2. INTRODUCTION
• Pattern of glomerulosclerosis - focal, involving a minority of
glomeruli, and segmental- involving a portion of the
glomerular tuft.
• FSGS represents as many as 35% of cases in adults and is a
major cause of end-stage renal disease (ESRD)
• Annual incidence rates ranged from 0.2 to 1.8/100,000
population per year
• 1.5-fold higher in men
6. • Familial/Genetic*
• Mutations in nephrin (NPHS1)
• Mutations in podocin (NPHS2)
• Mutations in α-actinin 4 (ACTN4)
• Mutations in transient receptor potential cation
channel (TRPC6)
• Mutations in Wilms tumor suppressor (WT1)
• Mutations in inverted formin-2 (INF2)
• Mutations in phospholipase C epsilon 1 (PLCE1)
• Risk alleles for apolipoprotein L1 (APOL1)
7. •Mediated by Adaptive Structural-Functional
Responses
• REDUCED RENAL MASS
• Oligomeganephronia
• Very low birth weight
• Unilateral renal agenesis
• Renal dysplasia
• Reflux nephropathy
• Sequela to cortical necrosis
• Surgical renal ablation
• Chronic allograft nephropathy
• Any advanced renal disease with reduction in functioning nephrons
8. •INITIALLY NORMAL RENAL MASS
• Hypertension
• Aeroembolism or other acute vaso-occlusive processes
• Obesity
• Increased lean body mass
• Cyanotic congenital heart disease
• Sickle cell anemia
9. Morphologic Variants of Focal Segmental
Glomerulosclerosis
• FSGS, not otherwise specified (NOS; also known as classic
FSGS)
• FSGS, perihilar variant
• FSGS, cellular variant
• FSGS, collapsing variant (also known as collapsing
glomerulopathy)
• FSGS, tip variant
10. Classic Focal Segmental Glomerulosclerosis
• Common generic form of the disease
• Accumulations of ECM that occlude glomerular capillaries, forming
discrete segmental solidifications
• Hyalinosis -plasmatic insudation of amorphous glassy material
beneath the GBM
• Endocapillary foam cells & Wrinkling of the GBM
• Adhesions or synechiae to the Bowman capsule are common
• Overlying visceral epithelial cells often appear swollen and form a
cellular “cap” over the sclerosing segment
• Mild podocyte swelling
11. • Immunofluorescence (IF) - Deposition of immunoglobulin M (IgM),
C3, and more variably C1q
• On EM- Increased ECM, wrinkling and retraction of the GBM,
accumulation of infra-membranous hyaline
No electron-dense deposits are found
Podocyte detachment with parietal cell coverage
• Nonsclerotic glomerular capillaries- Foot process effacement with
variable microvillous transformation
12.
13.
14. Perihilar Variant
• Perihilar hyalinosis and sclerosis involving more than 50% of glomeruli
with segmental lesions
• Podocyte hyperplasia is uncommon
• Frequent in secondary forms of FSGS mediated by adaptive structural-
functional responses
• Glomerular hypertrophy (glomerulomegaly) and relatively mild foot
process effacement
15.
16. Cellular Variant
• Focal and segmental endocapillary hypercellularity
• Glomerular capillaries are segmentally occluded -
Foam cells, Infiltrating leukocytes, Karyorrhectic
debris & Hyaline
• Hyperplasia of the visceral epithelial cells-
Pseudocrescents
• Foot process effacement is severe
• Usually seen in Primary FSGS
17.
18. Collapsing Variant
• At least one glomerulus with segmental or global collapse and
overlying hypertrophy and hyperplasia of visceral epithelial cells
• Occlusion of glomerular capillary lumina by implosive GBM
wrinkling and collapse
• Pseudocrescents
• Distinguished by the absence of endocapillary hypercellularity
• Prominent tubulointerstitial disease, including tubular atrophy,
interstitial fibrosis, interstitial edema, and inflammation
• Dlated tubules forming microcysts that contain proteinaceous
casts
19. • Severe foot process effacement affecting both collapsed and
noncollapsed glomeruli
• Primary & Secondary-HIV infection, parvovirus B19 infection,
lupus podocytopathy, hemophagocytic syndrome, interferon
therapy, tyrosine kinase inhibitor use, or pamidronate
toxicity
• Endothelial tubuloreticular inclusions - HIV-associated
nephropathy, lupus podocytopathy & Interferon therapy
20.
21.
22. Tip Variant
• Tip domain, the outer 25% of the tuft next to the origin of the
proximal tubule
• Either adhesion between the tuft and Bowman capsule or confluence
of swollen podocytes with parietal or tubular epithelial cells at the
tubular lumen or neck
• Lesions may evolve more centrally.
• Foot process effacement is usually severe
• Most cases are primary and resemble MCD clinically
23.
