Mascarenhas-Melo Filipa, Martins Bruna, Monteiro Inês, Lohani Alka, Krambeck Karolline
Higher School of Health, Polytechnic Institute of Guarda, Rua da Cadeia, 6300-307 Guarda, Portugal.
BRIDGES-Biotechnology Research, Innovation and Design for Health Products, Polytechnic University of Guarda, Avenida Dr. Francisco Sá Carneiro, No. 50, 6300-559 Guarda, Portugal.
Int J Mol Sci. 2025 Sep 9;26(18):8760. doi: 10.3390/ijms26188760.
Focal segmental glomerulosclerosis (FSGS) is a histopathological pattern of segmental glomerulosclerosis that arises from diverse primary and secondary causes. Primary (idiopathic) FSGS is rare and is often linked to intrinsic podocyte injury, while secondary forms are more prevalent and may reflect adaptative, toxic, genetic, or viral etiologies. This pattern of injury can lead to progressive renal dysfunction and, in some cases, end-stage kidney disease. The pathophysiology is multifactorial and includes direct podocyte injury (e.g., genetic defects, mechanical or toxic injury), immune-mediated processes (e.g., circulating permeability factors, inflammatory mediators), and metabolic disturbances. In particular, disturbance of lipid metabolism, including intracellular cholesterol accumulation in podocytes, have been implicated as a contributory mechanism in podocyte dysfunction and progression of disease in proteinuric/nephrotic presentations and in specific disease subtypes. Diagnosis relies on clinical assessment, laboratory testing, and histological examination, with kidney biopsy remaining the gold standard. Conventional treatments include corticosteroids, and other immunosuppressants when indicated, and measures to reduce proteinuria and control blood pressure, but the therapeutic response is variable and many patients show progression, highlighting the need for more effective and novel therapeutic approaches. Cyclodextrins (CDs), widely used as drug carriers to enhance solubility, can also mobilize and promote efflux of cholesterol from cells. Preclinical studies show that CDs reduce renal lipid accumulation and ameliorate podocyte injury in experimental models, supporting the idea that CDs could have a dual role as drug carriers and as direct modulators of lipid-related podocyte injury in lipid-associated forms of FSGS. Given the limited direct clinical data in FSGS, in this article we discuss the biological rationale, preclinical evidence, and remaining knowledge gaps for exploring CDs as an innovative therapeutic strategy.
局灶节段性肾小球硬化（FSGS）是一种节段性肾小球硬化的组织病理学模式，由多种原发性和继发性原因引起。原发性（特发性）FSGS较为罕见，常与足细胞内在损伤有关，而继发性形式更为常见，可能反映适应性、毒性、遗传或病毒病因。这种损伤模式可导致进行性肾功能不全，在某些情况下可导致终末期肾病。其病理生理学是多因素的，包括直接足细胞损伤（如基因缺陷、机械或毒性损伤）、免疫介导过程（如循环通透性因子、炎症介质）和代谢紊乱。特别是，脂质代谢紊乱，包括足细胞内胆固醇蓄积，被认为是蛋白尿/肾病表现及特定疾病亚型中足细胞功能障碍和疾病进展的一个促成机制。诊断依赖于临床评估、实验室检查和组织学检查，肾活检仍是金标准。传统治疗包括使用糖皮质激素，必要时使用其他免疫抑制剂，以及降低蛋白尿和控制血压的措施，但治疗反应不一，许多患者病情仍会进展，这凸显了对更有效和新颖治疗方法的需求。环糊精（CDs）被广泛用作药物载体以提高溶解度，也能动员并促进细胞内胆固醇外流。临床前研究表明，CDs可减少实验模型中的肾脏脂质蓄积并改善足细胞损伤，这支持了CDs在脂质相关型FSGS中可兼具药物载体和脂质相关足细胞损伤直接调节剂双重作用的观点。鉴于FSGS的直接临床数据有限，在本文中我们讨论将CDs作为一种创新治疗策略的生物学原理、临床前证据及尚存的知识空白。
