Focal Segmental Glomerulosclerosis: Comprehensive Review and Exploration of the Dual Potential of Cyclodextrins in Therapeutic Optimization.

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.