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

Abstract

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 m2) 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.

Comparative Gut Microbiome Differences between Ferric Citrate and Calcium Carbonate Phosphate Binders in Patients with End-Stage Kidney Disease

“…The precision of dietary intake can benefit from having more objective dietary records. Third, other phosphate binders (e.g., lanthanum carbonate, sevelamer hydrochloride/carbonate, or sucroferric oxyhydroxide) that potentially affect gut microbiota were not evaluated in this study [ 24 , 53 , 54 ]. Fourth, the study was performed on Asian HD patients whose diet may be different from other populations.…”

Intestinal Chelators, Sorbants, and Gut-Derived Uremic Toxins

“…Another recent report indicated that sevelamer carbonate was able to adsorb IAA but not indole and p-cresol. The results can, perhaps, be explained by the compounds’ respective chemical structures: IAA has a carboxylic acid group (like bile acids, which are also chelated by sevelamer) but none of the precursors have functional groups that would enable chelation by sevelamer [ 78 ] ( Table 2 ).…”

“…In a recent, multicenter, comparative, randomized, clinical trial in dialysis patients, neither sevelamer nor nicotinamide induced a change in gut-derived uremic toxin levels [ 85 ]. Likewise, in a multicenter, double-blind, placebo-controlled, randomized, clinical trial in grades 3 and 4 CKD patients, a three-month course of sevelamer carbonate was not associated with significant changes in the serum concentrations of pCS, IS, or IAA [ 78 ].…”

A Renal Clinician's Guide to the Gut Microbiota

“…78 Observational and controlled trials have targeted the production, absorption, and removal of indoles and indoxyl sulfate. Some of the mechanisms to decrease circulating indoxyl sulfate include limiting the production of indole by very-low 80 and low-protein diets, 81 therapies targeting the gut microbiota (i.e., pro-, pre-, and synbiotics 82 ), reduction of indole absorption through adsorptive therapies (i.e., AST-120 83,84 and sevelamer [85][86][87][88], and enhanced removal via hemodiafiltration. 89,90 Recently, the infusion of an albumin-binding competitor, ibuprofen, during dialysis led to a reduction in serum levels of indoxyl sulfate.…”

“…Trimethylamine N-Oxide In the colon, dietary choline, carnitine, and g-butyrobetaine are cleaved to form trimethylamine, which is absorbed intestinally and oxidized in the liver to TMAO. [82][83][84][85] Contrary to indoxyl sulfate and p-cresyl sulfate, TMAO is not protein bound and is cleared through tubular secretion or hemodialysis. 104 The interest in TMAO increased substantially after Wang et al 2 reported that metabolites derived from microbial metabolism of phosphatidylcholine were associated with increased risk of major adverse cardiovascular mortality.…”