Mary C Perianayagam1, Bertrand L Jaber. 1. Department of Medicine, Division of Nephrology, Kidney and Dialysis Research Laboratory, Caritas St Elizabeth's Medical Center, Boston, Massachusetts 02135, USA.
Abstract
BACKGROUND: Sevelamer hydrochloride has been shown to attenuate circulating biomarkers of inflammation in patients with chronic kidney failure. We hypothesize that sevelamer hydrochloride binds bacterial endotoxin (ET) resulting in a decrease in ET levels and cytokine production. METHODS: To assess the ET-binding affinity of sevelamer hydrochloride, purified Escherichia coli ET was incubated with sevelamer hydrochloride (0-50 mg/ml). After incubation, ET was measured in supernatants. In addition, THP-1-derived monocytes were co-incubated with supernatants of sevelamer hydrochloride and ET. After 24-hour incubation, TNF-alpha was measured. The effect of pH on the ET-binding affinity of sevelamer hydrochloride, as well as cooperative binding between ET and phosphate for sevelamer hydrochloride were assessed. RESULTS: Sevelamer hydrochloride exhibited time- and dose-dependent binding affinity for ET, resulting in a marked reduction in free ET levels. The 1-hour dose-dependent ET-binding effect of sevelamer hydrochloride translated into a marked reduction in TNF-alpha levels. Varying the pH conditions did not affect the ET-binding affinity of sevelamer hydrochloride. The addition of phosphate (0-50 mM) resulted in a further reduction in free ET levels, translating into a further increase in the binding affinity of sevelamer hydrochloride for ET. CONCLUSIONS: This study demonstrates that sevelamer hydrochloride binds to ET, thereby reducing free ET and cytokine levels. Positive cooperative binding was also noted between phosphate and ET for sevelamer hydrochloride. This study supports the hypothesis that sevelamer hydrochloride might bind to ET in the intestinal lumen and reduce systemic inflammation. Animal and human studies are required to examine this hypothesis. Copyright 2008 S. Karger AG, Basel.
BACKGROUND:Sevelamer hydrochloride has been shown to attenuate circulating biomarkers of inflammation in patients with chronic kidney failure. We hypothesize that sevelamer hydrochloride binds bacterial endotoxin (ET) resulting in a decrease in ET levels and cytokine production. METHODS: To assess the ET-binding affinity of sevelamer hydrochloride, purified Escherichia coli ET was incubated with sevelamer hydrochloride (0-50 mg/ml). After incubation, ET was measured in supernatants. In addition, THP-1-derived monocytes were co-incubated with supernatants of sevelamer hydrochloride and ET. After 24-hour incubation, TNF-alpha was measured. The effect of pH on the ET-binding affinity of sevelamer hydrochloride, as well as cooperative binding between ET and phosphate for sevelamer hydrochloride were assessed. RESULTS:Sevelamer hydrochloride exhibited time- and dose-dependent binding affinity for ET, resulting in a marked reduction in free ET levels. The 1-hour dose-dependent ET-binding effect of sevelamer hydrochloride translated into a marked reduction in TNF-alpha levels. Varying the pH conditions did not affect the ET-binding affinity of sevelamer hydrochloride. The addition of phosphate (0-50 mM) resulted in a further reduction in free ET levels, translating into a further increase in the binding affinity of sevelamer hydrochloride for ET. CONCLUSIONS: This study demonstrates that sevelamer hydrochloride binds to ET, thereby reducing free ET and cytokine levels. Positive cooperative binding was also noted between phosphate and ET for sevelamer hydrochloride. This study supports the hypothesis that sevelamer hydrochloride might bind to ET in the intestinal lumen and reduce systemic inflammation. Animal and human studies are required to examine this hypothesis. Copyright 2008 S. Karger AG, Basel.
Authors: Annabel Biruete; Kathleen M Hill Gallant; Stephen R Lindemann; Gretchen N Wiese; Neal X Chen; Sharon M Moe Journal: J Ren Nutr Date: 2019-03-04 Impact factor: 3.655
Authors: Juan F Navarro-González; Carmen Mora-Fernández; Mercedes Muros de Fuentes; Javier Donate-Correa; Violeta Cazaña-Pérez; Javier García-Pérez Journal: Clin J Am Soc Nephrol Date: 2011-07-22 Impact factor: 8.237
Authors: Jan Kristoff; George Haret-Richter; Dongzhu Ma; Ruy M Ribeiro; Cuiling Xu; Elaine Cornell; Jennifer L Stock; Tianyu He; Adam D Mobley; Samantha Ross; Anita Trichel; Cara Wilson; Russell Tracy; Alan Landay; Cristian Apetrei; Ivona Pandrea Journal: J Clin Invest Date: 2014-05-16 Impact factor: 14.808