The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial
High serum levels of gut-derived uremic toxins, especially p-cresyl sulfate (pCS), indoxyl sulfate (IS) and indole acetic acid (IAA), have been linked to adverse outcomes in patients with chronic kidney disease (CKD). Sevelamer carbonate could represent an interesting option to limit the elevation o...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-05-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/11/5/279 |
| _version_ | 1828115957171617792 |
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| author | Youssef Bennis Yan Cluet Dimitri Titeca-Beauport Najeh El Esper Pablo Ureña Sandra Bodeau Christian Combe Bertrand Dussol Denis Fouque Gabriel Choukroun Sophie Liabeuf |
| author_facet | Youssef Bennis Yan Cluet Dimitri Titeca-Beauport Najeh El Esper Pablo Ureña Sandra Bodeau Christian Combe Bertrand Dussol Denis Fouque Gabriel Choukroun Sophie Liabeuf |
| author_sort | Youssef Bennis |
| collection | DOAJ |
| description | High serum levels of gut-derived uremic toxins, especially p-cresyl sulfate (pCS), indoxyl sulfate (IS) and indole acetic acid (IAA), have been linked to adverse outcomes in patients with chronic kidney disease (CKD). Sevelamer carbonate could represent an interesting option to limit the elevation of gut-derived uremic toxins. The aim of the present study was to evaluate the adsorptive effect of sevelamer carbonate on different gut-derived protein-bound uremic toxins or their precursors in vitro, and its impact on the serum levels of pCS, IS and IAA in patients with CKD stage 3b/4. For the in vitro experiments, IAA, p-cresol (precursor of pCS) and indole (precursor of IS), each at a final concentration of 1 or 10 µg/mL, were incubated in centrifugal 30 kDa filter devices with 3 or 15 mg/mL sevelamer carbonate in phosphate-buffered saline at a pH adjusted to 6 or 8. Then, samples were centrifuged and free uremic toxins in the filtrates were analyzed. As a control experiment, the adsorption of phosphate was also evaluated. Additionally, patients with stage 3b/4 CKD (defined as an eGFR between 15 and 45 mL/min per 1.73 m<sup>2</sup>) were included in a multicenter, double-blind, placebo-controlled, randomized clinical trial. The participants received either placebo or sevelamer carbonate (4.8 g) three times a day for 12 weeks. The concentrations of the toxins and their precursors were measured using a validated high-performance liquid chromatography method with a diode array detector. In vitro, regardless of the pH and concentration tested, sevelamer carbonate did not show adsorption of indole and p-cresol. Conversely, with 10 µg/mL IAA, use of a high concentration of sevelamer carbonate (15 mg/mL) resulted in a significant toxin adsorption both at pH 8 (mean reduction: 26.3 ± 3.4%) and pH 6 (mean reduction: 38.7 ± 1.7%). In patients with CKD stage 3b/4, a 12-week course of treatment with sevelamer carbonate was not associated with significant decreases in serum pCS, IS and IAA levels (median difference to baseline levels: −0.12, 0.26 and −0.06 µg/mL in the sevelamer group vs. 1.97, 0.38 and 0.05 µg/mL in the placebo group, respectively). Finally, in vitro, sevelamer carbonate was capable of chelating a gut-derived uremic toxin IAA but not p-cresol and indole, the precursors of pCS and IS in the gut. In a well-designed clinical study of patients with stage 3b/4 CKD, a 12-week course of treatment with sevelamer carbonate was not associated with significant changes in the serum concentrations of pCS, IS and IAA. |
| first_indexed | 2024-04-11T12:49:38Z |
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| id | doaj.art-4790423124b8492190b57318e3cbd841 |
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| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-04-11T12:49:38Z |
| publishDate | 2019-05-01 |
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| record_format | Article |
| series | Toxins |
