Approach to Focal Segmental Glomerulosclerosis

1. FSGS
Beka Aberra M.D
Renal Fellow
Year 1

2. Outline
• Case Summary
• Introduction
• Pathogenesis-Pathology
• Natural History and Prognosis
• Treatment options
• Way Forward
• Take Home Message

3. Case Summary
• 23 Yrs/M
• 10 yrs Hx of Renal disease, 07 yrs as a Steroid dependent NS
• 4 yrs since Renal Biopsy, FSGS 10 vs 20 [No report, ?EM]
• Loss to follow-up 16 months
• Tried on different immunosuppressive regimens
• Prednisolone, Cyclosporine
• MMF, Dexamethasone
• Put on diuretics, statins, ASA, EPO, Iron, CPT, ACEI intolerant
(Rise in Cr)

4. Labs Summary
• 24 hr urine protein pattern from 1.8 gm on Jan 22,2019 >>5.67>> 6.14 gm
on Dec 20, 2021.
• Serum Alb 1.2>1
• Cr Pattern 1.3>1.1>0.8>1.4>1.8>1.2>1.5 eGFR 54-70 on Nov 19,2020.
• Dec 21-31,2021 5.7>5.6>>>>5.4 eGFR 13-14 Pulsed and discharged.
• Dyslipidemia Highest Chol 927 >>418; LDL 713 >>292
• Anemia Hgb 8.4>7.4>7.7>8.4 + reactive thrombocytosis 574K
• Iron Panel Transferrin Sat [Iron 82/ TIBC 96] 85% Ferritin 556 H
• PTH 152 [*2E]; Ca+2 8.4, Po4 5; Abd US 8*4cm BL

5. What is FSGS?
A Lesion or A Disease???

6. FSGS
• FSGS refers to a pattern of renal injury characterized by [Segmental]
glomerular scars that involve some but not all glomeruli [Focal].
• As the disease progresses, more [Diffuse] and [Global] glomerulosclerosis
evolves
• Represents as many as 35% of cases in adult NS.
• ½ of nephrotic syndrome in African Americans
• Incidence is Increasing

7. FSGS
• Marked increase in the number of known underlying causes for the lesion
of FSGS over the last 10–20 years.
• Perhaps that the incidence, the age of onset, and the clinical presentation
have also dramatically altered over this timeframe.
• FSGS is now one of the most common patterns of glomerular injury
encountered in human kidney biopsies. [AA, Hispanics]

8.  50+
 [AD, AR,
X linked,
Mitochondrial]
 35+

9. FSGS- Pathogenesis
• In all these forms of FSGS, injury directed to or inherent within the
podocyte is a Central Pathogenic Mediator, podocytopathy.
• These injuries promote altered cell signaling, reorganization of the actin
cytoskeleton, and resulting foot process effacement.
• Stress placed on remaining podocytes >>> local propagation of damage.

10. FSGS- Pathogenesis
• Not completely understood
1. An Initiating Event [Permeability factor, genetic mutation,
toxic-viral, HD stress, IC deposition or Insitu formation,…]
2. Podocyte injury [Apoptosis, impaired autophagy,
detachment, dedifferentiation]
3. Paracrine effects [Spread to adjacent podocyte]
4. Upregulation of signaling pathway [Hypertrophied podocyte
+ dedifferentiation, fibrosis]
5. Impaired Healing [Regeneration of podocyte….]

11. ppfFSGS / Primary FSGS
• A circulating factor (non-Ig or Ig) arises that inflicts injury to
podocyte.
• Molecular nature Unknown- may be several (CLCF-1, suPAR,
IL13, anti CD40, CASK, etc.)
• Cellular source- unknown (?T cells; B cells, Both)

12. G-FSGS [>50+]
• Monogenetic or complex di-genetic disorders commonly underlies FSGS
in children (20-75%) vs adults (15-30%?)
• AD, AR, X linked and Mitochondrial, Some are Sporadic
• 50+ separate genes identified; 90% due to mutations at 6 loci (NPHS1,
NPHS2, TRPC6, IFN2…) + Polymorphic alleles at APOL 1in AA, LCAT
• Pre Rx Screening in Children FSGS, Adults with steroid resistant lesion
• Subclinical genetic variation (CDAP, NPHS2, APOL1…) susceptible to
secondary forms FSGS [Massive obesity, COVAN)

14. Secondary FSGS [>35+]
• Maladaptive- [DM, Obesity, Cyanotic CHD, SS ds, GSD..]
• Oligo-nephronia- [Reflux, Partial Nephrectomy, IUGR, LBW..]
• Infections- [HIV,HCV, Parvo, Polyoma, CMV, EBV, Covid,
HLH/MAS..]
• Drugs/ Physical agents- [Biphosphonates, IF, NSAIDS, Lithium,
CNI, Radiation…]
• Neoplasia- [PCV, CML, Carcinomas, Lymphomas]
• Superimposed- Any 10/20 GN [IgaN, MN, LN, C1qN, C3G,DN..]
• Other- Lupus Podocytopathy, Auto immune myelofibrosis