24. Other Variants
• Diffuse mesangial hypercellularity
• FSGS on a background of generalized hypercellularity
• Exclusively in young children
• C1q Nephropathy
• IF staining for C1q
• Mesangial electron-dense deposits
• Light microscopic findings resembling FSGS or MCD with variable
mesangial hypercellularity
25. PATHOGENESIS
• FSGS is a diverse syndrome that arises after podocyte injury from
diverse causes
• Sources of podocyte injury are varied -circulating factors [primary
FSGS], genetic abnormalities, viral infection, and medication
• Progressive loss of injured podocytes into the urinary space
• Podocyte depletion arising from an inability to replicate
• Podocytes compensate by hypertrophy to cover more of the
glomerular capillary surface
26. Primary FSGS
• The mechanism of podocyte injury -involves a circulating factor,
possibly a cytokine
• Recurrent FSGS immediately (on a scale of hours to several weeks)
after kidney transplant
• A kidney was transplanted into a recipient with FSGS; proteinuria
developed, and the transplanted kidney showed podocyte foot
process effacement. Subsequently, the kidney was removed and
transplanted into a patient with ESRD due to diabetes, and in the new
host, the kidney functioned well without proteinuria
27. • Current candidates for the recurrent FSGS factor
• Cardiotrophin-like cytokine factor 1
• ApoA1b (an isoform of ApoA1)
• Anti-CD40 antibody
• Soluble urokinase type plasminogen activator receptor (suPAR)-immature
myeloid cells of the bone marrow
• Most common form in adolescents and young adults
• Nephrotic-range proteinuria ,reduced plasma albumin levels, and
hyperlipidemia
• Tip variant, collapsing variant, or NOS variant.
• Current therapy for primary FSGS is on the basis of
immunosuppressive agents-glucocorticoids and calcineurin inhibitors
28. Adaptive FSGS
• Associated with an increase in total kidney GFR
• Congenital cyanotic heart disease
• Sickle cell anemia
• Obesity
• Androgen abuse
• Sleep apnea
• High-protein diet
• Duration of single-nephron glomerular hyperfiltration is typically
measured in decades before progressive glomerulosclerosis
eventually reduces total GFR
29. • Conditions associated with reduced renal mass
• Prematurity and/or small for gestation age
• Renal anomalies
• Reflux nephropathy
• AKI
• Chronic glomerular or tubular disease may reduce the total nephron
function and result in adaptive FSGS that is superimposed on the
primary disorder
• Increased single-nephron GFR (intraglomerular hypertension),
glomerular hypertrophy. podocyte hypertrophy. Stress
depletion synechia formation and excess extracellular matrix
deposition within the glomerulus
30. • Obesity-related glomerulopathy (ORG), is increasingly common
worldwide
• ORG usually lacks the full nephrotic syndrome and has a low risk for
progression to ESRD
• Renal biopsy -large glomeruli, a preponderance of perihilar scars only
• Partial foot process effacement
• Clinical features include a normal serum albumin, which is unusual in
primary FSGS.
• Complete response to RAAS antagonism, particularly when combined
with sodium restriction
31. Genetic FSGS
• More than 44 recessive and 8 dominant genes have been discovered
to cause NS in humans, if mutated
• four genes were major SRNS genes:
• NPHS2 (9.93%),
• NPHS1 (7.34%),
• WT1 (4.77%)
• PLCE1 (2.17%).
• GENITIC TESTING
• SRNS with onset before 25 years of age
• adult-onset FSGS, genetic testing is indicated if there is a positive family
history
33. Virus-Associated FSGS
• HIV-1 is strongly associated with FSGS-collapsing glomerulopathy
variant
• HIV-associated nephropathy (HIVAN) have one or two APOL1 risk
alleles.
