The document provides a comprehensive overview of glomerular diseases, focusing on their classification, etiology, histological findings, and management. It highlights specific conditions such as acute proliferative glomerulonephritis, minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy, detailing their pathophysiology and treatment options. The document emphasizes the importance of accurate diagnosis and tailored therapeutic approaches to improve patient outcomes.

1. GLOMERULAR DISEASES
Prof Olutayo Alebiosu
Osun State University BSc, MBChB, FWACP

2. Objectives
• Participants able to review the classification of
glomerular diseases
• Participants able to discuss the etiology of glomerular
diseases.
• Participants able to highlight the histological findings
associated with glomerular diseases.
• Participants able to outline the management
considerations for the different diseases grouped under
the term 'glomerulonephritis.'
•

3. Introduction
• Numerous inflammatory and non inflammatory
diseases affect the glomerulus and lead to
alterations in glomerular permeability, structure and
function.
• However, not all glomerular diseases is caused by GN
and other causes need to be considered in its
differential diagnosis including diabetic nephropathy,
amyloidosis and hereditary nephropathies including
Alports syndrome

4. Introduction – Pathogenesis
• In GN, the dominant histologic lesions are in the glomeruli, at
times described as focal or diffuse; may be segmental or global.
• Lesions may also be hypercellular due to either an increase in
endogenous endothelial or mesangial cells – proliferative,
and / or to an infiltration of inflammatory leukocytes –
exudative changes.
• Severe acute inflammation may produce glomerular necrosis,
which is often segmental.
• Crescents may develop which are inflammatory collections of
cells in Bowmans space, and consist of proliferating parietal
and visceral epithelial cells, infiltrating fibroblasts,
lymphoblasts and monocytes/macrophages, often with local
fibrin deposition.

5. Introduction – Pathogenesis and Classification
• Indirect immunofluorescence and immunoperoxidase
staining are both used to identify immune reactants,
looking for the deposition of immunoglobulins IgG, IgA,
and IgM, for components of both the classical and
alternative pathways of complements – usually C3, C4
and C1q, and for the presence of fibrin.
• Granular deposits in glomerular are called immune
complexes which are local formation of
antigen/antibody complex in the glomerulus.

7. Acute Proliferative Glomerulonephritis

8. • This condition is characterized histologically by diffuse
proliferation of glomerular cells, associated with influx of
leucocytes, typically caused by immune complexes. The
inciting antigen may be exogenous or endogenous.
• The prototype exogenous antigen-induced disease
pattern is post-infectious glomerulonephritis.
• APGN has mainly two types-
• Post-streptococcal Glomerulonephritis
• Non-Streptococcal Glomerulonephritis

9. Poststreptoccocal Glomerulonephritis
• Produces the nephritic syndrome (hematuria, red cell
casts, moderate proteinuria and edema) in children two
weeks following a respiratory or skin infection with a
"nephritogenic strain" of group A, beta-hemolytic
streptococci.
• Clinically, this disease is manifested by a rather abrupt
onset of gross hematuria, edema, proteinuria,
hypertension and impaired renal function.
• The serum levels of hemolytic complement activity and
C3 protein are abnormally reduced.

10. Poststreptoccocal Glomerulonephritis
• Latent period between infection and onset of
nephritis is compatible with the time required for the
production of antibodies and formation of immune
complexes.
• There is deposition of circulating immune complexes
which fix complement and attract PMN's.
• This chokes off their blood supply, making the
glomeruli hypercellular and bloodless.
• This explains the oliguria, edema, and hypertension;
2% to 5% patient die during acute episode.

11. Acute Proliferative GMN - LM

12. Acute Proliferative GMN - Immunofluorescence

13. Acute Proliferative Glomerulonephritis - EM

14. Acute Proliferative Glomerulonephritis

15. Minimal Change Disease

16. Introduction
Minimal Change Disease is a glomerular disorder
that leads to the sudden onset of nephrotic-range
proteinuria with edema of the extremities and face,
hypoalbuminemia.
Others: hyperlipidemia, hypercoagulability.

17. Epidemiology
• Race: Asians may be at increased risk.
• Sex: twice as frequently in boys than in girls. Same in
both sexes in adulthood.
• Age: incidence peaks in children aged 2 years
(approximately 80% are below 6 years at the time of
diagnosis).
• In adults, the mean age of onset is 40 years.

