title: Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD.
abstract: In CKD, phosphate retention arising from diminished GFR is a key early step in a pathologic cascade leading to hyperthyroidism, metabolic bone disease, vascular calcification, and cardiovascular mortality. Tenapanor, a minimally systemically available inhibitor of the intestinal sodium-hydrogen exchanger 3, is being evaluated in clinical trials for its potential to (1) lower gastrointestinal sodium absorption, (2) improve fluid overload-related symptoms, such as hypertension and proteinuria, in patients with CKD, and (3) reduce interdialytic weight gain and intradialytic hypotension in ESRD. Here, we report the effects of tenapanor on dietary phosphorous absorption. Oral administration of tenapanor or other intestinal sodium-hydrogen exchanger 3 inhibitors increased fecal phosphorus, decreased urine phosphorus excretion, and reduced [(33)P]orthophosphate uptake in rats. In a rat model of CKD and vascular calcification, tenapanor reduced sodium and phosphorus absorption and significantly decreased ectopic calcification, serum creatinine and serum phosphorus levels, circulating phosphaturic hormone fibroblast growth factor-23 levels, and heart mass. These results indicate that tenapanor is an effective inhibitor of dietary phosphorus absorption and suggest a new approach to phosphate management in renal disease and associated mineral disorders.
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Labonté
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Carreras
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Leadbetter
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kozuka
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Jill
authors.initials: J
authors.lastname: Kohler
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Samantha
authors.initials: S
authors.lastname: Koo-McCoy
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Limin
authors.initials: L
authors.lastname: He
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Edward
authors.initials: E
authors.lastname: Dy
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Deborah
authors.initials: D
authors.lastname: Black
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Ziyang
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Langsetmo
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Spencer
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Noah
authors.initials: N
authors.lastname: Bell
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Desiree
authors.initials: D
authors.lastname: Deshpande
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Marc
authors.initials: M
authors.lastname: Navre
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Lewis
authors.affiliation: Ardelyx, Inc., Fremont, California.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Jacobs
authors.affiliation: Ardelyx, Inc., Fremont, California dcharmot@ardelyx.com.
authors.forename: Dominique
authors.initials: D
authors.lastname: Charmot
mesh_terms: D000818:Animals; D002114:Calcinosis / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D010758:Phosphorus / Q000652:urine*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D007546:Isoquinolines; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D013449:Sulfonamides; D010758:Phosphorus; D012964:Sodium; C000599417:tenapanor
keywords: coronary calcification; epithelial sodium; hyperphosphatemia; hypertrophy; intestine; phosphate uptake; transport