Zha Dongqing, Gao Ping, Wu Xiaoyan
Division of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan 430070, China.
Int J Med Sci. 2025 Jul 28;22(14):3543-3555. doi: 10.7150/ijms.114382. eCollection 2025.
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.
慢性肾脏病（CKD）的特征是持续的肾脏损害或功能障碍，持续至少3个月，且通常呈进行性和不可逆的发展轨迹。代谢紊乱如高尿酸血症、血脂异常、肥胖和2型糖尿病的患病率不断上升，导致CKD的发病率增加，目前它已成为全球重大的公共卫生问题。越来越多的证据强调了不同代谢紊乱之间的复杂关系，以及它们如何促进CKD的发生和发展，并最终导致终末期肾病（ESRD）。代谢异常通过多种机制促进CKD的进展，包括氧化应激、慢性炎症、自噬失调、肾小球高滤过和血流动力学紊乱、内皮功能障碍以及肠道微生物群失调。异位脂质沉积和脂质过氧化诱导的氧化还原失衡导致线粒体功能障碍、活性氧（ROS）过度产生以及p38丝裂原活化蛋白激酶（MAPK）、细胞外信号调节激酶（ERK）和c-Jun氨基末端激酶（JNK）信号通路的激活。代谢失调激活核因子κB（NF-κB）信号通路和NLRP3炎性小体，导致促炎因子产生增加、溶酶体功能障碍和自噬清除受损，随后代谢废物积累和足细胞损伤。肥胖和高脂血症可导致肾素-血管紧张素-醛固酮系统（RAAS）过度激活，进而引起肾小球高滤过、内皮细胞和系膜细胞损伤及增殖，最终导致肾小球硬化。针对这些机制的多种干预措施已显示出治疗潜力，其中包括药物治疗（使用黄嘌呤氧化酶抑制剂降低尿酸水平、他汀类药物调节血脂，以及使用钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂和胰高血糖素样肽-1（GLP-1）受体激动剂改善肾脏和心血管结局）、生活方式干预（低盐和低蛋白饮食、体重管理、戒烟和限制饮酒）、间歇性禁食以及针对微生物群的治疗。本综述分析了代谢异常影响CKD发病和进展的途径，确定了具有预防或治疗潜在用途的策略，并为未来有效临床干预措施的开发提供了坚实的理论基础。
