Patients with chronic kidney disease (CKD) demonstrate a disproportionate burden of atherosclerosis compared with individuals possessing normal kidney function, which contributes to the excessive morbidity and mortality in this group. Moreover, a higher prevalence of traditional risk factors for the development of atherosclerosis, such as diabetes and hyperlipidemia, only partially accounts for the accelerated atherosclerosis observed in CKD patients, implying that unique risk factors must be present in this population. Accumulating evidence suggests that alterations in the intestinal microbiome may facilitate the development of multiple pathologic processes which are commonly found in patients with impaired kidney function, including atherosclerosis. More specifically, several byproducts of intestinal bacteria have been observed to potentiate atherosclerosis formation in animals and associate with atherosclerosis-related clinical outcomes in humans. Among these compounds are trimethylamine-N- oxide (TMAO), an organic compound derived from the metabolism of dietary L-carnitine and choline by intestinal bacteria, and lipopolysaccharide (LPS), a bacterial endotoxin produced by Gram-negative bacteria that populate the intestinal lumen. Interestingly, recent published and unpublished evidence from our group and others suggests that circulating concentrations of both TMAO and LPS become substantially elevated with kidney disease progression and associate with adverse clinical outcomes in CKD patients. Rifaximin is a minimally absorbed, oral antibiotic that is concentrated in the gastrointestinal tract and currently utilized as a chronic therapy in patients with advanced liver disease to prevent recurrent hepatic encephalopathy that partially stems from the systemic accumulation of neurotoxins derived from intestinal bacteria. Rifaximin is unique in that chronic administration appears to result in very limited disruption of the overall balance of the intestinal microbiome, while possibly enhancing the presence of symbiotic bacteria that promote intestinal health. We hypothesize that byproducts of the intestinal microbiome contribute to accelerated atherosclerosis formation and the pro-inflammatory phenotype in patients with CKD. In the proposed pilot study, we will determine if short-term rifaximin therapy to target intestinal microbes can lower circulating concentrations of purported atherosclerotic risk factors (TMAO, LPS) and pro-inflammatory cytokines (IL-6, TNF?, and hsCRP) in patients with advanced-stage CKD. Additional exploratory outcomes of this work will include assessment of circulating concentrations of purported regulators of vascular endothelial function (ADMA, SDMA, and FGF23) and alterations in HDL cholesterol efflux function in response to therapy.

Public Health Relevance

Patients with decreased kidney function exhibit a disproportionate burden of cholesterol plaque buildup in their arteries (atherosclerosis) compared to similar patients with normal kidney function, which ultimately results in these patients suffering from a much higher rate of heart attacks, strokes, and death when compared to the general population. Recent evidence suggests that patients with decreased kidney function exhibit elevated blood levels of bacterial byproducts that may promote atherosclerosis formation. In the proposed work, we will determine if rifaximin, an oral antibiotic that suppresses growth of intestinal bacteria, can reduce circulating levels of bacterial byproducts that are believed to promote atherosclerosis formation in patients with kidney disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-DKUS-J (56))
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Flessner, Michael Francis
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University of Kansas
Internal Medicine/Medicine
Schools of Medicine
Kansas City
United States
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