Pathogenesis of Focal Segmental Glomerulosclerosis and Related Disorders

Abstract

Focal segmental glomerulosclerosis (FSGS) is the morphologic manifestation of a spectrum of kidney diseases that primarily impact podocytes, cells that create the filtration barrier of the glomerulus. As its name implies, only parts of the kidney and glomeruli are affected, and only a portion of the affected glomerulus may be sclerosed. Although the diagnosis is based primarily on microscopic features, patient stratification relies on clinical data such as proteinuria and etiological criteria. FSGS affects both children and adults and has an elevated risk of progression to end-stage renal disease. The prevalence of FSGS is rising among various populations, and the efficacy of various therapies is limited. Therefore, understanding the pathophysiology of FSGS and developing targeted therapies to address the complex needs of FSGS patients are topics of great interest that are currently being studied across various clinical trials. We discuss the etiology of FSGS, describe the major contributing pathophysiological pathways, and outline emerging therapeutic strategies along with their pitfalls.

Keywords: FSGS; innate immunity; integrin; kidney; podocyte; suPAR.

Figure 1

The spectrum of glomerular injury leading to the disruption of the glomerular filtration barrier in FSGS. Abbreviations: COVID-19, coronavirus disease 2019; FP, foot process; FSGS, focal segmental glomerulosclerosis; HIV, human immunodeficiency virus; IFN, interferon; suPAR, soluble urokinase-type plasminogen activator receptor. Figure adapted from images created with BioRender.com.

Figure 2

Common glomerular histological changes in FSGS. (a) A normal glomerulus with a tuft of capillaries and surrounding proximal and distal convoluted tubules. (b) The partially sclerosed glomeruli in FSGS. The condition is characterized by the effacement, detachment, and death of podocytes, resulting in an area of denuded GBM and extensive deposits composed of the remains of damaged podocytes, PECs, and GBM components. FSGS lesions are associated with adhesion of PECs, which are originally located along the Bowman’s capsule, to the glomerular tuft. In some cases, the lesions form hyalinosis (prominent serum protein casts), causing obliteration of glomerular capillaries. Additionally, activated PECs may migrate toward the tubular orifice and obstruct the urine flow. Abbreviations: FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; PEC, parietal epithelial cell. Figure adapted from images created with BioRender.com.