LAUSR

Tenapanor inhibits sodium/hydrogen exchanger isoform 3 to reduce intestinal phosphate absorption via reduction of passive paracellular phosphate flux. Phosphate in flux Kidney failure can decrease the excretion of phosphate, leading to elevated phosphate in the blood and cardiovascular complications. King et al. studied whether tenapanor, an inhibitor of the sodium/hydrogen exchanger isoform 3, could help reduce intestinal phosphate absorption. Using rodent models and human intestinal cell–derived monolayers, the authors showed that inhibition of the sodium/hydrogen exchanger isoform 3 reduced urinary sodium and phosphate excretion and cell permeability to phosphate by increasing transepithelial electrical resistance. Administering tenapanor to healthy humans increased stool phosphorus excretion. Understanding tenapanor’s mechanism of action could improve treatment options for hyperphosphatemia. Hyperphosphatemia is common in patients with chronic kidney disease and is increasingly associated with poor clinical outcomes. Current management of hyperphosphatemia with dietary restriction and oral phosphate binders often proves inadequate. Tenapanor, a minimally absorbed, small-molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), acts locally in the gastrointestinal tract to inhibit sodium absorption. Because tenapanor also reduces intestinal phosphate absorption, it may have potential as a therapy for hyperphosphatemia. We investigated the mechanism by which tenapanor reduces gastrointestinal phosphate uptake, using in vivo studies in rodents and translational experiments on human small intestinal stem cell–derived enteroid monolayers to model ion transport physiology. We found that tenapanor produces its effect by modulating tight junctions, which increases transepithelial electrical resistance (TEER) and reduces permeability to phosphate, reducing paracellular phosphate absorption. NHE3-deficient monolayers mimicked the phosphate phenotype of tenapanor treatment, and tenapanor did not affect TEER or phosphate flux in the absence of NHE3. Tenapanor also prevents active transcellular phosphate absorption compensation by decreasing the expression of NaPi2b, the major active intestinal phosphate transporter. In healthy human volunteers, tenapanor (15 mg, given twice daily for 4 days) increased stool phosphorus and decreased urinary phosphorus excretion. We determined that tenapanor reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux, an effect mediated exclusively via on-target NHE3 inhibition.