Focal and Segmental Glomerulosclerosis
This article was published in Renal Fellow Network website
Focal and Segmental Glomerulosclerosis (FSGS)
A group of podocytopathies (of varying etiologies) share a common morphologic feature of focal segmental glomerulosclerosis (FSGS), typically with moderate to heavy proteinuria.
The term “sclerosis” means healing and it is characterized by accumulation of glomerular collagen (type IV).
Some of the segmental lesions are not sclerosis, but hyaline deposits or hyalinosis. This feature originated the classical denomination, more of the French school, focal and segmental hyalinosis.
Other investigators designate those cases in which there are hyaline segments as “FSGS with hyalinosis”.
There is no a clear explanation why in some cases there are hyaline segments and while none in others. Some authors consider that hyaline lesions are precursory of those sclerosing lesions. Nevertheless, it seems
Figure 1. Columbia classification of morphology of FSGS www.ajkd.org/article/S0272-6386(03)01381-7/fulltext
Figure 2. Features of morphologic variants of the Columbia classification
Origins and Epidemiology
Focal and segmental glomerular hyalinization and capillary loop degradation described by Fahr in 1925.
FSGS was recognized as distinct entity by International Study of Kidney Diseases in Children in 1970s
Most common cause of nephrotic syndrome in adults
Apparent increase in incidence over past 2 decades.
Pathogenesis
Familial podocytes protein defects (mutations in different proteins like TRPC6, podocin, Nephrin , and WT-1 transcription factor)
Abnormal cytokines thought to play major role in idiopathic (primary) FSGS development
Podocyte dysregulation/dysfunction
Loss of podocytes leads to adhesions
Risk factor in patients with African descent is APOL1 gene
Figure 4. Opinion-based approach to genetic testing in adult-onset FSGS. Note that viral- and drug-associated forms of FSGS are usually excluded by clinical and serologic evaluation. An S. De Vriese et al. JASN 2018
Pathologic Features
Light Micrscopy
Glomeruli
Sclerosis involves some glomeruli (focal) and only portion of glomerular tuft (segmental). Of note, global sclerosis may be incidental finding and is not particularly useful in making diagnosis of FSGS (image 1).
Adhesions (synechiae) of glomerular tuft to Bowman space often accompany segmental sclerosis and are often seen early in sclerosis process.
Hyalinosis.
FSGS has zonal distribution, beginning in corticomedullary (juxtamedullary) junction (CMJ)
Glomerular hypertrophy often accompanies FSGS
Adequate sample of glomeruli is crucial to make diagnosis of FSGS since focal lesions may be missed with small samples
Multiple levels (step sections) may be needed to identify focal segmental lesions
Tubules
Tubular epithelial cells contain PAS(+) reabsorption droplets due to glomerular proteinuria.
Tubular atrophy is typically only focal early in course of FSGS.
Tubulointerstitial changes pronounced in collapsing variants of FSGS and in HIVAN.
Interstitium
Interstitial fibrosis (IF) may be present and is typically focal.
Interstitial inflammation is absent or minimal.
Vessels
Arteriolar hyalinosis and arterial intimal fibrosis may be prominent late in course of FSGS.
Image 1: Trichrome stained slide with one glomerulus demonstrating segmental obliteration of peripheral glomerular tuft with sclerosis
Image 2: Silver stained slide shows collapsing FSGS. Glomerulus shows segmental collapse of the capillary tuft, accompanied by hyperplastic and swelling of overlying epithelial cells.
Image 3. Histopathology of minimal change disease and focal segmental glomerulosclerosis. Rosenberg et al CJASN 2017.
Image 4. There is segmental staining for IgM by immunofluorescence corresponding to segmental scar
Immunofluorescence
IgM and C3 often positive in sclerotic areas or areas of increased mesangial matrix (image 4)
Image 5. Electron microscopy shows segmental intramembranous electron dense material, consistent with hyaline. Overlying podocytes are focally detached.
Electron Microscopy
Foot process effacement (FPE) typically not complete, less
Secondary FSGS usually shows less FPE than idiopathic forms of FSGS
In HIVAN, tubuloreticular inclusions can sometimes be identified
Subepithelial multilamination of GBM in collapsing variant
Differential diagnosis
Focal Glomerulonephritis
IgA nephropathy, lupus, and other inflammatory glomerulonephritis can result in segmental scars in glomeruli
Breaks in GBM sometimes evident in PAS/silver stains (not seen in FSGS)
Minimal Change Disease
No segmental sclerosis, unless segmental sclerosis is preexistent due to other etiology
FPE is usually diffuse in MCD but is typically less in most cases of FSGS
Numerous globally sclerotic glomeruli and vascular changes in patient with nephrotic syndrome are suggestive of FSGS even if no segmental lesions are seen
Difference in outcome between MCD and FSGS equivalent to difference between benign and malignant
