Persistent inflammation underpins the accelerated atherosclerosis and increased prevalence of protein-energy wasting in maintenance hemodialysis (MHD) patients. However, the etiology of unprovoked inflammation in MHD patients remains unresolved. The human gut harbors 1014 bacteria, and gut microbial imbalance has been linked to inflammation, insulin resistance and atheroscleroisis. Prebiotic oligofructose enriched inulin (p-inulin) has been shown to restore gut microbial balance, thereby reducing endotoxin generation and inflammation. Pentoxifylline (PTX) blocks cytokine generation in response to endotoxemia at the tissue level, and hence complements the actions of p-inulin. In a two-by-two factorial clinical trial, we will randomize 120 MHD patients to receiv p-inulin/PTX/placebo daily for 12 months. First, we will demonstrate the feasibility of recruitment randomization, and retention of study participants in order to record endpoints in at least 90% of participants. Secondly, we will establish the safety and efficacy of p-inulin and PTX in reducing systemic inflammation. Finally, we propose to evaluate the effect of study intervention on selected exploratory clinical end-points: (a) Progression/regression of atherosclerosis will be determined using phase-sensitive dual inversion recovery magnetic resonance (MR) spectroscopy technique;(b) Alterations in muscle mass and visceral fat mass will be examined by MR imaging of thigh and abdomen;and (c) Changes in presence and severity of protein-energy wasting will be determined according to the International Society of Renal Nutrition and Metabolism criteria. This pilot study will prove the concept, establish feasibility and generate preliminary data to justify the launching of a full-clinical trial.

Public Health Relevance

Excess inflammation is associated with obesity, heart disease, and muscle wasting in hemodialysis patients. Toxins produced by the bacteria in the intestine may be an important cause of inflammation. We propose to use prebiotic inulin and pentoxifyllin to decrease inflammation, which we believe will decrease fat mass, increase muscle mass, and lower heart disease in hemodialysis patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK099914-02
Application #
8731233
Study Section
Special Emphasis Panel (ZDK1-GRB-J (M1))
Program Officer
Kimmel, Paul
Project Start
2013-09-15
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$385,000
Indirect Cost
$142,098
Name
George Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
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Rambod, Mehdi; Heine, Gunnar H; Seiler, Sarah et al. (2014) Association of vascular endothelial factors with cardiovascular outcome and mortality in chronic kidney disease patients: a 4-year cohort study. Atherosclerosis 236:360-5

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