title: Pharmacologic inhibition of intestinal sodium uptake: a gut centric approach to sodium management.
abstract: OBJECTIVE
  Impaired sodium excretion in patients with chronic kidney disease (CKD) can drive fluid overload and hypertension and accelerate CKD progression. Diuretics reduce fluid overload but require residual kidney function to work. Adherence to dietary sodium restriction is generally poor. Here, we review an alternative pharmacologic strategy aimed at reducing sodium absorption from the gut.
  
  
  RESULTS
  Genetic studies implicate the sodium/hydrogen exchanger isoform 3 (NHE3) as the major absorptive sodium transporter. Pharmacologic inhibition of apically expressed gut NHE3 offers the potential of reducing sodium absorption and fluid overload independent of kidney function and with better safety than systemic drugs. Two small-molecule inhibitors of NHE3 (tenapanor and SAR218034) with minimal systemic exposure reduce urinary sodium and increase stool sodium in a dose-dependent manner in rodents, with similar results observed with tenapanor in humans. These molecules also reduce blood pressure in rat models of CKD (tenapanor) and hypertension (SAR218034). Clinical trials of tenapanor in patients with CKD-related disorders are ongoing.
  
  
  CONCLUSIONS
  Pharmacologic inhibition of gut NHE3 may be a viable strategy for managing sodium load in patients with CKD or with sodium-sensitive hypertension in general. Ongoing clinical trials will shed further light on the potential benefits of this approach.
authors.affiliation: aArdelyx, Inc., Fremont, California, USA bAstraZeneca Research and Development, Mölndal, Sweden.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Spencer
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Greasley
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D007413:Intestinal Mucosa / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D012982:Sodium, Dietary / Q000378:metabolism*
chemical_list: D012982:Sodium, Dietary; D012964:Sodium