Trans Glomerularpatho Final

OS 214 Renal Dr.
Teresita Tuazon
Pathology of Glomerular Diseases Exam # 1
OUTLINE
I. Review of the Glomerulus
II. Histologic Alterations
III. Pathogenesis of Glomerular Injury
IV. The Glomerular Diseases
a. Nephrotic Syndrome
b. Minimal Change Disease
V. Focal Segmental Glomerulosclerosis
(FSGS)
VI. Membranous Glomerulonephropathy
VII. Nephritic Syndrome
VIII. Acute Glomerulonephritis
IX. Glomerulonephropathies Associated
with Isolated “Essential” Hematuria
a. IgA Nephropathy ( Berger’s Disease
)
b. Thin Basement Membrane Disease
c. Alport’s Disease Figure 3. low power EM of renal glomerulus; CL – capillary
d. Non-specific changes lumen; MES – mesangium; END – endothelium; US –
urinary space
X. Membranoproliferative
Glomerulonephritis
XI. Acute Renal Failure
Review of the Glomerulus
Figure 4.picture of glomerulus
Figure 1. The normal glomerulus Figure 5. glomerular BM and blood space interface.
Podocytes are seen oriented toward the epithelial cell.
Glomerular BM negatively charged thus anionic molecules
are repelled.
Normal Glomerulus
• Consists of an anastomosing network of
capillaries lined by fenestrated endothelium
invested by two layers of epithelium
• The anatomical glomerulus is enclosed by two
layers of epithelium, Bowman's capsule.
• Cells of the outer or parietal layer of Bowman's
capsule form a simple squamous epithelium.
• Cells of the inner layer, podocytes in the
visceral layer, are extremely complex in shape.
Figure 2. glomerulus (normal) • Between the podocytes and the endothelial cells
of the capillaries we find a comparatively thick
basal membrane.
• Mesangial cells in the glomerulus form the
connective tissue that gives structural support to
March 3, 2009 | Tuesday Page 1 of 16

Canoy, Carasco, Cielo,
Co
OS 214 Renal Dr. Teresita Tuazon
podocytes and vessels. Figure 8. Collapsed capillaries, a feature of

sclerosis
From Block B Trans:
Pathogenesis of Glomerular Injury
Histologic Alterations
1. ANTIBODY MEDIATED
1. HYPERCELLULARITY • In situ Immune Complex formation
a. Cellular proliferation of mesangial or • Deposition of circulating immune complexes
endothelial cells • Antineutrophil cytoplasmic immune complexes
b. Leukocytic infiltration consisting of
neutrophils, monocytes and From Block B Trans:
lymphocytes. Complement Activation
c. Formation of crescents. • Ag-Ab complexes may be intrinsic or extrinsic
Accumulations of cells composed of • Complexes can either be circulating in the
proliferating parietal epithelial cells and bloodstream or are in situ (extrinsic Ag deposited
infiltrating leukocytes at the GBM and Ab complexes with it directly)
• After some time, these complexes may cause
tissue lesions due to complement activation
which elaborates other molecules and eventually
cause glomerular injury.
Figure 6. Collapsed glomerular tuft. Note the

crescent-shaped mass (demarcated)
2. BASEMENT MEMBRANE THICKENING

- Thickening of the capillary walls in light
microscopy
Figure 9. Circulating complexes
Figure 7. Thickened capillary wall pointed in

arrow.
3. HYALINIZATION AND SCLEROSIS

- Accumulation of homogenous and
eosinophilic material
- Contributes to the obliteration of the
capillary lumina of the glomerular tuft

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• Due to loss of adhesive interactions with the

GBM.
• Detachment contributes to protein leakage
• No antigens involved
Figure 12. Epithelial cell injury leading to detachment.
4. CELL-MEDIATED IMMUNITY
• Sensitized T cells can cause glomerular
injury
• Presence of macrophages and T
lymphocytes in glomeruli, particularly in
allografts
Figure 10. Complement activation • May account for no deposits in GN or non-
2. GLOMERULAR LOCALIZATION OF IMMUNE correlation of deposits with severity of
COMPLEXES damage
• Molecular charge and size From Block B Trans:
• Highly CATIONIC – cross GBM – a. Neutrophils and monocytes release
(1) subepithelial protease (GBM degradation), free
radicals (cell damage), and arachidonic
• Highly ANIONIC – repelled - (2) subendothelial
acid metabolites (decrease in GFR)
• More NEUTRAL charge – (4) mesangial b. Macrophages, T-lymphocytes and
• Large complexes are cleared by the natural killer cells when activated
reticuloendothelial system release a vast number of biologically
active molecules.
c. Platelets release eiconasoids and
1 2 growth factors that contribute to the
manisfestation of glomerulonephritis.
d. Resident glomerular cells like
4 mesangial cells can be stimulated to
produce cytokines, chemokines and
growth factors
5. CELL-MEDIATED MECHANISMS
3 • Minimal change disease, crescenteric GN type
III, allograft rejection, acute drug-induced
interstitial nephritis, various vasculitides
o Endogenous antigens
o Exogenous antigens
• Anti-TBM disease in Brown-Norway rats, acute
tubulointerstitial nephritis in mice, acute
glomerulitis in bursectomized chicken
Figure 11. Localization of immune complexes in the
glomerulus
3. EPITHELIAL DETACHMENT
• Results when an antibody cytokine toxin destroys
the BM leaving no more surface for the cells to
attach
• Effacement of foot processes, vacuolization,
retraction and detachment of cells from the GBM.

