Aurelie Lenglet1,2, Nicolas Fabresse3,4, Méline Taupin3, Cathy Gomila1,5, Sophie Liabeuf1,6, Said Kamel1,5, Jean Claude Alvarez3,4, Tilman B Drueke7,8,9, Ziad A Massy10,11,12,13. 1. EA7517, MP3CV, Laboratory, CURS, Jules Verne University of Picardie, Amiens, France. 2. Pharmacy, University Hospital, Amiens, France. 3. Laboratory of Pharmacology and Toxicology, CHU Raymond Poincare, Garches, France. 4. INSERM U-1173, UFR des Sciences de la Santé Simone Veil, Montigny le Bretonneux, Université de Versailles-Saint-Quentin-en-Yvelines, Versailles, France. 5. Laboratory of Biochimie, University Hospital, Amiens, France. 6. Clinical Research Centre and Division of Clinical Pharmacology, University Hospital, Amiens, France. 7. Inserm U-1018 Centre de Recherche en Epidémiologie et Santé des Populations (CESP), Equipe 5, Villejuif, France. 8. University of Paris West-Versailles-Saint Quentin en Yvelines, Versailles, France. 9. University of Paris Sud, Paris Saclay, Villejuif, France. 10. Inserm U-1018 Centre de Recherche en Epidémiologie et Santé des Populations (CESP), Equipe 5, Villejuif, France. ziad.massy@aphp.fr. 11. University of Paris West-Versailles-Saint Quentin en Yvelines, Versailles, France. ziad.massy@aphp.fr. 12. University of Paris Sud, Paris Saclay, Villejuif, France. ziad.massy@aphp.fr. 13. Division of Nephrology, Ambroise Paré Hospital, Assistance Publique - Hôpitaux de Paris and Paris Ile de France Ouest University, 9 Avenue Charles de Gaulle, 92104, Boulogne Billancourt Cedex, France. ziad.massy@aphp.fr.
Abstract
BACKGROUND: Hyperphosphatemia control is a major issue in hemodialysis patients. Both sevelamer and nicotinamide are prescribed for this purpose. In addition, they exert pleiotropic effects such as an improvement of inflammatory status and potentially enhanced clearance of uremic toxins. In the present secondary analysis of the NICOREN trial, we investigated the impact of sevelamer and nicotinamide on uremic toxins, toxin precursors, and endotoxemia in chronic hemodialysis patients. METHODS: Circulating uremic toxins (including phenylacetylglutamine, trimethylamine-N-oxide, p-cresyl sulfate, indoxyl sulfate, kynurenine, hippuric acid, indole-3-acetic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, kynurenic acid, and p-cresyl glucuronide) and precursors were measured by ultra-performance liquid chromatography-tandem mass spectrometry, and urea, uric acid, phosphate, C-reactive protein, and intact parathyroid hormone by routine biochemistry methods. Serum endotoxin (evaluated by lipopolysaccharide levels) and C-terminal fibroblast growth factor-23 levels were measured using enzyme-linked immunosorbent assay kits. RESULTS:One hundred hemodialysis patients were randomized to receive either nicotinamide or sevelamer treatment. Among them, 63% were male, mean (± standard deviation) age was 65 ± 14 years, 47% had diabetes mellitus, and 51% had a history of cardiovascular disease. In the sevelamer group, but not the nicotinamide group, serum levels of urea, uric acid, and fibroblast growth factor-23 were significantly reduced after 6 months of treatment. The other circulating uremic toxins and toxin precursors remained unchanged in response to either phosphate-lowering agent. Sevelamer treatment led to a marked decrease in serum lipopolysaccharide (p < 0.001) whereas nicotinamide treatment induced an only modest decrease of borderline significance (p = 0.057). There was no change in C-reactive protein levels. CONCLUSION: In contrast to sevelamer, nicotinamide did not reduce circulating levels of low-molecular-weight uremic toxins other than phosphate, and neither agent reduced circulating uremic toxins of high-molecular-weight or protein-bound toxins. Sevelamer, but not nicotinamide, reduced serum endotoxin levels. Despite no change in serum C-reactive protein, the endotoxin-lowering effect of sevelamer may help to attenuate the inflammatory status of patients with chronic kidney disease.
RCT Entities:
BACKGROUND:Hyperphosphatemia control is a major issue in hemodialysis patients. Both sevelamer and nicotinamide are prescribed for this purpose. In addition, they exert pleiotropic effects such as an improvement of inflammatory status and potentially enhanced clearance of uremic toxins. In the present secondary analysis of the NICOREN trial, we investigated the impact of sevelamer and nicotinamide on uremic toxins, toxin precursors, and endotoxemia in chronic hemodialysispatients. METHODS: Circulating uremic toxins (including phenylacetylglutamine, trimethylamine-N-oxide, p-cresyl sulfate, indoxyl sulfate, kynurenine, hippuric acid, indole-3-acetic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, kynurenic acid, and p-cresyl glucuronide) and precursors were measured by ultra-performance liquid chromatography-tandem mass spectrometry, and urea, uric acid, phosphate, C-reactive protein, and intact parathyroid hormone by routine biochemistry methods. Serum endotoxin (evaluated by lipopolysaccharide levels) and C-terminal fibroblast growth factor-23 levels were measured using enzyme-linked immunosorbent assay kits. RESULTS: One hundred hemodialysis patients were randomized to receive either nicotinamide or sevelamer treatment. Among them, 63% were male, mean (± standard deviation) age was 65 ± 14 years, 47% had diabetes mellitus, and 51% had a history of cardiovascular disease. In the sevelamer group, but not the nicotinamide group, serum levels of urea, uric acid, and fibroblast growth factor-23 were significantly reduced after 6 months of treatment. The other circulating uremic toxins and toxin precursors remained unchanged in response to either phosphate-lowering agent. Sevelamer treatment led to a marked decrease in serum lipopolysaccharide (p < 0.001) whereas nicotinamide treatment induced an only modest decrease of borderline significance (p = 0.057). There was no change in C-reactive protein levels. CONCLUSION: In contrast to sevelamer, nicotinamide did not reduce circulating levels of low-molecular-weight uremic toxins other than phosphate, and neither agent reduced circulating uremic toxins of high-molecular-weight or protein-bound toxins. Sevelamer, but not nicotinamide, reduced serum endotoxin levels. Despite no change in serum C-reactive protein, the endotoxin-lowering effect of sevelamer may help to attenuate the inflammatory status of patients with chronic kidney disease.
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