Department of Pathology, Columbia University Medical Center, 630 W. 168 Street, Room VC14-224, New York, New York 10032, USA.
Department of Nephrology and Hypertension, Rabin Medical Center, 39 Jabotinsky Street, 4941492, Petah Tikva, Israel and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Nat Rev Nephrol. 2016 Aug;12(8):453-71. doi: 10.1038/nrneph.2016.75. Epub 2016 Jun 6.
The prevalence of obesity-related glomerulopathy is increasing in parallel with the worldwide obesity epidemic. Glomerular hypertrophy and adaptive focal segmental glomerulosclerosis define the condition pathologically. The glomerulus enlarges in response to obesity-induced increases in glomerular filtration rate, renal plasma flow, filtration fraction and tubular sodium reabsorption. Normal insulin/phosphatidylinositol 3-kinase/Akt and mTOR signalling are critical for podocyte hypertrophy and adaptation. Adipokines and ectopic lipid accumulation in the kidney promote insulin resistance of podocytes and maladaptive responses to cope with the mechanical forces of renal hyperfiltration. Although most patients have stable or slowly progressive proteinuria, up to one-third develop progressive renal failure and end-stage renal disease. Renin-angiotensin-aldosterone blockade is effective in the short-term but weight loss by hypocaloric diet or bariatric surgery has induced more consistent and dramatic antiproteinuric effects and reversal of hyperfiltration. Altered fatty acid and cholesterol metabolism are increasingly recognized as key mediators of renal lipid accumulation, inflammation, oxidative stress and fibrosis. Newer therapies directed to lipid metabolism, including SREBP antagonists, PPARα agonists, FXR and TGR5 agonists, and LXR agonists, hold therapeutic promise.
肥胖相关性肾小球病的患病率与全球肥胖流行呈平行上升趋势。肾小球肥大和适应性局灶节段性肾小球硬化症在病理学上定义了这种疾病。肾小球增大是对肥胖引起的肾小球滤过率、肾血浆流量、滤过分数和肾小管钠重吸收增加的反应。正常的胰岛素/磷脂酰肌醇 3-激酶/Akt 和 mTOR 信号通路对于足细胞肥大和适应至关重要。脂肪细胞因子和肾脏内异位脂质堆积促进了足细胞的胰岛素抵抗和对肾脏高滤过的机械力的适应性反应。尽管大多数患者的蛋白尿稳定或缓慢进展，但多达三分之一的患者进展为进行性肾衰竭和终末期肾病。短期肾素-血管紧张素-醛固酮阻断有效，但低热量饮食或减肥手术引起的体重减轻可诱导更一致和显著的降蛋白尿作用和高滤过的逆转。脂肪酸和胆固醇代谢的改变被越来越多地认为是肾脏脂质堆积、炎症、氧化应激和纤维化的关键介质。针对脂质代谢的新型治疗方法，包括 SREBP 拮抗剂、PPARα 激动剂、FXR 和 TGR5 激动剂以及 LXR 激动剂，具有治疗前景。