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o children >40 mg/h

• Clinical features
o Proteinuria
o Edema
o Hyperlipidemia
o Hypoalbuminemia
• Hypercoagulable
o urinary loss of anti-thrombin III and
plasminogen
o hemoconcentration
• Risk of Infections
Types
• Primary
o Membranous Glomerulopathy
o Focal Segmental Glomerulosclerosis
o Minimal Change Disease
o Membranoproliferative GN
Figure 13. Mediators of immune glomerular injury • Secondary
including cells and soluble mediators o Diabetic glomerulosclerosis
o Paraproteinemia/Amyloidosis
Glomerular Diseases o Lupus Nephritis
Evaluation
• Asymptomatic proteinuria • History and Physical Exam
• Nephrotic syndrome • Urine Analysis
• Asymptomatic hematuria • Lab Studies
• Nephritic syndrome • Renal Biopsy
• Rapidly progressive nephritic syndrome
Table 1. Urine Sediment Types.
Nephrotic Syndrome Nephritic Urine Nephrotic Urine Chronic GN
Red cells Heavy Proteinuria
• Proteinuria greater than 3.5 gms/ 24 hours (hematuria) proteinuria
(less in children) Variable proteinuria Free fat Variable
droplets hematuria
• Hypoalbuminemia- plasma albumin Granular casts Fatty casts Broad waxy
less than 3 g/dL casts
• Edema
• Hyperlipidemia and lipiduria Minimal Change Disease
• The initial event is a derangement in glomerular
capillary walls resulting increased permeability Clinical Features
to plasma proteins • Most common features – proteinuria and
• Diseases frequently responsible for nephrotic periorbital edema, with or without other
syndrome include (each will be discussed manifestations of nephrotic syndrome
separately in this trans): • Most frequent cause of nephrotic syndrome in
o Minimal change disease children
o Focal segmental glomerulosclerosis Light Microscopy
o Membranous glomerulopathy • Minimal histologic changes
(idiopathic) • Normal cellularity
• Proximal convoluted tubules with resorption
droplets
• Vessels and interstitium are unremarkable
Figure 14. Primary nephrotic syndrome
From 2011 Trans: Figure 15. Minimal Change Disease

More stringent definition
• Nephrotic range proteinuria • In electron microscopy: in the visceral epithelial
o adults >3.0-3.5 grams/d cells
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o uniform and diffuse effacement of foot

processes Pathogenesis
o replaced by a rim of cytoplasm often • Loss of polyanions and the glomerular charge-
showing vacuolization, swelling and barrier > loss of negative charge of BM
hyperplasia of villi • Primary visceral epithelial cell injury
o “fusion” of foot processes/ effacement • Immune dysfunction leads to production of
> proteinuria cytokine-like circulating substance that affects
o 85% responsive to steroids with reversal visceral epithelial cells
of ultrastructural changes; overall
prognosis good Focal Segmental Glomerulosclerosis (FSGS)
Clinical Features
• Severe proteinuria or nephrotic syndrome- most
common manifestation
• Hematuria common, usually microscopic
• Hypertension common
• Male preponderance
• May be primary or secondary
Light Microscopy
• Some glomeruli (especially juxtamedullary ones)
with segmental sclerosis (mesangial matrix
material, collapse, basement membrane- like
material , +/- hyalinosis
Figure 16. Normal podocytes (individually sticking out)

with slit pores. Endothelial layer has fenestrations >
basement membrane
Figure 18. Focal collapse of glomerulus (encircled).
Figure 17. Fused podocytes in minimal change disease

(white arrows)
• In immunofluorescence microscopy:
o Negative immunofluorescence staining
within glomeruli – no immune
complexes
Figure 20. Hyalinosis in glomerulus
Figure 18. Immunofluorescence microscopy of Minimal

Change Disease

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Figure 23. EM – denuded BM, will progress to ESRD ->

dialysis, transplant. Accumulation in collapsed loops of
matrix like material
Pathogenesis
• initiating pathogenetic mechanisms are varied
• common element is injury manifested by
sclerosis in the setting of nephrotic range
proteinuria.,
• Degeneration and focal disruption of visceral
epithelial cells
• Hyalinosis and sclerosis represent entrapment
of plasma proteins in extremely hyperpermeable
foci with increased ECM deposition
• Mutations in genes encoding for the proteins
nephrin and/or podocin causes increased
permeability to proteins – PROTEINURIA!
Figure 21. Tubular atrophy – normal glomerulus but with
thickened tubular walls, it could indicate presence of Primary/idiopathic FSGS
FSGS even if glomerulus is normal as seen here.
Secondary/variants FSGS
Immunofluorescence Microscopy • I.V. drugs
• Usually normal except for sclerotic segment • Collapsing gn: HIV, parvovirus B-19,
which may have IgM, with or without C3 pamidronate, CS2, Loa Loa
• Obesity-associated - reversible with weight
reduction
• Familial FSGS - podocin, alpha-actinin-4
mutations
• Congenital - Finnish type (nephrin mutation)
• Cholesterol emboli
• Lithium
• Mitochondrial myopathies/cytopathies
Figure 22. IF – usually normal except for sclerotic

segment which may have IgM, with or without C3.
Electron Microscopy and Course of Disease

