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Access Type

WSU Access

Date of Award

January 2022

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Nutrition and Food Science

First Advisor

Smiti Gupta

Abstract

Markers of inflammation, oxidative stress and dyslipidemia have found to be novel uremia related risk factors observed in maintenance hemodialysis patients (MHD). It has been reported that these markers are associated with higher rates of cardiovascular diseases (CVD) among MHD patients. Considering the increased risk for mortality and morbidity among MHD patients due to CVD, there has been a growing interest in recent research to improve the well-being of these patients with different treatment modalities. A naturally occurring dietary supplement such as tocotrienols considered to possess a strong antioxidant capacity and can potentially exert an anti-inflammatory effect which may improve the health outcome of MHD patients. Supplementation of Tocotrienol Rich Fraction (TRF) is considered a potential strategy to overcome non-traditional risk factors associated with CVD among hemodialysis population. Palm Tocotrienols in Chronic Hemodialysis (PATCH) was an interventional double blind randomized clinical trial carried out in MHD patients who were supplemented with TRF to investigate the effect of tocotrienols on markers of oxidative stress, inflammation, and blood lipid profile of MHD as compared to a placebo. And the metabolomics study was carried out as a secondary analysis of the PATCH study to investigate the effect of TRF on the plasma metabolomic profile of MHD patients. To date no studies have been conducted to examine the effect of TRF supplementation on the metabolomic profile of MHD patients. Therefore, the purpose of this study is to identify changes in the plasma metabolomic profile of the placebo group with renal disease and how TRF supplementation could modulate these metabolomic changes over time from baseline to 12 months in the US (n = 85) and Malaysian (n =80) MHD patients. Based on the different comorbidities observed at baseline the study participants from US were categorized into four different subgroups; study participants with diabetes mellitus, hypertension, dyslipidemia (TAG/ HDL ≥ 3.8) and participant who are on Statin drug. Whereas the Malaysian study participants were sub-grouped based on the presence of dyslipidemia and diabetic mellitus. The metabolomics analysis was carried out in each of these subgroups separately including the entire US and Malaysian cohorts. Changes in plasma metabolomic profile of the MHD patients with or without TRF supplements for 12 months period were investigated using 1H-NMR based metabolomics approach including multivariate data analysis, metabolite identification and quantification followed by pathway analysis and biomarker validation. According to partial linear square discriminate analysis (PLS-DA), the metabolomic profile of the MHD in both placebo and TRF groups had shown a significant variation from baseline to 12 months in the entire US and Malaysian cohorts as well as within each subgroup. Further, based on the PLS-DA analysis, the metabolomic profile between the placebo and TRF groups was found to be significantly different at 12 months in both cohorts including the subgroups. Metabolite identification and quantification followed by pathway analysis showed that the key metabolites linked with arginine and proline metabolism pathway and synthesis and degradation of ketone bodies pathways were significantly (p < 0.05) different between the placebo and TRF groups over 12 months in the US cohort. These key metabolites include proline, trans-4-hydroxyproline, ornithine, arginine, glutamate, acetoacetate, 3-hydroxybutyrate, trimethylamine and 3-aminoisobutyrate. In the Malaysian cohort, the levels of proline, trans-4-hydroxyproline, ornithine, glutamate, 3-aminoisobutyrate and 4-aminobutyrate were significantly (p < 0.05) altered between the two tested groups over 12 months period. Hence, the arginine and proline metabolism pathway was most predominately altered in the Malaysian cohort. Interestingly, the TRF supplementation had shown to modulate these metabolites that are altered with renal disease in a favorable direction indicating a potential beneficial impact of the TRF supplementation in MHD patients. Based on the ROC-curve based biomarker analysis, the biomarker models created using the significant metabolites altered between the placebo and TRF groups over 12 months had shown good predictive accuracy in both US (0.85) and Malaysian (0.82) cohorts. Further, the sensitivity and specificity values were found to be 76 % and 84 % with a classification rate of 80 % in the US cohort. Similar results were observed in the Malaysian cohort where the sensitivity and specificity values were found to be 78 % and 77 % with a classification rate of 76 %. Further model validation relied on permutation test with 1000 permutations. The observed statistics was at p < 0.001, validating the predictive ability of the original bio marker model created using the key metabolites in both cohorts. The biomarker meta-analysis revealed that trans-4-hydroxyproline, proline, acetoacetate, ornithine, 3-hydroxybutyrate, 3-aminoisobutyrate and glutamate had similar expression pattern in both cohorts. Thus, these key metabolites may serve as biomarkers for kidney disease and/ or for evaluating efficacy of TRF/drug supplementation in MHD patients.

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