UC Davis

Chronic kidney disease (CKD) leading to kidney failure and end-stage renal disease (ESRD) is aserious medical condition associated with increased morbidity, mortality, and in particular cardiovascular disease (CVD) risk. CKD is characterized by a range of complex deleterious physiological and metabolic function alterations including disruptions in lipid, amino acid, and carbohydrate metabolism; skeletal muscle dysfunction, insulin resistance, and heightened inflammation/oxidative stress. In addition, concurrent comorbidities such as diabetes, hypertension, and dyslipidemia further exacerbate cardiometabolic risk and worsen patient outcomes. Emerging evidence suggest that dysfunctional mitochondria have a pivotal role in both the development of CKD and its associated comorbidities highlighting it as a promising target for therapeutic intervention. The goal of my work was to comprehensively explore the diverse pathophysiologies linked to CKD, its nutritional implications, and treatment modalities; and the potential to modify health and outcome by pharmacological and non-pharmacological means. By elucidating the interplay between CKD and metabolic derangements, as well as the impact of mitochondrial dysfunction, we aimed to pave the way for novel therapeutic approaches that address management of CKD and improve patient prognosis. In this dissertation, we have focused on patient-oriented research using metabolic imaging and multi-omics approaches to better understand the pathophysiology of CKD and linking alterations in metabolism with muscle function and physical performance. In doing so, we performed a 2 comprehensive investigation of metabolic, physiological, and cardiometabolic disturbances in CKD. Chapter 1 provides a comprehensive overview of CKD and CKD-related comorbidities as well as metabolic and physiological complications. Chapter 2 investigates the impact of nicotinamide riboside (NR) and coenzyme Q10 (CoQ10) that target mitochondrial metabolism for their potential effects on systemic markers of mitochondrial metabolism and physical endurance in a sedentary CKD cohort. Chapter 3 and 4 investigate metabolic derangements in non-diabetic moderate-severe CKD. Chapter 3 focuses on identifying altered metabolic pathways contributing to disruptions to insulin response in response to oral glucose tolerance testing in CKD. In chapter 4 we build on the findings from chapter 3 by investigating postprandial incretin hormone levels and their determinants using a standardized OGTT comparing non-diabetic patients with CKD and controls. We separately investigate the association of postprandial circulating incretin hormones with insulin, c-peptide, and glucagon levels during an OGTT by CKD status. Chapter 5 provides a summary of the work performed, concluding remarks, and plans for future studies.