• uniform and diffuse effacement of foot processes
on sclerotic and non-sclerotic areas plus
• focal detachment of epithelial cells with
denudation of the underlying GBM
• Accumulation in collapsed loops of matrix- like
material
Figure 24. FSGS survival rate
• Course – 15% responsive to steroids, over 1/3
progress to end stage renal disease

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Figure 25. Reductions in renal mass leading to focal

glomerulosclerosis which in turn leads to reductions in
renal mass creating a cycle
Does hyperfiltration injure the glomerulus?
Observations:
1. Subtotal nephrectomy (83%) in rats is followed

by:
a. Increase blood flow and filtration per
glomerulus
b. Proteinuria
c. Focal glomerular sclerosis
d. Progressive renal failure
2. High protein diets
a. Increase GFR and accelerate
glomerular sclerosis Figure 26. LM: Hypercellularity of glomerular tuft
3. Low protein diets
4. Similar lesions occur in some patients with
unilateral renal agenesis and in association with
other diseases that reduce renal function mass
Membranous Glomerulonephropathy
Clinical Features
• Proteinuria with or without the full nephrotic
syndrome - most common finding
• Peak incidence in the fourth to fifth decades
• Male preponderance
• Most common cause of nephrotic syndrome in
adults (remember minimal change disease –
most common cause of NS in children!)
Clinical Course
• Spontaneous remission of proteinuria occur in
approximately ¼ of patients, approximately half Figure 27. LM: silver staining BM spikes trying to cover
will have stable renal function with or without the deposits
continued proteinuria
• Minority of patients will have slow decline in renal
function, a few will have rapid decline in renal
function
• 1/3 progress, 1/3 remit, 1/3 protenuria only
In light microscopy:
• Normal to extreme diffuse thickening of the
capillary wall
• +/- tuft hypercellularity
• foam cells in interstitium
In electron microscopy:
• Numerous subepithelial deposits (+/-) spikes of
GBM in between
In immunofluorescence microscopy:
• Finely granular diffuse capillary wall staining (-) Figure 28. IF: Finely granular diffuse capillary wall
IgG, (+/-) C3 and other immunoreactants

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Figure 30. LM: Uniformly and diffusely enlarged

Figure 29. EM: Large subendothelial deposit (not just a
hypercellular glomeruli and reduced Bowman spaces
hump)
Immunofluorescence Microscopy
Pathogenesis
• Coarse granular staining in first few weeks for
• Believed to be chronic antigen-antibody mediated
IgG and C3
• Genetic susceptibility
• Later, predominant C3 and IgG scant to absent
• Circulating immune complexes in 15-25%
• Direct action of C5b-9, the membrane –attack
complex of complement
• in-situ immune complex formation in the
subepithelial zone
• Native or foreign antigens planted in the
glomerular basement membranes are present
beforehand and antibodies to these antigens
combine with them in situ to form immune
complexes.
• presence of immune complexes alters the
permeability of the capillary loops leading to
proteinuria.
Nephritic Syndrome
• Hematuria
• Proteinuria
• Decreased glomerular filtration rate
• Elevated BUN and serum creatinine Figure 31. IF: Variable-sized coarse granular deposits of
• Oliguria immunoglobulins and complement in glomerular loops.
• Salt and water retention
• Edema
Electron Microscopy
• Hypertension
• “Immune-type” deposits on subepithelial
Glomerular Changes surface described as “humps”
• Leucocytic infiltration • Occasional patchy GBM thickening
• Hyperplasia of glomerular cells
• Necrosis (severe lesions)
• Injury to capillaries
Acute Glomerulonephritis
Clinical Features
• Also called poststreptococcal or postinfectious
glomerulonephritis
• Latent period between infection and onset of GN
( 1-2 wks for pharyngitis and 3-6 wks for skin
infections )
• Smoky urine and edema common initial manif,
hypertension common, transient oliguria
Light microscopy
• Global and usually uniform hypercellularity
• Capillary lumina may be occluded Figure 32. EM: Variable-sized granular dense deposits of
• Neutrophils frequent in the acute phase IgG and C3 (“humps”) irregularly arrayed in the
( exudative glomerulonephritis) subepithelial space of the glomeruli.
Pathogenesis

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Figure 34. Glomerular tuft with global mesangial

• Streptococcal antigens from the infection elicit hypercellularity/proliferation. (Note that “normal” is less
the production of anti-streptococcal antibodies. than or equal to 2 or 3 cells per mesangial area)
• Immune complexes form in situ in glomeruli due
to previously planted streptococcal antigens.
• The immune complex formation with complement
activation incites acute glomerular inflammation
Figure 35. Red cell casts (arrows)
Immunofluorescence Microscopy
• Mesangial granular IgA (in the absence of SLE,
Figure 33. Hypercellular glmeruli due to proliferation of HSP, active liver disease)
endothelial cells and mesangial cells, swelling of • Usually C1q is absent
endothelial cells, and inflammatory infiltrate (neutrophils
and monocytes). Initially, tubules are not affected (but as
disease progresses, they may present hydropic change).
Glomerulonephropathies Associated with