• Other viruses -cytomegalovirus, parvovirus B19, and Epstein-Barr
virus
• Certain parasites - Plasmodium (malaria) ,Schistosoma mansoni and
filiariasis
• Presumably by stimulating innate immune pathways in ways that injure
podocytes
34. Medication-Associated FSGS
• IFN-α, -β, or -γ therapy has been associated with the development of
collapsing glomerulopathy
• Bisphosphonates are associated with podocyte injury, including MCD,
FSGS, and particularly, collapsing FSGS
• Lithium therapy has been associated with MCD and FSGS which
typically reverses within weeks after stopping the medication
• Sirolimus, particularly when the plasma levels are high, has been
associated with FSGS
• Anthracycline medications, including doxorubicin (doxorubicin, a
podocyte toxin) and daunomycin, have been associated with FSGS-
(PRKDC)
35. APOL1-Associated FSGS
• APOL1-associated FSGS is a major form of FSGS in countries with
individuals of sub-Saharan African descent
• Recessive, requiring two risk alleles, although a single copy of a risk
allele has a significant association with HIVAN
• 40% of ESRD attributed to FSGS occurs in blacks, and of this, 72% is
associated with APOL1 genetic variants
• May present as a
• Primary FSGS, with severe nephrotic syndrome
• Recurrence after kidney transplant
• Adaptive FSGS with preserved serum albumin and minimal edema
• Present as collapsing glomerulopathy
• HIVAN, in which 72% have two APOL1 high-risk alleles
• Use of exogenous IFN
• Lupus
36. • APOL1 are protective against infection by Trypanosoma brucei,the
parasite that causes African sleeping sickness
• APOL1risk alleles represented confer susceptibility, but most
subjects with two risk alleles will not develop kidney disease
• APOL1 differs from the high-penetrance genetic variants in
most other forms of genetic FSGS
• Most common form of genetic FSGS in countries with
substantial African descent populations
• Implications for prognosis, with more rapid progression to
ESRD, and it may have implications for the selection of living
donors
37. Characteristic
Features
Primary FSGS Adaptive FSGS APOL1 FSGS Genetic FSGS
Infection/Inflammation
Associated
Medication-
Associated
FSGS
Mechanism of
Podocyte Injury
Circulating factor,
possibly a cytokine
Mismatch between
metabolic load and
glomerular capacity
APOL1 variant–
initiated
inflammation
High-penetrance
genetic variants
(Mendelian or
mitochondrial
inheritance)
Postulated role of IFN and
possible other cytokines
Presumed direct
effect on
podocytes
History Acute onset of edema
Reduced renal mass: low
birth weight,
oligomeganephronia,
ureteral reflux, morbid
obesity; increased single-
nephron GFR: cyanotic
congenital heart disease,
sickle cell anemia
Family history, may
be unremarkable
Family history, may be
unremarkable with
recessive inheritance
genes
HIV, CMV, possible:
parvovirus B19, Still
disease, natural killer cell
leukemia
Bisphosphonate,
lithium
Laboratory tests
Many have high-grade
proteinuria and
nephrotic syndrome
Any level of proteinuria,
serum albumin may be
normal
Any level of
proteinuria
Any level of proteinuria Any level of proteinuria
Any level of
proteinuria
Renal pathology
Widespread foot process
effacement
Large glomeruli, perihilar
sclerosis variant most
typical, partial foot
process effacement
May resemble
primary or adaptive
forms
Variable Variable Variable
Treatment and
response
May respond to IST
Responds well to RAAS
antagonism, often with
>50% proteinuria
reduction
May respond to
therapies used for
primary and
adaptive forms
High-penetrance
genetic mutations:
usually does not
respond to IST
Treat the virus
Stop the
medication
Possible if
38. MCD versus FSGS
• corticosteroid-responsive patients who exhibit MCD on initial biopsy
subsequently relapse and display FSGS on repeated biopsy
• sampling error in the initial biopsy
• FSGS truly appears to have evolved from an initial MCD pattern
• sequential biopsy samples of recurrent FSGS in the allograft show it
may pass through an early stage that mimics MCD
• MCD and FSGS are often considered together under the rubric of
“podocytopathies.”
• proteinuria in FSGS is usually nonselective, including albumin and
higher-molecular-weight macromolecules
39. Clinical Manifestations
• Presentation- asymptomatic proteinuria or the full nephrotic
syndrome
• Nephrotic-range proteinuria at onset children- 70% to 90%
adults-50% to 70%
• Hypertension is found in 30% to 65%
• Microhematuria is found in 30% to 75% of these patients
• Decreased GFR is noted at presentation in 20% to 50%
• Proteinuria is typically nonselective
• Complement levels and other serologic test results are normal
• Glycosuria, aminoaciduria, phosphaturia, or a concentrating defect
indicating functional tubular damage and glomerular injury
40. • Tip variant of FSGS CF similar MCD
• They often present with an abrupt clinical onset of the full nephrotic
syndrome (almost 90%),
• More severe proteinuria
• Less chronic tubulointerstitial disease than in FSGS not otherwise specified
(NOS)
• The cellular variant
• Greater proteinuria
• Higher incidence of nephrotic syndrome than FSGS NOS.
• Collapsing variant
• Greater proteinuria,
• Full-blown nephrotic syndrome
• Lower GFR.
41. Natural History and Prognosis
• Most unresponsive children and adults have a similar course and
develop ESRD 5 to 20 years from presentation,
• With approximately 50% of such patients reaching ESRD by 10 years1
42.