15. FSGSuc- Undetermined Cause
• Despite extensive evaluation, a clear aetiology cannot be
determined for many patients with an FSGS lesion.
• The clinical presentation and EM findings of these patients are
often similar to those of patients with maladaptive FSGS.
• A study of patients with FSGS in Olmsted County, MN, USA,
showed that the cause of the lesion remained unknown in
>60% of patients with features characteristic of secondary
FSGS.

16. Primary vs Non-Primary
• The Non-primary [genetic and secondary] forms of FSGS are
notably slow progressors, non nephrotic proteinuria and normo-
albuminemia, by resistance to steroid treatment and by a very
low risk of recurrence in renal allografts.
• However, a specific cause of non-primary FSGS is only proven
in ~50%.

17. FSGS- Pathology
• Classical description of FSGS includes
• Segmental increase of mesangial matrix with obliteration of the capillaries
• Sclerosis
• Hyalinosis
• Foam cells
• Segmental scarring
• Adhesion between the glomerular tuft and Bowman’s capsule
• Five histologic variants [after Fogo/ D’Agati]
 Perihilar variant, in which more than 50% of glomeruli with segmental lesions
display hyalinosis and sclerosis involving the vascular pole region;
 Cellular variant, manifesting endocapillary hypercellularity;
 Collapsing variant, in which at least one glomerulus has global collapse and
overlying visceral cell hypertrophy and hyperplasia; and
 Tip variant, with segmental lesions involving the tubular pole.
 Other, more controversial histologic variants of FSGS include FSGS with
diffuse mesangial hypercellularity and C1q nephropathy.

18. FSGS, NOS (Classic variant)
70 %
NOS
often
Primary/
Genetic

19. FSGS, Per hilar variant
7%
Per-hilar
often
Maladaptive

20. FSGS, Cellular variant
3 %
Cellular
often
Viral/
Drugs

21. FSGS, Tip variant
10 %
“Tip”
often
Primary/
Variant
of MCD

22. FSGS, Collapsing variant
12 %
Collapsing
often Higher in
AA with APOL1
risk alleles,
HIV, Drugs,
MAS, Lupus
podocytopathy.

23. The presence of different Columbia classification
subtypes in a single biopsy underlines the inability of
light microscopy alone to classify a focal segmental
glomerulosclerosis lesion aetiologically.
Electron microscopy showed diffuse foot process
effacement. DX of EXCLUSION ppfFSGS.
The diagnosis of presumed permeability factor focal
segmental glomerulosclerosis was made.

24.  Electron microscopy enabled a diagnosis of
fibrillary glomerulonephritis to be made and
avoided an erroneous diagnosis of focal segmental
glomerulosclerosis (FSGS) based on light
microscopy alone.

25. FSGS- Clinical Features
• Asymptomatic proteinuria or full nephrotic syndrome
At Presentation
• Nephrotic-range proteinuria at onset
• Children: 70% to 90%
• Adults: 50% to 70%
• Secondary FSGS
• Sub nephrotic proteinuria; Normal serum albumin
• Hypertension 30%-65%
• Micro hematuria 30%-75%
• Reduced GFR 20-50%

26. FSGS- Clinical Features
• The Tip Variant of FSGS have clinical features more similar to those of
MCD. They present with abrupt clinical onset of the full nephrotic
syndrome (~90%), shorter time course to renal biopsy, more severe
proteinuria, & less chronic tubulointerstitial disease than in FSGS (NOS).
• The Cellular Variant also typically manifests with greater proteinuria and
higher incidence of nephrotic syndrome than FSGS NOS.
• The Collapsing variant usually manifests with greater proteinuria, more
full-blown nephrotic syndrome, and lower GFR than FSGS NOS.

27. FSGS- Natural History & Prognosis
• Varied natural history
• Spontaneous remission: 5-25%
• Without therapy or response to therapy, the majority of patients
with primary FSGS will experience a progressive increase in
proteinuria and progression to renal failure
• ESRD 5 to 20 years from presentation
• [50% by 10 years]

28. FSGS- Natural History & Prognosis
• Prognosis in patients with ppfFSGS is predicted by the severity
and persistence of proteinuria.
• Patients with non-nephrotic proteinuria have a good prognosis, with
kidney survival rates of more than 95% after a mean follow-up of 6.5 to
9.3 years, even in older studies when few patients, if any, were treated
with RAS blockade.
Beaufils 1978, Cameron 1978, Velosa 1983, Korbet 1995

29. FSGS- Natural History & Prognosis

30. FSGS- Natural History & Prognosis
• Resistance to corticosteroids and immunosuppressive therapy
is now considered the strongest predictor of ESRD.
• Prognosis is poor in patients who do not achieve remission, with
5-year kidney survival averaging 65% (60–90%) and 10-year
kidney survival 30% (25–56%).