Isolated “Essential” Hematuria
• IgA Nephropathy ( Berger’s Disease )

• Thin Basement Membrane Disease
• Alport’s Disease
• Non-specific changes
IgA Nephropathy
Clinical Features
• Most common during the 2nd and 3rd decades Figure 36. IF: Granular deposits of IgA and C3 in the
• Male preponderance glomerular mesangium. The fundamental characteristic in
• Asymptomatic microhematuria to rapidly IgA Nephropathy is the intense, diffuse mesangial
progressive renal failure immunostaining for IgA that is limited to mesangial areas,
• 5 to 15% have nephrotic syndrome (without deposits in capillary walls). Diagnosis rests on the
finding of dominant IgA mesangial deposits. C3 is also
Light Microscopy Histologic Subclasses present in mesangial areas, but usually equal to or less
• Type I – Minimal histologic lesion than IgA staining.
• Type II- Focal segmental glomerulosclerosis-like Electron Microscopy & Clinical Course
• Type III – Focal proliferative glomerulonephritis • Mesangial electron dense deposits
• Type IV – Diffuse proliferative GN • Variable clinical course and prognosis
• Type V – Advanced chronic GN
Figure 37.
Pathogenesis
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– presence of IgA immune complexes in the Unfortunately it usually destroys the transplant.
glomerular tufts
– Presumably mucosal derived IgA combines with
antigens to form circulating immune complexes Membranoproliferative Glomerulonephritis
that deposit in the glomerular mesangium.,
Clinical Features
• Nephrotic syndrome common
• May have manifestations of the acute nephritic
syndrome such as hematuria,
• ( gross or microscopic), hypertension
MPGN Type I
Light Microscopy
• Proliferative, polymorphonuclears
• Lobulation/ tram-tracking
Figure 38. EM: Electron-dense mesangial deposits and

foot process effacement.
Thin Basement Membrane Disease

• thin GBM nephropathy is a genetically
heterogeneous disorder, with some but not all
familial cases linked to mutations within the
genetic locus encoding the α3 and α4 chains of
type IV collagen (COL4A3/COL4A4 locus).
Figure 40. There is massive mesangial cell proliferation,

mesangial matrix expansion and diffuse thickening and
focal splitting of the glomerular basement membrane.
There is also accentuation of lobular architecture, swelling
of cells lining peripheral capillaries, and influx of
leukocytes.Basement membrane thickening is due to
mesangial cell and mesangial matrix interposition along
the subendothelial side of the lamina densa with
consequent neoformation of basement membrane –
basically a doubling or complex replication of the BM that
gives the morphological aspect of ‘double contour’ (tram-
tracking). In other words, tram-tracking is caused by an
increase in mesangial cells and matrix in the capillary
loops, called ‘mesangial interposition’, which leads to new
subendothelial basement membrane deposition. The
mesangial matrix increase can be more severe in
Figure 39. The main morphological feature in Thin
peripheral areas of the tuft, giving the glomerular tuft a
Basement Membrane Disease (TBMD) is diffuse thinning
‘lobular’ appearance.
of the GBM, particularly the lamina densa. Accurate
measurement of the GBM thickness is therefore essential
in the diagnosis of TBMD.
Alport syndrome
• In Alport syndrome, type IV collagen, one of the
proteins that makes up the GBM, is absent or
abnormal. Although the GBM looks normal in
childhood, it deteriorates with time because it
lacks the special type IV collagen that should be
there
• Alport syndrome is much more common in boys
and men because the gene that usually causes it
(called COL4A5) is on the X chromosome.
Women have two X chromosomes (XX), so they
usually have a normal copy as well as an
abnormal copy of the gene
• in less than 1 in 20 Alport transplants) kidney
transplants meet with a unique problem. Figure 41. Increased mesangial matrix (stained black with
• Because the transplanted kidney has normal type silver stain)
IV collagen, the immune system may see it as
'foreign' and attack it. This causes Alport anti- Immunofluorescence Microscopy
GBM disease, which is very similar to the kidney • Broad capillary wall deposits –
disease seen in Goodpasture's disease. • C3 +/- other things
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Figure 44. Schematic representation of patterns in the two

