permeability to phosphate and then decrease in phosphate absorption. 59 , 60

Figure 1 Schematic representation of intestinal phosphate transport.

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