31. FSGS- Treatment
• Considerable debate still, LARGE UNMET Need.
• Older studies: 10-30% remission, high relapse esp. ppfFSGS.
• There is a significant percentage with no response to therapy;
hence, the potential benefits vs risks of immunosuppressive
therapy.

33. FSGS- Treatment
1. Targeting the permeability factor(s) [Plasmapheresis, antiCD40 Bleselumab]
2. Suppressing permeability factor formation [Steroids, CNIs, MMF,
Dexamethasone, Rituximab]
3. Targeting haemodynamic abnormalities [Sparsentan ETA & Ang-2R Antag]
4. Targeting genetic mutations [APOL1-targeted antisense oligonucleotide..]
5. Protecting podocytes and promoting regeneration. Agents that are intended
to non-specifically protect injured podocytes or promote podocyte regeneration
[Steroids, CNIs, Rituximab, ACTH, Abatacept anti CD80, TRPC5i…]
6. Targeting inflammation and fibrosis. Agents that are intended to suppress
the inflammatory, pro-fibrotic component of the FSGS lesion [CCR2i, potent
Nrf2 activator bardoxolone, adalimumab, Losmapimod…]

34. FSGS- Treatment
Corticosteroids
• Prior to 1985, Primary FSGS was considered a steroid resistant
disease with poor outcome.
• In contrast, observational studies conducted after 1985 have
reported better outcomes and suggested that this improvement
in response was associated with a higher initial dose and
longer duration [>16 Weeks] of treatment with
corticosteroids.

35. FSGS- Treatment
Corticosteroids
• Treatment routines have varied with durations from 4 to 24
months, and prednisone dosing from 0.3 to 1.5 mg/kg/d,
reported complete remission rates range from 28% to 74%, and
partial remission rates from 0% to 50%.
• The average time to complete remission is 3–4 months, with a
range up to 8 months.

36. FSGS- Treatment
Corticosteroids
• Corticosteroid therapy should only be considered for patients
with Primary FSGS associated with nephrotic syndrome.
• Numerous observational studies to support the use, No RCT.
• There are no data to support treatment with corticosteroids in
patients without nephrotic-range proteinuria.

37. Corticosteroid-responsive patients are significantly less likely to develop renal failure than are
nonresponders and untreated patients. (Modified from reference 67.)

38. FSGS- Treatment
Corticosteroids
• The timing of prednisone therapy initiation has debates.
• Spontaneous remissions do occur, with reported rates varying
from 5% to 23%.
• Spontaneous remissions are more likely to occur in patients
with tip lesions, with preserved kidney function, and lower
grades of proteinuria.

39. FSGS- Treatment
Corticosteroids
• In the absence of any evidence specific for FSGS, guidelines
for adult MCD are used to direct further therapy in steroid-
responsive primary FSGS.
• There is no evidence to support the use of corticosteroids in
secondary FSGS and, in current practice, such patients are not
treated with immunosuppressive therapy.

41. FSGS- Treatment
Other Immunosuppressive Agents
• A retrospective observational study compared high-dose oral
prednisone (1 mg/kg/d) for at least 4 months and tapering
thereafter, with low-dose prednisone (0.5 mg/kg/d) in
combination with cyclosporine (3 mg/kg/d initial dose, tapering
to 50 mg/d) or azathioprine (2 mg/kg/d initial dose, tapering to
0.5 mg/kg/d).
• Average duration of treatment was 20 months.
• Low-dose prednisone was given to 16 patients with obesity, bone
disease, or mild diabetes.
• Remission rates were comparable; 63% for prednisone (n9), 80% for
prednisone plus azathioprine (n6), and 86% for prednisone plus
cyclosporine (n10).

42. FSGS- Treatment
Other Immunosuppressive Agents
• Another study used tacrolimus as initial therapy in six patients
and noted a remission in all
• A randomized study in adult patients with FSGS and persistent
nephrotic syndrome after 6 months of RAS blockade compared
MMF (2 g/d for 6 months) plus low dose prednisone (0.5
mg/kg/d for 8–12 weeks) to high dose prednisone (1 mg/kg/d for
12–24 weeks, followed by tapering over 8 weeks)
• Similar remission rates were observed in the two regimens, 71% (12/17
patients) vs. 69% (11/16 patients)

43. FSGS- Treatment
Other Immunosuppressive Agents
• These limited data suggest that patients who do not tolerate
prolonged high-dose prednisone might benefit from alternative
immunosuppressive agents, alone or in combination with a
lower dose of prednisone.
A CNI is favored in view of the evidence derived from
studies in patients with steroid-resistant FSGS.

