1. Art and Diseño

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Morphologic patterns of focal and segmental
glomerulosclerosis: controversial aspects and
prognostic implications
Luis F. Arias, MD, PhD.
Departamento de Patología
Facultad de Medicina
Universidad de Antioquia
Medellín, Colombia
CIN2011
6th Congress of
Nephrology in Internet
Focal segmental glomerulosclerosis
• Focal and segmental glomerulosclerosis is a
“pattern of injury”
• It is not a specific disease entity
• There are many associated factors o “causes”
of secondary FSGS (infections, legal and illegal
drugs, hemodynamic factors, and genetics)
• Cases without known cause: Primary
Focal segmental glomerulosclerosis
• Our ignorance has led us to try to dividing the
disease according to histological features
• The Columbia classification is now the more
used morphologic classification
• But, there are controversial aspects
• Are there clear etiologic and/or prognostic
implications of the histological variants?
FSGS Variants
(The Columbia classification)
The five variants:
•
•
•
•
•
Perihilar
Cellular
Tip
Collapsing
Not otherwise specified (NOS)
FSGS - Perihilar Variant
• At least 1 glomerulus with perihilar hyalinosis
• >50% of glomeruli with lesions have perihilar
sclerosis/hyalinosis
• Commonly associated with nephron loss or
glomerular hypertension
• Many cases without associated factors: primary
• Many cases with subnephrotic proteinuria
• In our series 4.7% of 322 FSGS cases – all adults
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Una Universidad investigadora, innovadora y humanista al servicio de las regiones y del país
FSGS - Perihilar Variant
• It is required that the tip variant be excluded
• But:
- If >50% of segmental lesions are perihilar (at
least 1 with hyalinosis) + tip lesion(s)= perihilar,
because “the presence of any perihilar
sclerosis” excludes tip variant.
• Then, it would probably be better to say: “Tip
variant category requires that the perihilar
variant of FSGS be excluded”
FSGS - Perihilar Variant
• perihilar lesions (sclerosis and hyalinosis) in
<50% of affected glomeruli + tip lesions = NOS
• >50% of glomeruli with perihilar sclerosis but
there is not hyalinosis = NOS
• Prognosis: almost similar to NOS variant.
• In our series ~50% have progressed to chronic
renal failure
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Una Universidad investigadora, innovadora y humanista al servicio de las regiones y del país
Una Universidad investigadora, innovadora y humanista al servicio de las regiones y del país
FSGS - Cellular Variant
• At least 1 glomerulus with endocapillary
hypercellularity in ≥25% of the tuft and causing
occlusion of the capillary lumen/lumina
• Cells: foam cells, macrophages, endothelial
cells, neutrophils, lymphocytes
• There may be pyknotic or karyorrhectic debris
and endocapillary fibrin
• Features of proliferative endocapillary GN
Patient with nephrotic syndrome. IF: negative
Appearance similar to endocapillary proliferative GN
A difficult diagnosis
FSGS - Cellular Variant
• Endocapillary hypercellularity involving the tip
domain rules out the cellular variant, as
endocapillary hypercellularity may characterize
lesions in tip variant.
• Neither hyalinosis nor segmental sclerosis are
required features
• Then, it is a difficult diagnosis
FSGS - Cellular Variant
• The difficulty on its diagnosis contributes to the
low frequency of this variant?