types of membranoproliferative GN. In type I there are
subendothelial deposits; type II is characterized by
intramembranous dense deposits (dense-deposit
disease). In both, mesangial interposition gives the
appearance of split basement membranes when viewed in
Figure 42. Immunofluorescence microscopy reveals the light microscope.
granular staining for the complement protein C3
MPGN Type II/Dense Deposit Disease (DDD)
Electron Microscopy Notes from http://path.upmc.edu/cases/case148/dx.html
• Interposition of mesangial cells and matrix Membranoproliferative glomerulonephritis type II (MPGN-II),
between GBM and capillary endothelium also known as dense deposit disease (DDD), is a
accounts for “tram-track” appearance clinicopathologic entity associated with renal abnormalities
which often culminate in renal failure. DDD commonly
• Subendothelial and mesangial deposit affects children and young adults with a roughly equal male
to female preponderance. These patients present with
varying degrees of hematuria and/or proteinuria. In addition,
serum analysis often but not invariably reveals
hypocomplementemia, particularly of the complement
protein C3, which has led some researchers to speculate
that abnormalities of the complement cascade contribute to
the pathogenesis of DDD.
Distinguishing DDD from membranoproliferative
glomerulonephritis type I (MPGN-I) may be quite difficult
clinically since both are characterized by a nephrotic and/or
nephritic clinical picture. However, microscopic examination
reveals differences that allow their separation. In MPGN-I,
most glomeruli demonstrate global hypercellularity in a
lobular pattern. This differs from DDD in which a variety of
light microscopic patterns may be seen - including
membranoproliferative glomerulonephritis (lobular
glomerulonephritis), glomerular sclerosis, pure mesangial
hypercellularity, membranous glomerulonephritis-like
pattern, cresenteric glomerulonephritis, minimal changes, or
Figure 43. EM: Subendothelial deposit incorporated into focal and segmental necrotizing glomerulonephritis.
mesangial matrix (M).
Light microscopy
• Any glomerular pattern (membranous,
membranoproliferative, normal, crescentic GN,
etc.)
Pathogenesis of MPGN I
• Immune complex mediated disorder.
• IC are deposited in the mesangium and
subendothelial spaces.
• Mesangial cells proliferate in response to the
immune complex deposition and extend beyond
the confines of the mesangium to mesangialize
the capillary loops.
• A second internal basement membrane is formed
by the mesangial cell and the undermined
endothelial cells
Figure 45.MPGN Type II – Light Microscope.
Immunoflourescence Microscopy
• Broad capillary wall deposits – C3 +/-, other
things, extraglomerular deposits

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Figure 46. IF: Presence of the complement protein C3

which produces a characteristic ribbon-like staining pattern
of the peripheral capillary loop; however, there is a lack of
staining of the dense deposits.
Electron Microscopy
• Large electron dense deposits in GBM, +/-
TBM,BC,etc
Robbins book notes
Types I and II have altogether different ultrastructural and
immunofluorescent features.
Type I MPGN (two thirds of cases) is characterized by the
presence of subendothelial electron-dense deposits.
Mesangial and occasional subepithelial deposits may also be
present. By immunofluorescence, C3 is deposited in a granular
pattern, and IgG and early complement components (C1q and
C4) are often also present, suggesting an immune complex
pathogenesis.
In Type II MPGN lesions, the lamina densa of the GBM is

