Focal segmental glomerular sclerosis (FSGS) is a frequently encountered cause of nephrotic syndrome, accounting for 40% of cases in adults and 20% in children.[1] Histologically, it is characterized by segmental scarring, involving a part of the glomerulus, and affects some but not all glomeruli sampled. Recent research has shed light on the pathogenesis of FSGS which is podocyte injury and damage, leading to protein loss and subsequent development of focal sclerosing lesions.[2] FSGS is broadly categorized into primary (idiopathic) and secondary forms, and such distinction carries both prognostic and therapeutic implications.[3]

Recent research has shed light on the pathogenesis and etiology of focal segmental glomerular sclerosis (FSGS), which is podocyte injury. Several genetic and acquired causes of podocyte injury have been identified.

Genetic

Several genes encoding slit diaphragm proteins, cell membrane proteins, cytoskeleton proteins, nuclear proteins, mitochondrial proteins, and lysosomal proteins have been identified to be abnormal/mutated leading to loss of integrity of glomerular filtration barrier resulting in FSGS.[4]

Circulating Permeability Factor

Primary FSGS has long been thought to be due to the presence of circulating permeability factors/cytokines which causes foot process effacement and proteinuria. These include cardiotrophin-like cytokine factor 1, apoA1b, anti-CD40 Ab and suPAR.[5][6][7]

Viruses

Viral causes include HIV[8][9], parvo B19, CMV, EBV, hepatitis C, and Simian virus 40.

Drugs

Drugs associated with FSGS include heroin, interferon, lithium, pamidronate, mTOR inhibitors, anabolic steroid.[10][11][12]

Adaptive response to several stimuli resulting in glomerular hypertension, hyperfiltration and eventual hypertrophy including diabetes mellitus, hypertension, obesity, renal aplasia, hypoplasia or dysplasia, renal artery stenosis, cholesterol emboli, and vascular disease can lead to FSGS. Histopathologically, these are characterized by large glomeruli, the predominance of perihilar scarring, and partial foot process effacement.[13][14]

The exact incidence and prevalence data of FSGS is difficult to ascertain due to significant racial and geographical differences in incidence.[15] The estimated incidence of FSGS is about 7 per 1 million with a prevalence of 4% as described by Kitiyakara et al. in 2003.[16]. In the United States, approximately 50% of nephrotic syndrome in AA is attributed to FSGS. However, the prevalence of FSGS has gradually increased over the years, and it is the most common primary glomerular process contributing to end-stage renal disease in the United States. The increasing incidence is likely due to improved recognition and detection of the entity, with a better understanding of the pathophysiology of podocyte injury and development of therapy targeting mediators of such injury.

The pathogenesis of focal segmental glomerular sclerosis (FSGS) involves a complex interplay of several cell types including podocytes, endothelial cells, and the basement membrane. Podocytes are terminally differentiated cells that provide structural support to the glomerulus and are essential in maintaining an intact glomerular filtration barrier essential to prevent nephrotic range proteinuria. Injury and loss of podocytes result in podocyte hypertrophy of remaining podocytes to cover the glomerular capillary surface resulting in effacement and protein loss.[17][18]

Histologically, focal segmental glomerular sclerosis (FSGS) is characterized by sclerosis, hyalinosis, adhesions/synechiae formation, resulting in segmental obliteration of glomerular capillaries. On EM, foot process effacement is the predominant finding without significant basement membrane abnormalities. Immunofluorescence shows staining for IgM and C3 in sclerotic areas. Juxtamedullary nephrons are affected first and hence inadequate sampling may miss focal lesions. 

Histologically, FSGS is classified into five variants: perihilar, tip, cellular, collapsing and NOS (not otherwise specified).[3][19][20]

Perihilar: The sclerosing lesion is located at the vascular pole of the glomerulus. This is commonly seen in adaptive FSGS due to increased pressure in the glomerulus which is in close proximity to the afferent arteriole. Foot process effacement is mild, resulting in subnephrotic proteinuria and relatively normal serum albumin levels. 

Tip: The segmental lesion involves the tubular pole of the glomerulus. This is commonly seen in Caucasians, presenting with diffuse foot process effacement and abrupt onset of nephrotic syndrome. These patients have lower baseline creatinine, have an excellent response to treatment, and the lowest rate of progression.[21]

Cellular: This is the least common variant of FSGS, characterized by hypercellular glomerulus including endocapillary and glomerular epithelial cell hyperplasia. It presents with diffuse foot process effacement and full-blown nephrotic syndrome.[22]

Collapsing:- This is characterized by hyperplasia and hypertrophy of visceral glomerular epithelial cells leading to the collapse of the glomerular tuft. This is commonly seen in viral (parvovirus B19, CMV, HIV)[23][24] and drug-associated forms of FSGS (IFN, pamidronate)[25] and presents with diffuse effacement of foot processes, heavy proteinuria with the lowest rate of remission, and the worst prognosis.

NOS: This is the most common subtype of FSGS and does not fit into any other morphological forms of FSGS. It presents with a variable degree of effacement and proteinuria.

Histopathology may sometimes resemble nodular sclerosis as in diabetes and other conditions.[26]