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?

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.

• Authors: Lu Dai, Björn K Meijers, Bert Bammens, Henriette de Loor, Leon J Schurgers, Abdul Rashid Qureshi, Peter Stenvinkel, Pieter Evenepoel
• Journal: Toxins (Toxins (Basel)) Vol. 12 Issue 6 (05 27 2020) ISSN: 2072-6651 [Electronic] Switzerland
• PMID: 32471179 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Toxins
• Biomarkers
• Chelating Agents
• Phosphates
• Sevelamer

Topics

• Adult
• Aged
• Bacteria (drug effects, metabolism)
• Bacterial Toxins (blood)
• Biomarkers (blood)
• Chelating Agents (adverse effects)
• Colon (microbiology)
• Female
• Gastrointestinal Microbiome (drug effects)
• Humans
• Kidney Failure, Chronic (blood, drug therapy, microbiology)
• Male
• Middle Aged
• Phosphates (blood)
• Risk Factors
• Sevelamer (adverse effects)
• Treatment Outcome
• Uremia (blood, drug therapy, microbiology)
• Vitamin K Deficiency (blood, chemically induced)