Tenapanor Beyond Phosphate: Gut Sodium Transport, Stool Transit, and Volume Balance in Dialysis

INTRODUCTION: Tenapanor, a minimally absorbed intestinal NHE3 inhibitor approved for hyperphosphatemia in dialysis, lowers phosphate and reduces intestinal sodium absorption. Its sodium-water signal may have implications beyond phosphate but remains poorly separated from diarrhea-mediated losses and dialysis prescription artifacts. METHODS: This perspective synthesizes pharmacologic, trial, dialysis physiology, and CKD-MBD evidence to propose a hypothesis-generating framework for evaluating tenapanor beyond serum phosphate. We focused on intestinal sodium handling, stool transit, interdialytic weight gain, ultrafiltration stress, hemodynamic tolerance, and fibroblast growth factor 23. FINDINGS: Tenapanor-associated diarrhea and modest serum sodium reduction should be interpreted not only as tolerability events but also as potential markers of on-target intestinal sodium-water modulation. In selected phenotypes, reduced effective sodium loading could theoretically attenuate thirst, lower interdialytic weight gain, and reduce ultrafiltration demand; in others, diarrhea-mediated losses could worsen hypovolemia or intradialytic instability. Tenapanor-induced fibroblast growth factor 23 reduction is biologically plausible but remains an unvalidated bridge to cardiovascular or patient-centered outcomes. DISCUSSION: Future studies should prospectively distinguish sodium-volume benefit from gastrointestinal intolerance using standardized dialysis endpoints, stool metrics, dialysate sodium data, bioimpedance, and imaging or patient-centered outcomes. Tenapanor should therefore be studied as an intestinal sodium-phosphate-volume intervention, not merely a phosphate-lowering drug.