transformed into an irregular, ribbon-like, extremely electron-
dense structure because of the deposition of dense material of
unknown composition in the GBM proper, giving rise to the
term dense-deposit disease. In type II, C3 is present in
irregular granular-linear foci in the basement membranes on
either side, but not within the dense deposits. C3 is also
present in the mesangium in characteristic circular aggregates
(mesangial rings). IgG is usually absent, as are the early-
acting complement
Figure components
47. Histologically, DDD(C1q and C4).by the presence
is defined
of irregular electron dense deposits in the lamina densa of Secondary MPGN arises in the following settings:
Pathophysiology
the glomerular basement membrane, which are observed
Although there are exceptions, most cases of type I MPGN  Chronic immune complex disorders, such as SLE;
by
present These
EM. deposits
evidence arecomplexes
of immune strongly PAS positive
in the and and
glomerulus are hepatitis B infection; hepatitis C infection, usually with
dark blue when
activation stained
of both with toluidine
classic blue. complement
and alternative cryoglobulinemia; endocarditis; infected
pathways. The antigens involved in idiopathic MPGN are ventriculoatrial shunts; chronic visceral abscesses;
unknown. Conversely, most patients with dense-deposit HIV infection; and schistosomiasis.
disease (type II) have abnormalities that suggest activation of  Partial lipodystrophy associated with C3NeF (type 2)
the alternative complement pathway. These patients have a
consistently decreased serumand C3, but normal C1 and C4, the  Alpha1 -Antitrypsin deficiency
MPGN Types I & II Course Diagnosis  Malignant diseases (chronic lymphocytic leukemia,
immune complex-activated early components of complement.
• Course: Progressive (many to renal failure)
They also have diminished serum levels of factor B and lymphoma, melanoma)
• Diagnosis: Low complement persistent, pathway.
properdin, components of the alternative complement nephritic  Hereditary complement deficiency states
More thanand/70%orofnephrotic
patients with syndrome
dense-deposit disease have a
•
circulatingAutoimmune
antibody termeddisorder
C3 nephritic factor (C3NeF), which Notes from http://path.upmc.edu/cases/case148/dx.html
C3 nephritic
is a •conformational factor which
autoantibody thatisbinds
an IgGto the alternative Distinguishing DDD from membranoproliferative
C3 convertase. Binding directed
immunoglobulin of the against
antibody C3 stabilizes
convertase the glomerulonephritis type I (MPGN-I) may be quite difficult
convertase, clinically since both are characterized by a nephrotic and/or
andprotecting it from
on binding enzymatic
stabilizes it. degradation and thus
favoring nephritic clinical picture. However, microscopic examination
• persistent C3 degradation
The stabilized and hypocomplementemia.
C3 convertase continuously drives reveals differences that allow their separation. In MPGN-I, most
There is also decreased C3 synthesis by the liver, further
the alternative complement
contributing to the profound hypocomplementemia.
pathway, consuming glomeruli demonstrate global hypercellularity in a lobular pattern.
Precisely complement.
how C3NeF is related to glomerular injury and the This differs from DDD in which a variety of light microscopic
• of As
nature the a consequence,
dense deposits arepatients
unknown. have marked
C3NeF activity also patterns may be seen, as mentioned above. The capillary walls
occurs in hypocomplementemia.
some patients with a genetically determined disease, in the glomeruli are markedly thickened and show intense
partial lipodystrophy, some of whom develop type II MPGN. staining with PAS in MPGN-I. Methenamine silver also stains the
glomerular basement membrane of the thickened capillary loops
Clinical Presentation to reveal splitting or tram tracking similar to what is observed in
The principal mode of presentation is the nephrotic DDD; however, the material deposited between the glomerular
syndrome occurring in older children or young adults, but basement membrane borders is nonargyrophilic and different
usually with nephritic component manifested by hematuria or, from the deposits in DDD. Tram tracking in MPGN-I is caused by
more insidiously, as mild proteinuria. Few remissions occur an increase in mesangial cells and mesangial matrix in the
spontaneously in either type, and the disease follows a slowly capillary loops, called 'mesangial interposition', which leads to
progressive but unremitting course. Some patients develop new subendothelial basement membrane deposition. Electron
numerous crescents and a clinical picture of RPGN. About microscopic findings in MPGN-I show mesangial interposition,
50% develop chronic renal failure within 10 years. Treatments subendothelial immune deposits and a new layer of
with steroids, immunosuppressive agents, and antiplatelet subendothelial basement membrane. Immunofluorescence
drugs have not been proved to be materially effective. There is microscopy reveals granular staining for the complement protein
aMarch 3, 2009
high incidence of |recurrence
Tuesdayin transplant recipients, C3 differs from the ribbony pattern seen inPage DDD. In12 addition,
of 16
particularly in type II disease; dense deposits may recur in MPGN-I biopsies, unlike those of DDD, may show staining for
90% of such patients, although renal failure in the allograft is complement proteins Clq, C4 and Canoy, Carasco,
one or more Cielo,
immunoglobulins,
much less common. particularly IgG and frequently IgM. MPGN-I has a recognized
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association with chronic hepatitis C infection and
Clinical Features
• Clinical onset of disease usually abrupt
• Severe oliguria or anuria common at initial
examination
• Course is aggressive if without treatment
Robbins book notes
Rapidly progressive glomerulonephritis (RPGN) is a syndrome
associated with severe glomerular injury and does not denote a
specific etiologic form of glomerulonephritis. It is characterized
clinically by rapid and progressive loss of renal function
associated with severe oliguria and (if untreated) death from
renal failure within weeks to months. Regardless of the cause,
the histologic picture is characterized by the presence of
crescents in most of the glomeruli (crescentic
glomerulonephritis). These are produced in part by proliferation
of the parietal epithelial cells and Bowman capsule and in part
by infiltration of monocytes and macrophages.
RPGN may be caused by a number of different diseases, some
restricted to the kidney and others systemic. Although no single
mechanism can explain all cases, there is little doubt that in
most cases the glomerular injury is immunologically mediated.
Thus, a practical classification divides RPGN into three groups
on the basis of immunologic findings. In each group, the
disease may be associated with a known disorder or it may be
idiopathic.
Notes from http://path.upmc.edu/cases/case148/dx.html

Crescentic glomerulonephritis or rapidly progressive
glomerulonephritis (RPGN) is a term given to a diverse group of
diseases which all have cresents present within the glomerular
tuft. These include primary or renal limited (so-called idiopathic)
Figure 48. The alternative complement pathway. Note that crescentic glomerulonephritis, anti-glomerular basment
C3NeF, present in the serum of patients with membrane (anti-GBM) antibody diseases, and systemic
membranoproliferative glomerulonephritis, acts at the disorders. Considered within the entire clinical spectrum of
same step as properdin, serving to stabilize the alternative renal disease, RPGN produces the most rapidly progressive
pathway C3 convertase, thus enhancing C3 breakdown and destructive of glomerular diseases which in the most
and causing hypocomplementemia. severe forms proceeds inexorably to renal failure if not treated
aggressively and early. Fortunately, RPGN accounts for only 2
to 7% of renal biopsies, with a disproportionately large
percentage of these patients progressing to end stage renal
MPGN Type III disease.
• with prominent subepithelial electron dense RPGN is categorized based on the biopsy immunofluorescence
deposits (Burkholder) pattern into three groups: RPGN Type I (20%), RPGN Type II
• with complex disruptions of the basement (40%), and RPGN Type III (40%) (Table 3). RPGN types I and II
membrane (Strife & Anders), focal and segmental have greater than 2+ (on a 4+ scale) immunofluorescence
gloerular hyalin deposits, and infiltration by foamy staining intensity with linear and granular staining patterns,
macrophages respectively. RPGN Type III or pauci-immune type has weak or
no demonstrable immunoglobulin / complement deposition,
Robbins book notes corresponding to an immunofluorescence staining intensity of <
Rare variants (type III) segregated because they exhibit both 2+.
subendothelial and subepithelial deposits are associated with
GBM disruption and reduplication.
Acute Renal Failure Table 1. Three Types of RPGN Based on
Immunofluorescence Pattern
• Creatinine increases rapidly over a few days
• Oliguria/anuria frequent
• Etiologies:
 Pre-renal
 Renal
 Post-renal
Robbins book notes

