Access Type

Open Access Dissertation

Date of Award

January 2014

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Nutrition and Food Science

First Advisor

Pramod Khosla

Abstract

Mortality rate in patients undergoing chronic hemodialysis (HD) in the United States remain unacceptably high despite improvement in dialysis technology. Cardiovascular disease (CVD) account for more than 50% of the premature death in this population. Evidences indicate that the accelerated CVD are attributed to by malnutrition, inflammation, dyslipidemia and oxidative stress. Dietary intervention using nutrients with antioxidant, anti-inflammatory, and potential lipid altering properties to correct the aforementioned problems remain inconclusive. Furthermore, such nutritional intervention trial is often hampered by poor compliance related to medical and socioeconomic barriers. Therefore, a series of randomized, double-blind, placebo-controlled, parallel trials were undertaken to document the technical feasibility of `directly observed treatment' and the global impact of several nutrients namely omega-3 and vitamin E tocotrienols on nutritional and oxidative indicators, inflammatory markers and lipid profiles in a cohort of chronic HD patients.

The objective of the first study was to evaluate the impact of omega-3 plus liquid protein supplement on serum albumin, plasma lipids and other indicator of nutrition and inflammation. markers. The study recruited 63 subjects and they were randomized into placebo+protein (n=32) and omega-3+protein (n=31) groups. The two intervention groups received 30mL of a liquid protein plus 2.4g omega-3 or placebo, three times per week after their routine dialysis session for 6 months. Directly observed nutritional supplement resulted in significant improvement in the LDLC/HDLC ratio in the omega-3 group as compared to the placebo group (P=0.043). In the omega-3 group, serum albumin was also marginally higher after 6 months as compared to the baseline (P=0.07). The observed increase in CRP levels in the placebo group over 6 months was not apparent in the omega-3 group, although there was no significant difference between groups. NFκB, MIS, nPNA, BMI and hemoglobin were unaffected by the intervention. Therefore, it is conclude that `directly observed treatment' with an omega-3 based supplement (as opposed to a pure protein supplement) showed beneficial effects on lipid profile, and CRP levels. Further studies using a combination of outpatient and inpatient `directly observed treatment' is warranted.

Given a proven feasibility of directly observed treatment in the first study, we conducted a second study using tocotrienol rich fractions (TRF) by incorporating the same design to maximize compliance but with additional take home supplements. Vitamin E tocotrienols have been reported to confer anti-inflammatory, antioxidant and a potential of lipid altering benefits in vitro, in vivo and in some other clinical population. However, the impact of this nutrient in HD population is unknown. Subjects were provided daily with capsules containing either vitamin E tocotrienol-rich fraction (TRF) (180 mg tocotrienols, 40 mg tocopherols) or placebo (0.48 mg tocotrienols, 0.88 mg tocopherols). For the results, TRF supplementation did not impact any nutritional, inflammatory, or oxidative status biomarkers over time when compared with the baseline within the group (one-way repeated measures analysis of variance) or when compared with the placebo group at a particular time point (independent t-test). However, the TRF supplemented group showed improvement in lipid profiles after 12 and 16 weeks of intervention when compared with placebo at the respective time points. Normalized plasma triacylglycerols (cf baseline) in the TRF group was reduced by 33 mg/dL (P=0.032) and 36 mg/dL (P=0.072) after 12 and 16 weeks of intervention but no significant improvement was seen in the placebo group. Similarly, normalized plasma high-density lipoprotein cholesterol was higher (P<0,05) in the TRF group as compared with placebo at both week 12 and week 16. The changes in the TRF group at week 12 and week 16 were associated with higher plasma apolipoprotein A1 concentration (P<0.02) and lower cholesteryl-ester transfer protein activity (P<0.001). As a conclusion, TRF supplementation improved lipid profiles in the study of maintenance HD patients. A multi-centered trial is warranted to confirm these observations.

Finally, following a positive impact of TRF supplementation on lipid profiles, we undertook a metabolomics approach to investigate whether the TRF supplementation lead to overall changes in patients' metabolomics profile and whether the observed changes in plasma lipids correlates with their metabolomics profile. Based on the principal component analysis (PCA), there was a separation pattern between the TRF and placebo groups at week-12. After applying partial least square-discriminant analysis (PLS-DA), there was a clear separation between the two groups indicating different metabolomics profiles. In addition, metabolomics profile in both TRF and placebo group was correlated with inflammatory markers and lipid profiles suggesting that some plasma metabolite could predict/ responsible for the changes in lipid profiles and inflammatory markers.

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