Sevelamer Use in End-Stage Kidney Disease (ESKD) Patients Associates with Poor Vitamin K Status and High Levels of Gut-Derived Uremic Toxins: A Drug-Bug Interaction?

Lu Dai,Peter Stenvinkel,Abdul Rashid Qureshi,Henriette De Loor,Pieter Evenepoel,Bert Bammens,Leon J Schurgers,Björn K Meijers

doi:10.3390/toxins12060351

Lu Dai, Peter Stenvinkel + Show 6 more

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https://doi.org/10.3390/toxins12060351

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Abstract

Gut microbial metabolism is not only an important source of uremic toxins but may also help to maintain the vitamin K stores of the host. We hypothesized that sevelamer therapy, a commonly used phosphate binder in patients with end-stage kidney disease (ESKD), associates with a disturbed gut microbial metabolism. Important representatives of gut-derived uremic toxins, including indoxyl sulfate (IndS), p-Cresyl sulfate (pCS), trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAG) and non-phosphorylated, uncarboxylated matrix-Gla protein (dp-ucMGP; a marker of vitamin K status), were analyzed in blood samples from 423 patients (65% males, median age 54 years) with ESKD. Demographics and laboratory data were extracted from electronic files. Sevelamer users (n = 172, 41%) were characterized by higher phosphate, IndS, TMAO, PAG and dp-ucMGP levels compared to non-users. Sevelamer was significantly associated with increased IndS, PAG and dp-ucMGP levels, independent of age, sex, calcium-containing phosphate binder, cohort, phosphate, creatinine and dialysis vintage. High dp-ucMGP levels, reflecting vitamin K deficiency, were independently and positively associated with PAG and TMAO levels. Sevelamer therapy associates with an unfavorable gut microbial metabolism pattern. Although the observational design precludes causal inference, present findings implicate a disturbed microbial metabolism and vitamin K deficiency as potential trade-offs of sevelamer therapy.

Highlights

Hyperphosphatemia is one of the most common metabolic disorders in patients with chronic kidney disease (CKD) [1] and associates with adverse clinical outcomes across the stages of disease [2,3].Phosphate binders, including calcium and non-calcium-containing agents, are a cornerstone in the treatment of hyperphosphatemia
Data from randomized clinical trials showed that, compared with calcium-containing phosphate binders (CCPB), sevelamer attenuated the progression of vascular calcification and conferred a survival benefit in prevalent and incident hemodialysis (HD) patients [5,6]
Compared with sevelamer non-users, patients who were treated with sevelamer were characterized by younger age, higher BMI, lower albumin levels and higher phosphate, creatinine, indoxyl sulfate (IndS), trimethylamine N-oxide (TMAO), PAG and dp-ucMGP levels

Summary

Introduction

Phosphate binders, including calcium and non-calcium-containing agents, are a cornerstone in the treatment of hyperphosphatemia. In 2001, sevelamer hydrochloride was launched as the first non-metal-containing, nonabsorbable anion exchange binder. Both sevelamer hydrochloride (HCl) and sevelamer carbonate are used in clinical practice. Sevelamer is a crosslinked polymer that exchanges HCl or carbonate for phosphate in the gastrointestinal tract. Data from randomized clinical trials showed that, compared with calcium-containing phosphate binders (CCPB), sevelamer attenuated the progression of vascular calcification and conferred a survival benefit in prevalent and incident hemodialysis (HD) patients [5,6]. Sevelamer is the first-line phosphate binder in many dialysis units [11]

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