18. Types: Primary or Secondary
Secondary: 10 to 15%
Drugs:
•NSAIDs and selective COX-2 Inhibitors
•Antimicrobials (ampicillin, rifampicin, cephalosporins)
•Lithium
•D-penicillamine, sulfasalazine (any 5-ASA derivative)
•Pamidronate (and presumably other bisphosphonates)
•Gamma interferon
•Immunizations
Neoplasia:
•Hodgkin Lymphoma (0.4%)
•Non-Hodgkin Lymphoma and Leukemia
•Cases of MCD are rarely associated with solid tumors
•MCD diagnosis may precede signs and symptoms of the malignancy
•Proteinuria typically resolves with treatment of the malignancy

19. Minimal change disease - secondary
Infections:
Rare associations with syphyllis, tuberculosis,
mycoplasma, Hep C, echinococcus
MCD has been described in HIV infection but
collapsing FSGS much more commonly seen
Allergy Associations:
•History of allergy described in up to 30% of cases
•Multiple allergens described (fungi, cat fur, poison ivy,
pollen, bee stings, house dust)
•Onset and relapses have been triggered by bee stings
and allergic reactions
•Limited evidence for involvement of food allergy

20. Association with Glomerular Diseases
•Association with IgA Nephropathy, with mesangial IgA
deposits and mild mesangial proliferation seen in
concurrence with MCD on biopsy
•There are reports of MCD also occur with the
following conditions, but rare:
– Systemic Lupus Erythematosus
– Type 1 Diabetes
– Polycystic Kidney Diseases
Minimal change disease - secondary

21. Pathology
The pathological/histological features distinguish the
various forms of NS.
•LM: not much different from normal glomeruli but in
some cases there are some increase in cells or
deposition of mesangium noted.
•IM: no antibody deposits
•EM: shows the characteristic foot process effacement

22. Minimal change disease
• Accounts for 80% of all cases of the idiopathic
nephrotic syndrome in children.
• Majority of cases are seen in 3 - 4 year age groups.
• Male predominance of 2.5:1 in children but no
difference seen in adults.
• 80-90% idiopathic.
• Associated with infectious diseases, recent
immunization, ingestion of heavy metals.
• In adults, also related to use of NSAIDS.

23. Minimal change disease
• The most common presentation is a full blown
nephrotic syndrome with heavy proteinuria often of
selective type.
• On light microscopy, changes may be seen in the
convoluted tubules where large amounts of lipid and
protein droplets accumulate in the cell cytoplasm
(lipoid nephrosis)
• In contrast all the glomeruli appear normal.

24. MCD – Light Microscopy
Glomerulus is normocellular, capillary loops are patent, & the BM is normal in thickness

25. MCD - Immunofluorescence
No deposits of complement or immunoglobulins seen in IF. (nil deposit disease)

26. MCD – Electron microscope
Portion of a glomerulus from a patient with MCD showing obliteration of
foot processes. The epithelial cell cytoplasm is hyperactive and shows
microvillus and cyst formation.

27. Work up
• Laboratory Studies:
- diagnosis
- monitoring
- complications
- biopsy
- steroid therapy
• Imaging Studies
• Biopsy and histology

28. Treatment
• Currently available therapies
• New approaches with available drugs
• Selected novel pathways that have been found to
mediate podocyte injury will be highlighted:
these pathways may offer the potential to develop better
targeted and more effective therapies for the future.

29. Currently available therapies
Glucocorticoid therapy
Treatment of choice initially
- Prednisone 1 mg/kg daily (max 80 mg daily)
Complete response and remission defined as reduction of
proteinuria to 300 mg/day
A partial response is a reduction of ≥50 percent, and to less
than 3.5 g/day.
Relapse defined as return to 3.5g/day or more after previous
remission
Frequent relapse is defined as 3 or more relapses per year
- Remission occurs in 85-90% with steroids but may take several
months to remit in adults (25% take longer than 3-6 months)
- Response to initial steroid therapy most important prognostic
indicator

30. • Steroid dependence is considered relapse on therapy
or patients who must stay on steroids to maintain
remission
• Steroid resistance: little or no reduction in
proteinuria after 16 weeks of adequate prednisone
therapy
• Relapses may be triggered by infection or allergy.
Most relapses occur within one year of stopping
therapy but have been known to occur up to 25
years later
• Steroid taper should not be started for minimum of 8
weeks or 1-2 weeks after complete remission
- Very slow tapering is recommended to prevent
relapse

31. Second line therapy
Though most patients achieve complete remission after an initial course but
most case series indicate that ≥50% of adult MCD patients eventually relapse
In relapse patients, repeat steroid course
Relapsing while on steroids or frequent relapsers may need additional
treatment
 Alkylating agents such as cyclophosphamide can be used but must be
monitored closely
 Antimetabolites (azathioprine, mycophenolate mofetil) are often helpful
 CNIs such as cyclosporine or tacrolimus effective but may cause renal
injury
 Direct antiproteinuric effect on the podocyte
 Continuous low-dose prednisone often considered but watch out for
long-term side effects
 Alternative agents are also useful where side effects preclude the
further use of steroids.