| spelling | doaj.art-4790423124b8492190b57318e3cbd8412022-12-22T04:23:15ZengMDPI AGToxins2072-66512019-05-0111527910.3390/toxins11050279toxins11050279The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical TrialYoussef Bennis0Yan Cluet1Dimitri Titeca-Beauport2Najeh El Esper3Pablo Ureña4Sandra Bodeau5Christian Combe6Bertrand Dussol7Denis Fouque8Gabriel Choukroun9Sophie Liabeuf10Pharmacology Department, Amiens University Hospital, 80000 Amiens, FrancePharmacology Department, Amiens University Hospital, 80000 Amiens, FranceMP3CV Laboratory, EA7517, University of Picardie Jules Verne, 80000 Amiens, FranceNephrology Department, Amiens University Hospital, 80000 Amiens, FranceDepartment of Nephrology and Dialysis, AURA Nord Saint Ouen, 93400 Saint Ouen, FrancePharmacology Department, Amiens University Hospital, 80000 Amiens, FranceNephrology Department, Bordeaux University Hospital, 33000 Bordeaux, FranceClinical Inverstigation Center, Aix Marseille University, 13354 Marseille, FranceDept Nephrology, Université de Lyon, Hospital Lyon Sud, F-69495 Pierre-Benite, FranceMP3CV Laboratory, EA7517, University of Picardie Jules Verne, 80000 Amiens, FrancePharmacology Department, Amiens University Hospital, 80000 Amiens, FranceHigh serum levels of gut-derived uremic toxins, especially p-cresyl sulfate (pCS), indoxyl sulfate (IS) and indole acetic acid (IAA), have been linked to adverse outcomes in patients with chronic kidney disease (CKD). Sevelamer carbonate could represent an interesting option to limit the elevation of gut-derived uremic toxins. The aim of the present study was to evaluate the adsorptive effect of sevelamer carbonate on different gut-derived protein-bound uremic toxins or their precursors in vitro, and its impact on the serum levels of pCS, IS and IAA in patients with CKD stage 3b/4. For the in vitro experiments, IAA, p-cresol (precursor of pCS) and indole (precursor of IS), each at a final concentration of 1 or 10 µg/mL, were incubated in centrifugal 30 kDa filter devices with 3 or 15 mg/mL sevelamer carbonate in phosphate-buffered saline at a pH adjusted to 6 or 8. Then, samples were centrifuged and free uremic toxins in the filtrates were analyzed. As a control experiment, the adsorption of phosphate was also evaluated. Additionally, patients with stage 3b/4 CKD (defined as an eGFR between 15 and 45 mL/min per 1.73 m<sup>2</sup>) were included in a multicenter, double-blind, placebo-controlled, randomized clinical trial. The participants received either placebo or sevelamer carbonate (4.8 g) three times a day for 12 weeks. The concentrations of the toxins and their precursors were measured using a validated high-performance liquid chromatography method with a diode array detector. In vitro, regardless of the pH and concentration tested, sevelamer carbonate did not show adsorption of indole and p-cresol. Conversely, with 10 µg/mL IAA, use of a high concentration of sevelamer carbonate (15 mg/mL) resulted in a significant toxin adsorption both at pH 8 (mean reduction: 26.3 ± 3.4%) and pH 6 (mean reduction: 38.7 ± 1.7%). In patients with CKD stage 3b/4, a 12-week course of treatment with sevelamer carbonate was not associated with significant decreases in serum pCS, IS and IAA levels (median difference to baseline levels: −0.12, 0.26 and −0.06 µg/mL in the sevelamer group vs. 1.97, 0.38 and 0.05 µg/mL in the placebo group, respectively). Finally, in vitro, sevelamer carbonate was capable of chelating a gut-derived uremic toxin IAA but not p-cresol and indole, the precursors of pCS and IS in the gut. In a well-designed clinical study of patients with stage 3b/4 CKD, a 12-week course of treatment with sevelamer carbonate was not associated with significant changes in the serum concentrations of pCS, IS and IAA.https://www.mdpi.com/2072-6651/11/5/279sevelameruremic toxins |
| spellingShingle | Youssef Bennis Yan Cluet Dimitri Titeca-Beauport Najeh El Esper Pablo Ureña Sandra Bodeau Christian Combe Bertrand Dussol Denis Fouque Gabriel Choukroun Sophie Liabeuf The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial Toxins sevelamer uremic toxins |
| title | The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial |
| title_full | The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial |
| title_fullStr | The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial |
| title_full_unstemmed | The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial |
| title_short | The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial |
| title_sort | effect of sevelamer on serum levels of gut derived uremic toxins results from in vitro experiments and a multicenter double blind placebo controlled randomized clinical trial |
| topic | sevelamer uremic toxins |
| url | https://www.mdpi.com/2072-6651/11/5/279 |
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