43. • Risk Factors for Progressive Renal Disease in Focal
Segmental Glomerulosclerosis
• Clinical Features at Biopsy
• Severity of nephrotic-range proteinuria
• Elevated serum creatinine
• Black race
• Histopathologic Features at Biopsy
• Collapsing variant
• Tubulointerstitial fibrosis
• Clinical Features during Disease Course
• Failure to achieve partial or complete remission
44. • Outcomes are best for tip variant and worst for collapsing variant of
primary FSGS, with intermediate outcome in FSGS NOS
• Percentage of complete and partial remission
• tip lesion (76%),
• cellular (44%)
• FSGS NOS (39%)
• collapsing variant (13%),
• ESRD
• collapsing variant (65%),
• FSGS NOS (35%)
• cellular variant (28%)
• tip lesion (6%),
45. • Collapsing variant are matched with patients with
FSGS NOS for baseline levels of renal function,
proteinuria, and immunosuppression, responses to
treatment are similar, highlighting the importance of
early detection and aggressive therapy
46. Treatment recommendations for children
with FSGS
Setting Therapy Comment
On presentation
Prednisone: initially daily and then
alternate days
Frequently relapsing or steroid dependent
Prednisone: initially daily and then
alternate days at lowest dose to
prevent relapse
Same, with steroid-related adverse events
Alkylating agent
(cyclophosphamide or
chlorambucil), calcineurin inhibitor,
levamisole, mycophenolate mofetil
No RCT comparing one agent with
another; listed in alphabetical
order
Steroid resistant Calcineurin inhibitor
Also ACE inhibitor and angiotensin
receptor blocker; sodium
restriction
If no remission, mycophenolate
mofetil, corticosteroids, or both
47. Treatment recommendations for adults with
FSGS
Setting Therapy Comment
Nephrotic forms of primary
FSGS, APOL1 FSGS, certain
steroid-sensitive genetic forms
of FSGS
Prednisone, initially daily or
alternate days
Alternate for patients at high
risk for steroid complications:
calcineurin inhibitors
Steroid-resistant FSGS with
nephrotic syndrome
Calcineurin inhibitor(cyclosporin
and possibly, tacrolimus)
Refractory FSGS with nephrotic
syndrome
Mycophenolate mofetil plus
high-dose dexamethasone
All forms of FSGS with
subnephrotic proteinuria
ACE inhibitor and angiotensin
receptor blocker; dietary sodium
restriction
Thiazide diuretic may potentiate
the antiproteinuric of RAAS
antagonism
48.
49. TREATMENT
• KDIGO guidelines recommend initial prednisone therapy in nephrotic
patients with primary FSGS, with the high dose to be continued for a
minimum of 4 weeks and a maximum of 16 weeks, with a slow taper
over 6 months
• KDIGO guidelines specifically suggest that cyclophosphamide not be
given to children with corticosteroid-resistant nephrotic syndrome
and to use alternative medicines such as calcineurin inhibitors (CNIs)
or mycophenolate mofetil 6 months after achieving complete
remission
50. • Adults with FSGS treated with oral cyclophosphamide or
chlorambucil, pooled data showed a high response rate for patients
with corticosteroid dependence or intolerance, but a remission rate
of less than 20% for corticosteroid-resistant patients
• Low-dose cyclosporine, 3 to 6 mg/kg/day for 2 to 6 months, to treat
corticosteroid-resistant FSGS
• Complete plus partial remission has been achieved in 60% to 70%
• High relapse rate when cyclosporine is discontinued after only 6
months, many clinicians use a 1-year course with slow taper in
patients who have had a favorable reduction of proteinuria with
cyclosporine
51.
52. • KDIGO guidelines suggests MMF and dexamethasone be considered
for corticosteroid-resistant patients who do not tolerate CNIs.
• Addition of plasma exchange to immunosuppressive medications,
which has been successful in treating some patients with recurrent
FSGS in the renal allograft
• Rituximab has been used in several studies of small numbers of
patients with FSGS who have either failed other treatments or
become dependent on these therapies
• Corticotropin (adrenocorticotropic hormone) has been beneficial in
small numbers of patients with FSGS resistant to multiple other
immunosuppressive agents
53. NEWER TREATMENT
• Phase 1 study -N-acetyl mannosamine (metabolic precursor of sialic acid)
• Phase 2/3 studies
• Sparsentan (a modified form of irbesartan that also antagonizes
endothelin-1),
• Abatacept (a fusion protein that targets CD80),
• Acthar (pituitary extract),
• Fresolimumab (mAb directed against TGF-β),
• Isotretinion (retinoic acid derivative),
• Losmapimod (an mitogen-activated protein kinase inhibitor).
• Dapagliflozin (Canada),
• Lipoprotein removal (Japan)
• Mesenchymal stem cell therapy (Iran)
54. POST Transplantation FSGS
• 30% of patients with primary FSGS who develop ESRD
and undergo renal transplantation develop recurrent
FSGS in the allograft
• Children with early-onset FSGS,
• Those with more severe proteinuria and a more rapid
course to renal failure in their native kidneys,
• Who have lost a prior allograft due to recurrent FSGS
