PHARMACOLOGY AND THERAPEUTICS: Edited by Adam Whaley-Connell and C. John SperatiPharmacologic inhibition of intestinal sodium uptake a gut centric approach to sodium managementSpencer, Andrew G.a; Greasley, Peter J.bAuthor Information aArdelyx, Inc., Fremont, California, USA bAstraZeneca Research and Development, Mölndal, Sweden Correspondence to Andrew G. Spencer, Ardelyx, Inc. 34175 Ardenwood Boulevard Suite 100, Fremont, CA 94555, USA. Tel: +1 510 745 1700; e-mail: [email protected] Current Opinion in Nephrology and Hypertension: September 2015 - Volume 24 - Issue 5 - p 410-416 doi: 10.1097/MNH.0000000000000154 Buy Metrics Abstract Purpose of review 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. Recent findings 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. Summary 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. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.