45. FSGS- Treatment
Other Immunosuppressive Agents
• A RCT of children and adults with SR-FSGS showed that the combination of a
12-month course of MMF with high-dose dexamethasone induced a 33%
combined PR/CR. Following discontinuation 18% relapsed, demonstrating only a
modest improvement with prolonged dexamethasone exposure and MMF.
• Case reports noting improvement in FSGS with sirolimus exist, but this drug
associated with worsening of RFT as well as new 10 FSGS in kidney allografts.
• Rituximab might prove effective in patients with FSGS in select cases, results are
mixed in 10 FSGS or recurrent FSGS patients following kidney transplantation.
• Finally, Plasma exchange has been successful in treating some patients with
recurrent FSGS in a kidney allograft, ppfFSGS.

48. FSGS- Treatment
For patients with secondary forms of FSGS
• Treatment of the primary disorder
• RAA blockers
• Reduce proteinuria, decrease intra glomerular pressure, and prolong kidney
survival
• Control hypertension
• Control dyslipidemia
• Salt restriction and diuretic
• Venous thromboembolism prevention
• Immunosuppression? NO ROLE

50. FSGS- Treatment
Management of Relapse
• There is very low–quality evidence to guide treatment of
relapses in steroid-responsive FSGS.
• We suggest that the guidelines for relapsing MCD are followed

51. FSGS- Treatment
Steroid-Resistant
• There is no agreement in the literature regarding the duration of
prednisone therapy that defines steroid-resistance.
• Some authors advise alternatives after 4–8 weeks of
prednisone, whereas others define resistance as persistent
nephrotic syndrome after 16 weeks in a dose of 1 mg/kg/d.
• We suggest that prednisone be given for 4 months/16 weeks
before defining resistance to therapy.

52. FSGS- Treatment
Steroid-Resistant
• Cyclosporine is effective in inducing remission of proteinuria
in patients with steroid-resistant FSGS.
• Remissions can develop slowly, and may take 3–6 months after
start of therapy.
• A partial remission provides a substantial outcome benefit.
• Relapses are very frequent after withdrawal of cyclosporine.

54. FSGS- Treatment
Steroid-Resistant
• More prolonged treatment may lead to more persistent
remissions.
• Relapses occur frequently when using cyclosporine for a 6-
month period. A longer duration of therapy and slow tapering
strategy in cyclosporine-responsive patients can be used in
FSGS similar to that advised in adults with MCD.
• There is limited evidence to support the efficacy of other
regimens in patients with steroid-resistant proteinuria

56. FSGS- Treatment
• Transplantation
• ppfFSGS recur in the graft
• Immediately or years later
• Similar histologic variant as the initial
• Profound effect of race
• African American- Same as non-FSGS
• Non African American- 1.3X higher
• Living related donor- better outcome

64. Way Forward
• A path forward for future trial design In our view, future treatment strategies
for patients with an FSGS lesion should combine a compound that targets
The cause of the lesion (those in categories I–IV) with a compound
That non-specifically protects or regenerates podocytes (category V) or
Prevents downstream damage (category VI).

65. Way Forward
• Trials should only recruit FSGS subtype that is expected to derive benefit
from the agent under study.
• If patients with different FSGS subtypes are eligible, stratified at
randomization to ensure balance between groups.
• Proper patient characterization at entry requires serum albumin, at least
two measurements of proteinuria, EM with evaluation of FPE, and genetic
analysis using the most recent FSGS gene panels or whole exon
sequencing; a 24-hr urine collection is preferred to UPCR on a random
‘spot’ urine sample.

66. Case analysis
• How sure is the diagnosis of FSGS and which type?
• What indication for biopsy is there in this patient?
• Role of genetic workup and secondary workup?
• Any need for Immunosuppressive's at this Stage?

67. • FSGS is a “Pattern of Injury” not a Specific disease affecting glomerular
podocytes, podocytopathy. EM essential to properly diagnose FSGS.
• CLINICO-PATHOLOGIC Approach [Primary, Genetic, Secondary,
Unknown] To understand the likely response to therapy.
• Remissions more important than histology for long term outcomes.
• Prolonged steroid treatment can obtain remission of NS and avoid ESRD in
60% or more of patients with ppfFSGS at expense of steroid side effects.
• Steroids are ineffective in Secondary and Genetic FSGS.
Take Home Message

68. References

69. Thank You