32. New approaches with available drugs
Rituximab: is a humanized monoclonal antibody
Some case reports described the use of rituximab in MCD.
Failed therapy with:
1. cyclosporine and mycophenolate mofetil, a 23-year old had a prolonged
remission (>28 months) after 4 weekly doses of 375 mg/m2
2. 15-year-old girl with MCD, with NS dependent on high-dose steroids, had
remission with a course of rituximab, allowing significant reduction of steroid
dose.
3. Rituximab, induced partial remission in a 20-year-old woman, who previously
had been nephrotic despite prednisone, tacrolimus, and MMF.
A retrospective review of 37 children with SDNS found that 375 mg/m weekly
for 1–4 courses 26 children (70%) for 12 months. Of 29 children followed
>2 years, 12 (41%) remained in remission.
Kemper et al Nephrol Dial Transplant (20112011) 0: 1–6

33. • Galactose – shown to bind the FSGS permeability factor with high
affinity and is able to alter glomerular permeability. Currently
being tested in Novel Therapies in resistant Focal Segmental
Glomerulosclerosis (FONT2) clinical trial
• Adalimumab – is a monoclonal anti-tumor necrosis factor (TNF)
antibody hence it binds TNF and prevents it from activating TNF
receptors in FSGS. Also being tested in (FONT2)
• Thiazolidinediones: improved CKD resulting from metabolic
syndrome. It reduced proteinuria, microalbuminuria, podocyte
injury, vascular injury, inflammation and fibrosis in both diabetic
nephropathy and nondiabetic glomerulosclerosis in animal models
and in humans. protected

34. Potential future treatments
• Protein kinases: p38 MAPK, MK2 and PKCα signaling
• Notch signaling
• IL-13
• Suppressing the unfolded protein response
• Maintaining redox homeostasis

35. Other treatments
• Renoprotection + treatment of hypertension: ACEI
and ARBs
• Loop diuretics
• Lipid lowering drugs: also renoprotective
• Anticoagulation - Warfarin
• Calcium and vitamin D therapy should be used to
decrease the risk of osteoporosis.
• Trimethoprim-sulfamethoxazole for prophylaxis
against Pneumocystis carinii in patients on >15
mg/day of prednisone; dapsone and atovaquone are
alternatives

36. Prognosis
• Excellent even in adults
• Spontaneous remission:
- approx 20% in untreated MCD cases at 6mths
- nearly 65% at 2 years
• With corticosteroid therapy remission in 80%-90%

37. Focal Segmental Glomerulosclerosis

38. Focal Segmental Glomerulosclerosis
• Focal segmental glomerulosclerosis (FSGS) defines a
characteristic pathologic pattern of glomerular injury.
• The hallmark of kidney biopsy is an increased degree of
scarring seen on light microscopy of some but not all of
the glomeruli present (focal) that involves some but
not all portions of the affected glomeruli (segmental).
• Characterized by proteinuria commonly in nephrotic
range.

39. Focal Segmental Glomerulosclerosis

40. Focal Segmental Glomerulosclerosis
• Primary FSGS makes up approximately 10% - 15% of
NS in children and 20% - 30% in adults.
• It is the predominant cause of idiopathic nephrotic
syndrome in adults.
• Mainly sporadic type, Onset is insidious.
• Involves children under 5 years of age and adults in
3rd & 4th decades.
• About 40% to 60% of patients progress to ESRD
disease within 10 to 20 years.

41. Focal Segmental Glomerulosclerosis - LM
• Focal and segmental lesions may involve only a minority of the
glomeruli and may be missed if the biopsy specimen contains an
insufficient number of glomeruli.
• The lesion initially tends to involve the juxtamedullary glomeruli and
subsequently becomes generalized. In the sclerotic segments there
is collapse of capillary loops, increase in matrix and segmental
deposition of plasma proteins along the capillary wall (hyalinosis).
• The hyalinosis may become so pronounced as to occlude the
capillary lumen. Lipid and foam cells are often present.
• Glomeruli that do not show segmental lesion usually appear normal.
•

42. Focal Segmental Glomerulosclerosis - LM
Biopsy from a
patient with
FSGS:
One of the
glomeruli
shows
segmental
sclerosis
while others
appear
unremarkable
Tubular
atrophy is
also seen.