Acute renal failure is dominated by oliguria or anuria (no urine
flow), with recent onset of azotemia*. It can result from
glomerular (e.g., crescentic glomerulonephritis), interstitial, and
vascular injury or acute tubular necrosis.
*Azotemia is a biochemical abnormality that refers to an
elevation of the blood urea nitrogen (BUN) and creatinine
levels and is related largely to a decreased glomerular filtration
rate (GFR). Azotemia is produced by many renal disorders, but
it also arises from extrarenal disorders. Prerenal azotemia is
encountered when there is hypoperfusion of the kidneys (e.g.,
in hemorrhage, shock, volume depletion, and congestive heart
failure) that impairs renal function in the absence of
parenchymal damage.
Crescentic Glomerulonephritis/Rapidly Progressive

Glomerulonephritis (RPGN)

Co
Light Microscopy
• Over 50% of glomeruli with crescents.
• Look at the most preserved glomeruli for tuft
hypercellularity
Figure 49. Collapsed glomerular tufts and crescent-

shaped mass of proliferating cells and leukocytes internal
to the Bowman capsule.
Robbins book notes

Type I RPGN is best remembered as anti-GBM disease and
hence is characterized by linear deposits of IgG and, in many
cases, C3 in the GBM, as previously described. In some of
these patients, the anti-GBM antibodies cross-react with
pulmonary alveolar basement membranes to produce the
clinical picture of pulmonary hemorrhages associated with renal
failure (Goodpasture syndrome). The Goodpasture antigen, as
noted, resides in the noncollagenous portion of the alpha3
chain of collagen type IV. What triggers the formation of these
Figure 50. is unclear in most patients. Exposure to viruses or
antibodies
hydrocarbon solvents (found in paints and dyes) has been
implicated in some patients, as have various drugs and
Immunoflourescence
cancers. Cigarette smoking appears to play a permissive role,
• most
since RPGN Typewho
patients 1 - Linear
developimmunoflourescence
pulmonary hemorrhage are
smokers. There o is 20%
a high prevalence of certain HLA subtypes
and haplotypes Goodpasture
o (e.g., HLA-DRB1),syndrome
a finding consistent with the
genetic predisposition to autoimmunity.basement membrane
o Anti-glomerular
Type II RPGN is an immune complex-mediated disease. It can
disease
be a complication of any of the immune complex nephritides,
• RPGN
including Type 2 - Granular
postinfectious immunoflourescence
glomerulonephritis, SLE, IgA
nephropathy, oand 40%Henoch-Schonlein purpura. In some cases,
immune complexeso Many can be primary and secondary
demonstrated, immune
but the underlying
cause is undetermined.
complex diseasesIn all of these cases,
immunofluorescence studies reveal the characteristic ("lumpy
• RPGN Type 3 - Negative (pauci-immune)
bumpy") granular pattern of staining. These patients cannot
usually immunoflourescence
be helped by plasmapheresis, and they require
treatment for the 40%
o underlying disease.
Type III RPGN, o also called pauci-immune type,anti-neutrophil
Predominately is defined by
the lack of anti-GBM antibodies orantibody
cytoplasmic immune complexes
associatedby
immunofluorescence and electron microscopy. Most of these
systemic vasculitis and renal limited
patients have antineutrophil cytoplasmic antibody (ANCA) in the
serum, which playscrescentic GN vasculitides. Hence, in some
a role in some
cases, type IIIoRPGN Weak or
is a component no demonstrable
of a systemic vasculitis
such as Wegener immunoglobulin/complement deposition,
granulomatosis or microscopic polyarteritis. Figure 51. This immunofluorescence pattern shows
In many cases, however, pauci-immune
corresponding to crescentic
an positivity with antibody to IgG and has a smooth, diffuse,
glomerulonephritis immunofluorescence
is isolated and hence idiopathic.
staining More than
intensity linear pattern that is characteristic for deposition of
90% of such idiopathic cases have C-ANCA or P-ANCA in the glomerular basement membrane antibody with
of <2+
sera.
Goodpasture syndrome.
To summarize, all three types of RPGN may be associated with
a well-defined renal or extrarenal disease, but in many cases
(approximately 50%) the disorder is idiopathic. Of the idiopathic
cases, about one fourth have anti-GBM disease (RPGN type I)
without lung involvement; another one fourth have type II
March
RPGN; and3,the2009 | Tuesday
remainder are pauci-immune or type III RPGN. Page 14 of 16
The common denominator in all types of RPGN is severe Canoy, Carasco, Cielo,
glomerular injury.
Co
Figure 52.
Figure 52. Granular Immunofluorescence (“lumpy bumpy”

granular pattern of staining)
Figure 53. Granular, cytoplasmic staining of C-ANCA and
Pathogenesis of Anti-GBM disease (RPGN Type 1) perinuclear staining typical of P-ANCA, respectively.
• autoimmune disorder
• Anti-glomerular basement membrane antibodies Electron Microscopy
are produced and complex with glomerular
basement membranes and in some instances
• Either glomerular deposits anywhere (immune
complexes ) or no deposits (either anti-GBM or
with the pulmonary alveolar basement
no deposit disease )
membranes leading to their destruction
Anti-neutrophil Cytoplasmic Antibodies (ANCA)

