Cassandra Kimber1,2, Shiqin Zhang1,2, Cassandra Johnson1, Raymond E West3, Alexander J Prokopienko3, Jonathan D Mahnken1,4, Alan S Yu1,2, Andrew N Hoofnagle5, Diana Ir6, Charles E Robertson6, Makoto Miyazaki7, Michel Chonchol7, Anna Jovanovich7,8, Bryan Kestenbaum9,10, Daniel N Frank6, Thomas D Nolin3, Jason R Stubbs1,2. 1. The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas. 2. Division of Nephrology and Hypertension, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas. 3. Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania. 4. Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas. 5. Department of Laboratory Medicine, University of Washington, Seattle, Washington. 6. Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Denver, Colorado. 7. Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 8. Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado. 9. Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington. 10. Kidney Research Institute, Seattle, Washington.
Abstract
BACKGROUND: Recent evidence suggests the systemic accumulation of by-products of gut microbes contributes to cardiovascular morbidity in patients with CKD. Limiting the generation of toxic bacterial by-products by manipulating the intestinal microbiota may be a novel strategy for reducing cardiovascular disease in CKD. Rifaximin is a minimally absorbed, oral antibiotic that targets intestinal pathogens and is commonly used as chronic therapy for the prevention of encephalopathy in patients with cirrhosis. METHODS: We conducted a randomized, double-blinded, placebo-controlled trial to determine the effect of a 10-day course of oral rifaximin 550 mg BID versus placebo on circulating concentrations of gut-derived cardiovascular toxins and proinflammatory cytokines in patients with stage 3-5 CKD (n=38). The primary clinical outcome was change in serum trimethylamine N-oxide (TMAO) concentrations from baseline to study end. Secondary outcomes included change in serum concentrations of p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines (C-reactive protein, IL-6, IL-1β), and change in composition and diversity of fecal microbiota. RESULTS: A total of 19 patients were randomized to each of the rifaximin and placebo arms, with n=17 and n=14 completing both study visits in these respective groups. We observed no difference in serum TMAO change (post-therapy minus baseline TMAO) between the rifaximin and placebo groups (mean TMAO change -3.9±15.4 for rifaximin versus 0.5±9.5 for placebo, P=0.49). Similarly, we found no significant change in serum concentrations for p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines. We did observe differences in colonic bacterial communities, with the rifaximin group exhibiting significant decreases in bacterial richness (Chao1, P=0.02) and diversity (Shannon H, P=0.05), along with altered abundance of several bacterial genera. CONCLUSIONS: Short-term rifaximin treatment failed to reduce gut-derived cardiovascular toxins and inflammatory cytokines in patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Rifaximin Therapy in Chronic Kidney Disease, NCT02342639.
BACKGROUND: Recent evidence suggests the systemic accumulation of by-products of gut microbes contributes to cardiovascular morbidity in patients with CKD. Limiting the generation of toxic bacterial by-products by manipulating the intestinal microbiota may be a novel strategy for reducing cardiovascular disease in CKD. Rifaximin is a minimally absorbed, oral antibiotic that targets intestinal pathogens and is commonly used as chronic therapy for the prevention of encephalopathy in patients with cirrhosis. METHODS: We conducted a randomized, double-blinded, placebo-controlled trial to determine the effect of a 10-day course of oral rifaximin 550 mg BID versus placebo on circulating concentrations of gut-derived cardiovascular toxins and proinflammatory cytokines in patients with stage 3-5 CKD (n=38). The primary clinical outcome was change in serum trimethylamine N-oxide (TMAO) concentrations from baseline to study end. Secondary outcomes included change in serum concentrations of p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines (C-reactive protein, IL-6, IL-1β), and change in composition and diversity of fecal microbiota. RESULTS: A total of 19 patients were randomized to each of the rifaximin and placebo arms, with n=17 and n=14 completing both study visits in these respective groups. We observed no difference in serum TMAO change (post-therapy minus baseline TMAO) between the rifaximin and placebo groups (mean TMAO change -3.9±15.4 for rifaximin versus 0.5±9.5 for placebo, P=0.49). Similarly, we found no significant change in serum concentrations for p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines. We did observe differences in colonic bacterial communities, with the rifaximin group exhibiting significant decreases in bacterial richness (Chao1, P=0.02) and diversity (Shannon H, P=0.05), along with altered abundance of several bacterial genera. CONCLUSIONS: Short-term rifaximin treatment failed to reduce gut-derived cardiovascular toxins and inflammatory cytokines in patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Rifaximin Therapy in Chronic Kidney Disease, NCT02342639.
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