43. Focal Segmental Glomeruloscerosis
narrowing of capillary lumens, proliferation and swelling of visceral epithelial cells, and
prominent accumulation of intracellular protein absorption droplets in the visceral epithelial
cells.

44. Focal Segmental Glomerulosclerosis – Variants
Glomerular Tip Lesion
Characterized by a
consolidation of the
glomerular segment
adjacent to the origin of
proximal tubule -
characterized by a "tip"
(from the glomerular
tip).
There are adhesions and
sclerosis, hyaline
deposits and
endocapillary
hypercellularity.

45. FSG - Immunofluorescence
Immunofluores
cence
microscopy
demonstrating
segmental
deposition of
IgM in a biopsy
from a patient

46. FSG – Electron Microscopy
Early FSG. There
is mild segmental
prominence of
the mesangium
(upper third) &
vacuolization of
the epithelial cell
cytoplasm.
A lipid-laden
intracapillary cell
with foamy cyto
plasm is also
seen (arrows).

47. Membraneous nephropathy

48. Membraneous nephropathy
• Common cause of nephrotic syndrome in adults.
• Characterized by diffuse accumulation of electron dense, Ig-
containing deposits along the sub-epithelial side of basement
membrane. [Formation of membrane attack protein (C5b-C9)
causes the capillary damage and hence leakage of proteins].
• In about 85% of patients, no associated condition can be
uncovered and are considered idiopathic. In about 15%
patients there is another systemic condition associated with it
and is referred to as secondary membranous glomerulopathy.

49. Membranous Nephropathy
• Secondary type is a form of chronic immune complex-mediated disease.
• The inciting antigens can sometimes be identified in the immune
complexes. For eg exogenous antigen (hepatitis B or Treponema),
Endogenous nonrenal antigens (thyroglobin), Endogenous renal
antigens (membrane protein antigen).
• The most notable associations are seen with:
a) Infections - Hepatitis B, Hepatitis C, Syphilis, malaria.
b) Drugs - Penicillamine, Captopril, Gold NSAIDs
c) Malignant tumors - Ca lung, Ca colon , Melanoma
d) SLE - 10%-15% of glomerulonephritis in SLE is of membranous type
e) Auto immune disorders - Thyroiditis.

50. Membranous Nephropathy
• Uniform, diffuse thickening of the glomerular
capillary wall.
• Basement membrane material is laid down between
these deposits, appearing as irregular spikes which
protrude from the GBM.
• These spikes are best seen by silver stains, which
color the basement membrane black.

51. • The course of the disease is variable but generally
indolent.
• Although proteinuria persists in more than 60% of
patients, only about 10% die or progress to renal
failure within 10 years,
• And no more than 40% eventually develop renal
insufficiency.
Membranous Nephropathy

52. Normal capillaries with thin walls Membranous capillaries with thick walls
Membranous Nephropathy - LM
Marked
diffuse
thickening
of the
capillary
walls
without an
increase in
the
number of
cells.
There are
prominent
spikes
projecting
from
basement
membrane.

53. Membranous Nephropathy - Immunofluorescence
Granular deposits contain both immunoglobulins & complement .

54. Membranous Nephropathy - EM
Electron micrograph showing electron dense deposits along the
epithelial side of the basement membrane. There is effacement of

55. Membranoploliferative GMN

56. Membranoploliferative GMN
• Accounts for 10% to 20% of cases of nephrotic
syndrome.
• MPGN is characterized by alteration of glomerular cells
and leukocyte infiltration. Persistent and slowly
progressive.
• Proliferation is predominantly in the mesengium and
involves capillary loops and thus the synonym
mesengiocapillary glomerulonephritis is used.

57. Membranoploliferative - Classification
• Primary MPGN :- when the cause is idiopathic.
• Secondary MPGN :- when associated with other systemic
disorders.
• On the basis of distinct ultra structural, immunofluorescence
and pathological findings it is divided into:-
• A) Type I MPGN
• B) Type II MPGN (dense deposit disease)
• C) Type III MPGN (very rare, it is characterized by a mixture of
subepithelial deposits and the typical pathological findings of
Type I disease)

58. Membrano-proliferative -Type 1 MPGN
• Account for 5% of the cases of end stage renal disease.
• Children and young adults are more frequently involved.
• Approx one third of patients present with nephritic
syndrome. Approx two thirds of the patients develop
hypocomplementemia with predominant depletion in C3
levels.
• Evidence of immune complexes in the glomerulus and
activation of both classical and alternative complement
pathways are usually present.
• Antigens involved are unknown, but sometimes believed to
be protein derived from infectious agents like hepatitis C
and B viruses.(planted antigens)

59. Membranoploliferative -Type 2 MPGN (Dense Deposit Dx)
• Rarer than type 1.
• Shows unique morphological appearance of basement
membrane best seen by electron microscopy.
• Type II MPGN tends to present with nephritis while MPGN
type I presents more often with nephrotic features.
• There is activation of alternative complement pathway.
Serum levels of C3 remains low for a longer period than
type I disease.
• More than 70% of patients have a circulating antibody
termed C3 nephiritic factor ( C3NeF ).