• In our series 0.9%
• In another series no cases
Chun MJ et al. J Am Soc Nephrol. 2004;15:2169
FSGS - Cellular Variant
• The term “cellular” is also used to denominate
the proliferative podocitary reaction in
collapsing glomerulopathy
• And it is also used to design the proliferation of
podocytes around sclerosing lesions in tip and
“NOS” variants
• The term “cellular” could be used with a
complementary phrase/note for understanding
what we want to describe
FSGS - Cellular Variant
• Endocapillary hypercellularity can also be
encountered in collapsing variant
• Cases of collapsing and cellular variants with
overlapping histological findings
• Endocapillary proliferation could be associated
with disease activity and progression in FSGS
Taneda S, et al. Int Urol Nephrol (In press)
• cellular variant may include cases of unsampled
tip or collapsing lesion
Stokes MB, et al. Kidney Int 2006;70:1783
FSGS - Cellular Variant
• Prognosis: few cases to know it clearly
• “Intermediate rates of remission and end-stage
renal disease compared to collapsing and tip
lesion”
• “No statistical differences with NOS variant”
Stokes MB, et al. Kidney Int 2006;70:1783
• Our series: 3 cases; 1: ESRD; 1: partial response
to steroids; 1: no follow-up
Histological appearance suggesting proliferative GN. But, clinical presentation (pure nephrotic syndrome)
and negative IF, led us to diagnose the cellular variant of FSGS. Newly, a difficult diagnosis
FSGS - Tip Variant
• At least 1 segmental lesion involving the tip
domain (the 25% of the tuft next to the origin of
the proximal tubule)
• The proximal tubular pole must be identified
• Segmental sclerosis or endocapillary
hypercellularity in perihilar location in any
glomerulus rules out tip variant
• Any collapsing lesion rule out the tip variant
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FSGS - Tip Variant
• Lesions may be adhesion to the Bowman’s
capsule at the tubular lumen or neck,
endocapillary hypercellularity (<50% of the
tuft), sclerosis or hyalinosis (<25% of the tuft)
• There often is podocyte hypertrophy/
hyperplasia overlying the involved segment
• Other glomeruli may show segmental sclerosis/
hyalinosis or endocapillary hypercellularity in
portions different to tip or perihilar segments
FSGS - Tip Variant
• Tip lesion simply represents a response to heavy
proteinuria?
Haas M, Yousefzadeh N. Am J Kidney Dis 2002;39:1168
• Original definition of tip lesion: “presence of
changes at the tubular origin and nowhere else”
Howie AJ, Brewer DB. J Pathol. 1984;142:205
Howie AJ, Brewer DB. J Pathol. 1985;147:245
• The Columbia classification includes cases with
peripheral and/or indeterminate lesions.
Different clinical or prognostic implications?
FSGS - Tip Variant
• Several reports suggest an excellent response to
steroids and favourable course similar to
minimal-change disease
• Other authors (series) report response and
course similar to FSGS (NOS) and question its
clinical significance
See references in the accompanying PDF text of this conference
FSGS - Tip Variant
•
•
•
•
Our series:
Chronic renal failure: 28.0%
End-stage renal disease: 16.0%
Median of follow-up 48.7 months (24.3 – 86.7)
Although the outcome was worse in NOS, tip
variant should not be considered a benign
disease
Arias LF et al. Nephrol Dial Transplant. 2011;26:2215
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Una Universidad investigadora, innovadora y humanista al servicio de las regiones y del país
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Una Universidad investigadora, innovadora y humanista al servicio de las regiones y del país
FSGS - Collapsing Variant
• It is also known as collapsing glomerulopathy (CG)
• At least 1 glomerulus with segmental or global
collapse and overlying podocyte hypertrophy and
hyperplasia
• Other glomeruli may contain segmental lesions of
any category
• Collapse: obliterated capillaries, loss of
endothelium, capillary walls wrinkled and/or
folded, no increase of collagen
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Una Universidad investigadora, innovadora y humanista al servicio de las regiones y del país
FSGS - Collapsing Variant
• Glomeruli may show segmental endocapillary
hypercellularity with foam cells and
macrophages
• It can be a primary disease or it can be
associated to infections, autoimmune diseases,
drug exposure, malignancies, genetic disorders,
atheroembolism, acute vaso-occlusive
disorders, and other
FSGS - Collapsing Variant
• Collapsing lesions has also been described in
chronic allograft nephropathy, probably related
to vascular or hemodynamic factors
• I have seen two cases of collapsing lesions in
transplanted kidneys with severe ischemia; in
both, there was not nephrotic proteinuria and
renal function normalized several weeks after
• Similar cases have been published
Canaud G, et al. Am J Kidney Dis. 2010;55:558
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Recently transplanted patient with DGF. The deceased donor was in ICU; he had systemic hypoperfusion.
