Past, Present, and Future of Phosphate Management

Abstract

Cardiovascular (CV) disease (CVD) accounts for >50% of deaths with known causes in patients on dialysis. Elevated serum phosphorus levels are an important nontraditional risk factor for bone mineral disease and CVD in patients with chronic kidney disease (CKD). Given that phosphorus concentrations drive other disorders associated with increased CV risk (e.g., endothelial dysfunction, vascular calcification, fibroblast growth factor-23, parathyroid hormone), phosphate is a logical target to improve CV health. Phosphate binders are the only pharmacologic treatment approved for hyperphosphatemia. Although their safety has improved since inception, the mechanism of action leads to characteristics that make ingestion difficult and unpleasant; large pill size, objectionable taste, and multiple pills required for each meal and snack make phosphate binders a burden. Side effects, especially those affecting the gastrointestinal (GI) system, are common with binders, often leading to treatment discontinuation. The presence of "hidden" phosphates in processed foods and certain medications makes phosphate management even more challenging. Owing to these significant issues, most patients on dialysis are not consistently achieving and maintaining target phosphorus concentrations of <5.5 mg/dl, let alone more normal levels of <4.5 mg/dl, indicating novel approaches to improve phosphate management and CV health are needed. Several new nonbinder therapies that target intestinal phosphate absorption pathways have been developed. These include EOS789, which acts on the transcellular pathway, and tenapanor, which targets the dominant paracellular pathway. As observational evidence has established a strong association between phosphorus concentration and clinical outcomes, such as mortality, phosphate is an important target for improving the health of patients with CKD and end-stage kidney disease (ESKD).

Keywords: chronic kidney disease; end stage renal disease; hyperphosphatemia; phosphate binder; phosphate management; serum phosphorus.

Figure 1

Timeline of phosphate binder development. Phosphate binders were first introduced in the 1970s. Severe safety concerns (e.g., cognitive disorders) were associated with aluminum-based binders, the earliest iteration of phosphate binders. The safety of phosphate binders has improved since their introduction, but adverse effects, particularly those affecting the GI system, are still common for current options. GI, gastrointestinal.

Figure 2

Intestinal phosphate absorption pathways.^,, (a) Phosphate absorption in the intestines takes place by the transcellular and the paracellular pathways. Phosphate uptake through the secondary transcellular pathway is facilitated by the sodium-dependent phosphate transporter NaPi2b. Passive phosphate diffusion in the dominant paracellular pathway occurs along the concentration gradient through tight junctions. (b) Tenapanor is a nonbinder phosphate control therapy that reduces paracellular phosphate absorption by decreasing tight junction permeability to phosphate.

Figure 3

Chronic kidney disease is a multifactorial disease that affects many physiological processes. The multifactorial nature of chronic kidney disease complicates the use of current surrogate outcomes in phosphate binder trials. (a) Ideally, an intervention influences the patient-centered or clinical outcome exclusively through the surrogate outcome. (b) This idealized situation may not be true for phosphate binder trials. Multiple confounding pathways (red arrows) between the surrogate and patient-centered or clinical outcome may induce correlation without causation. In addition, both favorable (blue arrows) and unfavorable (purple arrows) alternative pathways between the surrogate and patient-centered or clinical outcome may mean that the impact of the intervention on the clinical outcome is not fully captured by the surrogate outcomes.