Advances in the pathophysiology and treatment of focal segmental glomerulosclerosis: The importance of a timely and tailored approach

Table 1 Focal segmental glomerulosclerosis histologic variants

Focal segmental glomerulosclerosis histologic variants	Description
Collapsing	Clinically, the disease manifests as a nephrotic syndrome and a rapid, progressive loss of kidney function. Studies in animal models and investigations in patients have identified several clinical and genetic conditions associated with this form of glomerulopathy, as well as possible pathogenetic mechanisms, which are investigated here
Cellular	Shows a proliferation of cells in the affected glomeruli, with inflammatory proliferation and glomerular segments populated with inflammatory cells
Perihilar	This form mainly affects the perihilar region of the glomerulus and is frequently observed in patients with hyperfiltration and long-term adaptation to an increased renal stress
Apical pole (tip lesion)	It mainly involves the apical region of the glomeruli and is common in patients with nephrotic syndrome and a more favorable clinical prognosis
Not otherwise specified	This is the most common form and is used for cases that do not fall under the variants described above and have a less specific histologic picture

Table 2 Summary of ongoing clinical trials and investigational therapies in focal segmental glomerulosclerosis

Clinical trial	Targeted pathway	Findings/observations
DUET study	Endothelin and RAS receptors	Significant reduction in proteinuria observed; effectiveness on eGFR progression remains under evaluation
DUPLEX study	Sparsentan (endothelin and RAS)	Sustained antiproteinuric effect; no significant reduction in eGFR decline over two years
VX-147 trial	APOL1-targeting	Promising results in patients with APOL1 mutations; significant proteinuria reduction observed
Rituximab trials	B-cell depletion	Reduced relapses in steroid-dependent patients; limited efficacy in steroid-resistant cases
Anti-nephrin trials	Circulating anti-nephrin antibodies	Remission seen in patients with high antibody levels; further studies required to confirm pathogenic role
Adrenocorticotropic hormone gel studies	Mechanism not fully understood	Promising results in steroid-dependent patients; additional confirmation needed in larger clinical trials

APOL1: Apolipoprotein 1; EGFR: Estimated glomerular filtration rate; RAS: Renin-angiotensin system.