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Does the Administration of Sevelamer or Nicotinamide Modify Uremic Toxins or Endotoxemia in Chronic Hemodialysis Patients?

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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.

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Acknowledgements

The authors thank Prof. Albert Fournier who initiated this clinical study. They also thank Amiens University Hospital, especially the Clinical Research and Innovation Directorate, for logistical support; the Clinical Research Center for study management (Momar Diouf); the Biochemistry laboratory of CHU Amiens (Romuald Mentaverri) for their contribution to FG23 measurements, and the Department of Nephrology, Internal Medicine, Dialysis, Transplantation and Intensive Care (Gabriel Choukroun). Last but not least, the authors would like to thank the patients and the physicians of the 18 dialysis centers that participated in the NICOREN trial.

Author information

Authors and Affiliations

  1. EA7517, MP3CV, Laboratory, CURS, Jules Verne University of Picardie, Amiens, France

    Aurelie Lenglet, Cathy Gomila, Sophie Liabeuf & Said Kamel

  2. Pharmacy, University Hospital, Amiens, France

    Aurelie Lenglet

  3. Laboratory of Pharmacology and Toxicology, CHU Raymond Poincare, Garches, France

    Nicolas Fabresse, Méline Taupin & Jean Claude Alvarez

  4. INSERM U-1173, UFR des Sciences de la Santé Simone Veil, Montigny le Bretonneux, Université de Versailles-Saint-Quentin-en-Yvelines, Versailles, France

    Nicolas Fabresse & Jean Claude Alvarez

  5. Laboratory of Biochimie, University Hospital, Amiens, France

    Cathy Gomila & Said Kamel

  6. Clinical Research Centre and Division of Clinical Pharmacology, University Hospital, Amiens, France

    Sophie Liabeuf

  7. Inserm U-1018 Centre de Recherche en Epidémiologie et Santé des Populations (CESP), Equipe 5, Villejuif, France

    Tilman B. Drueke & Ziad A. Massy

  8. University of Paris West-Versailles-Saint Quentin en Yvelines, Versailles, France

    Tilman B. Drueke & Ziad A. Massy

  9. University of Paris Sud, Paris Saclay, Villejuif, France

    Tilman B. Drueke & Ziad A. Massy

  10. 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 A. Massy

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  1. Aurelie Lenglet
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Corresponding author

Correspondence to Ziad A. Massy.

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Funding

This study was funded by an interregional Grant (PHRC IR08: 2008-004673-17).

Conflict of interest

Ziad A. Massy reports grants for CKD REIN and other research projects from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp and Dohme-Chibret, Sanofi-Genzyme, Lilly, Otsuka, and the French Government, as well as fees and grants to charities from Astellas, Baxter, Daichii, Medice, and Sanofi-Genzyme. These sources of funding are not necessarily related to the content of the present manuscript. Tilman B. Drueke reports fees for advisor/consultant services from Amgen, F. Hoffman-La Roche, FMC, Glaxo-Smith-Kline, KfH-Stiftung Präventivmedizin, Sanofi-Genzyme, and Vifor and speaker fees from Akebia, Amgen, Astellas, Chugai, Kyowa Hakko Kirin, and Sanofi-Genzyme. Aurelie Lenglet, Nicolas Fabresse, Méline Taupin, Cathy Gomila, Sophie Liabeuf, Said Kamel, and Jean Claude Alvarez have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

The protocol was approved by a local investigational review board (CPP Nord Ouest II, Amiens, France; reference 2008-004673-17) and implemented in accordance with the ethical principles of the Declaration of Helsinki (ClinicalTrials.gov registration number NCT01011699).

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Lenglet, A., Fabresse, N., Taupin, M. et al. Does the Administration of Sevelamer or Nicotinamide Modify Uremic Toxins or Endotoxemia in Chronic Hemodialysis Patients?. Drugs 79, 855–862 (2019). https://doi.org/10.1007/s40265-019-01118-9

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