60. Membranoploliferative – Secondary

61. Membranoploliferative - LM
• Light microscopy of both types of MPGN are similar,
but the cellular proliferation, and especially the
circumferential mesengeal interposition is less
prominent in type 2 MPGN.
• Glomeruli are large and hypercellular.
• Hypercellularity is produced both by proliferation of
cells in the mesengium and endocapillary also.

62. Thickening of
capillary walls (global
& diffuse) with
hypercellularity.
Much of this
hypercellularity is
mesangial
proliferation, and
some of the capillary
wall thickening is
caused by mesangial
interposition into the
subendothelial zone
of the capillary loops.
Membranoploliferative - LM

63. • Glomeruli have lobular appearance due to
proliferating mesengial cells and increased
mesengeal matrix.
• The GBM is thickened, often segmentally.
• The glomerular capillary wall often show a double
contour or tram-track appearance especially evident
in silver or PAS stains. This is caused by splitting of
GBM.
Membranoploliferative - LM

64. Membranoploliferative – Type I
C3, IgG and IgM
deposits – frequently C3
. These deposits are
granular in the capillary
walls.
Often they are
elongated and smooth
in their external edge
because they are
subendothelial and they
are molded to the GBM.

67. Membranoploliferative – Type II
Immunofluorescence
The bright deposits
scattered along
capillary walls and in
the mesangium with
antibody to
complement
component C3 are
typical for type II
membranoproliferative
glomerulonephritis.

68. IgA Nephropathy
• It is the commonest form of glomerulonephritis resulting
in ESRD throughout the world. Male predominance.
• Also known as IgA nephritis, Berger's disease,
Synpharyngitic glomerulonephritis
• Frequent cause of gross and microscopic hematuria
• Characterized by the presence of prominent IgA deposits
in the mesengeal region.
• Suspected by light microscopy, but diagnosis is made
only by immunochemical method.

69. IgAN Pathogenesis
• Abnormalities of immune regulation leads to increased
IgA synthesis in response to respiratory or
gastrointestinal exposure to environmental agents.
• IgA1 (nephritogenic form) and IgA1-containing immune
complexes are then trapped in the mesangium, where
they activate the alternative complement pathway and
initiate glomerular injury.
• IgA nephropathy occurs with increased frequency in
individuals with gluten enteropathy and in liver diseases
(defective hepatobiliary clearance of IgA complexes)

70. IgAN
Light Microscopy
Glomeruli may be
normal or may
show mesangial
widening and
endocapillary
proliferation.
The mesangial
widening is due to
cell proliferation,
accumulation of
matrix and
immune deposits.

71. IgAN
Immunofluorescence
The IF pattern
parallels the
distribution of deposits
seen by EM.
It shows deposits of
IgA often with C3 and
properdin and lesser
amounts of IgG or IgM.
Early complement
components are
usually absent.

72. IgAN
Electron Microscopy
Portion of a
glomerulus from
a patient with
IgA nephropathy
showing
electron-dense
mesangial
deposits

73. Alport’s Syndrome

74. Alport’s Syndrome
• Alports Syndrome is a primary basement membrane
disorder manifested by progressive nephritis
(hematuria and proteinuria), deafness and ocular
abnormalities.
• Approximately 80%-85% of patients have X linked
form of syndrome resulting from mutation of
COL4A5.
• Gross or microscopic hematuria is the most common
and earliest manifestation.

75. Nonspecific findings.
There is focal and
segmental glomerular
hypercellularity of the
mesangial and
endothelial cells.
Renal interstitial foam
cells can be found and
represent lipid-laden
macrophages which
can be seen in many
renal diseases.
Alport’s Syndrome - LM

76. Alports Syndrome
Glomerular capillary loop showing diffuse, irregular thickening of GBM . The
lamina densa is split into multiple interwoven lamellae

77. Summary
• Overview of glomerular diseases was discussed
• It was noted that numerous inflammatory and non inflammatory diseases
affect the glomerulus and lead to alterations in glomerular permeability,
structure and function.
• However, not all glomerular diseases is caused by GN and other causes
were noted in its differential diagnosis inclusive of diabetic nephropathy,
amyloidosis, hereditary nephropathies and Alports syndrome
•

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