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Thachil, Amy

University of British Columbia

Despite advances in immunosuppression, kidney transplant success is limited by alloimmune mediated graft destruction and the gradual development of chronic rejection. Currently, we lack markers to predict the progression of the recipient alloimmune response at an early timepoint. Innate factors serve as potential targets to modulate the alloimmune environment and predict rejection risk. Metabolomics is a promising platform for identifying markers of alloimmune outcomes in kidney transplantation. Metabolite patterns reflect mechanisms occurring at the molecular, cellular, tissue, and organ level. Immune mechanisms persisting at the time of transplant produce a characteristic pattern of metabolites that may be detected in biospecimen. Additionally, cytokine profiling represents underlying immune signalling networks. By integrating patient metabolite and cytokine profiles, we develop a comprehensive assessment of recipient risk and identify targets for pre-transplant interventions. In the first study, we aimed to identify pre-transplant metabolite patterns related to i) early allograft inflammation (uCXCL10/Cr) and ii) early graft function (GFR) in pediatric renal transplant recipients. As part of this analysis, we applied a metabolite classifier that is predictive of chronic rejection in a cohort of adult kidney transplant recipients. In the third chapter, we summarized the existing literature on processing requirements for blood samples intended for use in metabolomics analyses. In the fourth chapter, we investigated the association between metabolome composition and age in a healthy pediatric cohort. We concluded by assessing differences in pre-transplant cytokine profiles associated with chronic rejection in adult kidney transplant recipients. We also compared the predictive utility of cytokine and metabolite profiling. We determined that pre-transplant metabolite patterns indicative of chronic rejection in adults are not associated with early graft inflammation or function in children. Furthermore, we report that age and body size are significant contributors to the measured pediatric metabolome and must be accounted for during biomarker identification. Our findings and literature review indicate the importance of standardized protocols to minimize sample processing-related metabolome perturbations. Finally, we identified differences in pre-transplant cytokine profiles related to chronic rejection and graft loss. We also report that the pre-transplant cytokine and metabolite profiles are correlated and improve in predictive capacity when combined.

Text

2023-10-18

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86200

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/