Hyperphosphatemia management in dialysis-dependent chronic kidney disease (CKD) has historically relied on dietary restriction and oral phosphate binders.1 Growing interest in non-binder-based approaches reflects and evolving understanding of intestinal phosphate handling, including active transporter-mediated pathways that may contribute to treatment goals.2,3
Intestinal phosphate absorption involves both passive paracellular diffusion, which is believed to account for a substantial portion of daily uptake under typical dietary conditions, and active transcellular transport mediated by several sodium-dependent mechanisms including the sodium-dependent inorganic phosphate cotransporter NaPi-2b and phosphate inorganic transporters PiT-1 and PiT-2.2,3 Although the relative contribution of specific transporters remains an area of active investigation, regulatory factors such as 1,25(OH)₂D₃ (Calcitriol) and fibroblast growth factor-23 (FGF23) are known to influence expression and activity of multiple components of the transcellular pathway.3,4 In addition, the sodium/hydrogen exchanger isoform 3 (NHE3) has gained attention for its role in facilitating secondary active phosphate absorption and as a potential therapeutic target.4
Traditional phosphate binders act exclusively within the intestinal lumen during meals, forming insoluble complexes with dietary phosphate that are excreted in feces.4 This mechanism inherently limits efficacy to periods of active digestion and requires coordination with food intake.
Targeting active phosphate transporters addresses limitations of binder-based therapy by reducing absorption continuously rather than episodically. Pharmacologic approaches targeting NaPi-2b represent a mechanistic shift from binder-based strategies, acting on active transcellular absorption in the gastrointestinal tract. While selective NaPi-2b inhibitors offered promise, they have not shown clinically meaningful efficacy in hemodialysis populations.5 Alternative inhibitors of intestinal phosphate transport including niacin and nicotinamide have shown variable efficacy in clinical studies.6
An alternative approach targeting NHE3 has emerged with clinical validation.4 Inhibition of NHE3 reduces paracellular phosphate uptake by altering epithelial tight junction permeability, providing a non-binder mechanism to lower serum phosphate levels. Tenapanor, an NHE3 inhibitor that reduces secondary active phosphate absorption in the small intestine, has achieved dose-dependent serum phosphate reductions in phase III trials, with adverse events limited primarily to diarrhea.4 Additional uncommon adverse events included fever and extremity pain, although incidence was not deemed signficant.4 This mechanism works independently of baseline binder regimens, addressing a distinct pathway for therapeutic intervention.4
The mechanistic distinctions merit consideration during treatment planning. Binders require multiple daily doses coordinated with meals, contributing to pill burden, and frequently cause gastrointestinal upset.7 Emerging therapies, such as tenapanor which is typically dosed 30mg twice daily, may simplify regimens and improve tolerability in selected patients, representing a conceptual evolution in addressing hyperphosphatemia in CKD.
Take our hyperphosphatemia quiz to see how your knowledge compares to your peers.