The tuft collapse is notorious. Glomerular lesions were focal. There was not nephrotic proteinuria. Notice
the acute tubular damage. Renal function normalized three weeks after biopsy.
Another patient with similar history and morphological features. He also was recently kidney transplanted.
Donor was brain-death. There are also tubular acute necrosis. Renal function normalized one month after
transplantation.
FSGS - Collapsing Variant
• CG may affect all renal epithelial cell
• Tubulointerstitial damage varies from case to
case and appears more pronounced in cases
where intrinsic epithelial cell damage, such as
viral infection, is the related factor
Albaqumi M, Barisoni L. J Am Soc Nephrol. 2008;19:1276
Notice the prominent tubular damage in this case of HIVAN
In this case there are notorious interstitial alterations
FSGS - Collapsing Variant
• Mitochondria appear to be important in pathogenesis
• Mutations in genes encoding proteins involved in the
mitochondrial respiratory chain may lead to CG
• Podocytes could be highly sensitive to hypoxic
conditions
• Hypoxia-inducible factor upregulation in podocytes
leads to proliferation and dedifferentiation in HIV
associated nephropathy
See references in the accompanying PDF text of this conference
FSGS - Collapsing Variant
• Injured podocytes show loss of some podocyte
markers, induction of expression of some
molecules and transdifferentiation to
macrophage lineage factor
Canaud G, et al. Am J Kidney Dis. 2010;55:558
FSGS - Collapsing Variant
• Since the 80’ CG was assumed as variant of FSGS
• However, CG is frequently a more aggressive
disease, with massive proteinuria and rapidly
progressive renal disease
• In our series (11 cases -3.4%): 6 cases: CRF in the
3 years after presentation; 2 patients died of
infectious complications; 1 patient with persistent
nephrotic syndrome (3 years of follow-up); 2 cases
without follow-up
FSGS - Collapsing Variant
• I think CG is a disease different from FSGS
because:
- A notoriously more aggressive outcome
- The phenotypic features of podocytes
• This hypothesis has been proposed by other
authors
Srivastava T, et al. Kidney Int. 2006;70:529
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Prominent protein resorption droplets and vacuoles in podocytes
FSGS - Not Otherwise Specified
(NOS Variant)
• Cases of FSGS when all other categories be
excluded
• It is the most common variant (78% in our series)
• It is a heterogeneous glomerulopathy
• It is a common morphological lesion in many
glomerular and non-glomerular diseases
• All the other 4 variants may evolve into this
pattern
FSGS - Not Otherwise Specified
(NOS Variant)
• NOS variant is an unspecific glomerulopathy with
many known and unknown etiologies
• It is a “collage” of glomerular alterations that
converge on a common morphological pattern
• Immunofluorescence is essential to rule out other
glomerular diseases
• clinical course highly variable
• In general, prognosis is not good
FSGS - Not Otherwise Specified
(NOS Variant)
The NOS variant is a "junk drawer" of
multiple glomerular alterations with this
common pattern of lesion, and a mixture of
pathophysiological mechanisms
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Una Universidad investigadora, innovadora y humanista al servicio de las regiones y del país
Una Universidad investigadora, innovadora y humanista al servicio de las regiones y del país
Una Universidad investigadora, innovadora y humanista al servicio de las regiones y del país
Conclusions
• FSGS is a variable morphological change common
to multiple glomerular alterations, with diverse
etiology/pathogenesis.
• Glomerular histological appearance does not
permit us to know its etiology and it is not a
perfect indicator of outcome.
Conclusions
As a personal view:
• I believe that the cellular variant is difficult to
diagnose, it is very infrequent and seems to have
no a different prognosis that NOS variant
• CG is a glomerular disease with clear differences
and would be better to separate it from FSGS
• I do not consider tip variant as a benign disease
Thanks a lot to organizers of the CIN2011 6th Congress of Nephrology in Internet for
this great initiative
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http://www.kidneypathology.com/