Role of Metabolic Abnormalities During the Progression of Chronic Kidney Disease and Preventive Strategies

Abstract

Chronic kidney disease (CKD) is characterized by persistent renal impairment or dysfunction that lasts for at least 3 months, and typically has a progressive and irreversible trajectory. The increasing prevalence of metabolic disorders, such as hyperuricemia, dyslipidemia, obesity, and type 2 diabetes mellitus, have contributed to the increasing incidence of CKD, and it is now a significant public health concern worldwide. Accumulating evidence underscores the intricate relationships of the different metabolic disorders and how they promote the initiation and progression of CKD, and ultimately lead to end-stage renal disease (ESRD). Metabolic abnormalities promote CKD progression by various mechanisms, including oxidative stress, chronic inflammation, dysregulation of autophagy, glomerular hyperfiltration and disruption of hemodynamics, endothelial dysfunction, and dysbiosis of gut microbiota. Ectopic lipid deposition and lipid peroxidation-induced redox imbalance lead to mitochondrial dysfunction, excessive production of reactive oxygen species (ROS), and activation of the p38 MAPK, ERK, and JNK signaling pathways. Metabolic dysregulation activates NF-κB signaling pathways and NLRP3 inflammasomes, leading to increased production of pro-inflammatory factors, lysosomal dysfunction, and impaired autophagic clearance, followed by accumulation of metabolic waste and podocyte injury. Obesity and hyperlipidemia can cause excessive activation of the renin-angiotensin-aldosterone system (RAAS), which then causes glomerular hyperfiltration, endothelial and mesangial cell injury and proliferation, and ultimately glomerulosclerosis. Multiple interventions that target these mechanisms have shown therapeutic potential, and these include pharmacological treatments (xanthine oxidase inhibitors to reduce uric acid levels, statins for lipid regulation, and SGLT2 inhibitors and GLP-1 receptor agonists to improve renal and cardiovascular outcomes), lifestyle interventions (low-salt and low-protein diets, weight management, smoking cessation, and alcohol limitation), intermittent fasting, and microbiome-targeted therapies. This review analyzes the pathways by which metabolic abnormalities affect the onset and progression of CKD, identifies strategies that have potential use for prevention or treatment, and offers a robust theoretical foundation for the future development of effective clinical interventions.

Keywords: autophagy; chronic kidney disease; inflammation; metabolic abnormalities; oxidative stress.

Figure 1

Hyperlipidemia and hyperuricemia increase the production of ROS and oxidative stress. Oxidative stress activates the P38MAPK, ERK, and JNK signaling pathways, which then leads to injury of tubular epithelial cells and accelerated progression of CKD.

Figure 2

Metabolic abnormalities increase the level of TNF-α and also damage mitochondria and endothelial cells. Mitochondrial dysfunction leads to the production of ROS, activation of NLRP3 inflammasomes, increased expression of IL-1β, and then activation of the NF-κB pathway. These mitochondria-mediated responses, concurrent with the increased levels of TNF-α and MCP-1, lead to injury of tubular epithelial cells and accelerated progression of CKD.

Figure 3

Metabolic abnormalities lead to lysosome dysfunction and impaired autophagy. The disruption of autophagy leads to the accumulation of metabolic waste, causing podocyte injury and accelerated progression of CKD.

Figure 4

Metabolic abnormalities lead to overactivation of the RAAS. This is followed by glomerular hyperfiltration, damage and proliferation of endothelial and mesangial cells, and accelerated progression of CKD.

Figure 5

Metabolic abnormalities decrease the level of AMPK, lead to overactivation of SREB-1, and increase the level of AGEs. Suppression of AMPK and overactivation of SREB-1 decreases fatty acid oxidation and increases lipid synthesis, leading to lipotoxicity and injury of tubular epithelial cells. Concurrently, AGEs bind with their receptor (RAGE), and this activates the MAPK and NF-κB pathways. The combined effects of these changes lead to accelerated progression of CKD.

Figure 6

Interactions among pathogenic mechanisms related to metabolic abnormalities. Metabolic abnormalities cause oxidative stress, inflammation, inhibition of autophagy and activation of RAAS, and the interaction of these processes jointly increase the progression of CKD.

Figure 7

Multiple interventions have the potential to prevent, treat, or slow the progression of CKD. These include medications that lower the levels of uric acid and lipids, and those that have anti-inflammatory and anti-fibrotic effects; lifestyle modifications, such a low-salt and low-protein diet; intermittent fasting; and restoration of the balance of the gut microbiome.