• A family of autoantibodies that have specificity for
proteases located in primary granules of
neutrophils and monocytes
• Useful in the diagnosis and monitoring of patients
with several forms of systemic vasculitis and
renal-limited (pauci-immune) crescentic
glomerulonephritis
Types of ANCA
1. C-ANCA - cytoplasmic pattern
• Major specificity: proteinase 3
• Major clinical association: Wegener’s
granulomatosis
2. P-ANCA - perinuclear pattern
• Major specificity: myeloperoxidase
• Major clinical associations: microscopic Figure 54. Cellular crescent formation*
polyangiitis and renal-limited crescentic
glomerulonephritis
Robbins book notes

Serum from many patients with vasculitis in small vessels
reacts with cytoplasmic antigens in neutrophils, indicating the
presence of antineutrophil cytoplasmic autoantibodies (ANCA).
ANCA comprise a heterogeneous group of autoantibodies
against enzymes mainly found within the azurophil or primary
granules in neutrophils but also found in the lysosomes of
monocytes and in endothelial cells. ANCA can be detected in
serum by immunofluorescent microscopy of ethanol-fixed
neutrophils and by immunochemical assays. Two main patterns
of immunofluorescent staining distinguish different ANCA types.
One ANCA type shows cytoplasmic localization of the staining
(c-ANCA), and the most common target antigen is proteinase 3
(PR-3), a neutrophil granule constituent. The second type
shows perinuclear staining (p-ANCA) and is usually specific for
myeloperoxidase (MPO). Either ANCA specificity may occur in a
patient with ANCA-associated small vessel vasculitis, but c-
ANCA (PR-3 specificity) are typically found in Wegener
granulomatosis and p-ANCA (MPO specificity) are found in Figure 55. Fibrous crescent*
most cases of microscopic polyangiitis and Churg-Strauss
syndrome. Approximately 10% of patients with these disorders,
however, do not demonstrate ANCA by typical assays. ANCA
serve as useful quantitative diagnostic markers for these
disorders, and their discovery has led to segregation of a group
of these disorders as the ANCA-associated vasculitides. The
close association between ANCA titers and disease activity,
particularly c-ANCA in Wegener granulomatosis, suggests that
they may be important in the pathogenesis of this disease, but
the precise mechanisms by which ANCA induce injury are
March 3, 2009 | Tuesday
unknown. Page 15 of 16
Co
Figure 56. RPGN Type III or pauci-immune type
Figure 57.
Figure 57.

Co

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OS 214 Renal Dr.

Figure 4.picture of glomerulus

March 3, 2009 | Tuesday Page 1 of 16

podocytes and vessels. Figure 8. Collapsed capillaries, a feature of

Figure 6. Collapsed glomerular tuft. Note the

2. BASEMENT MEMBRANE THICKENING

Figure 9. Circulating complexes

Figure 7. Thickened capillary wall pointed in

3. HYALINIZATION AND SCLEROSIS

March 3, 2009 | Tuesday Page 2 of 16

• Due to loss of adhesive interactions with the

Figure 12. Epithelial cell injury leading to detachment.

March 3, 2009 | Tuesday Page 3 of 16

o children >40 mg/h

Figure 14. Primary nephrotic syndrome

From 2011 Trans: Figure 15. Minimal Change Disease

o uniform and diffuse effacement of foot

Figure 16. Normal podocytes (individually sticking out)

Figure 18. Focal collapse of glomerulus (encircled).

Figure 17. Fused podocytes in minimal change disease

Figure 20. Hyalinosis in glomerulus

Figure 18. Immunofluorescence microscopy of Minimal

March 3, 2009 | Tuesday Page 5 of 16

Figure 23. EM – denuded BM, will progress to ESRD ->

Figure 22. IF – usually normal except for sclerotic

Electron Microscopy and Course of Disease

March 3, 2009 | Tuesday Page 6 of 16

Figure 25. Reductions in renal mass leading to focal

Does hyperfiltration injure the glomerulus?

1. Subtotal nephrectomy (83%) in rats is followed

March 3, 2009 | Tuesday Page 7 of 16

Figure 30. LM: Uniformly and diffusely enlarged

March 3, 2009 | Tuesday Page 8 of 16

Figure 34. Glomerular tuft with global mesangial

Figure 35. Red cell casts (arrows)

Glomerulonephropathies Associated with

• IgA Nephropathy ( Berger’s Disease )

Figure 38. EM: Electron-dense mesangial deposits and

Thin Basement Membrane Disease

Figure 40. There is massive mesangial cell proliferation,

Figure 44. Schematic representation of patterns in the two

Figure 45.MPGN Type II – Light Microscope.

March 3, 2009 | Tuesday Page 11 of 16

Figure 46. IF: Presence of the complement protein C3

In Type II MPGN lesions, the lamina densa of the GBM is

Notes from http://path.upmc.edu/cases/case148/dx.html

Robbins book notes

Crescentic Glomerulonephritis/Rapidly Progressive

March 3, 2009 | Tuesday Page 13 of 16

Figure 49. Collapsed glomerular tufts and crescent-

Robbins book notes

Figure 52. Granular Immunofluorescence (“lumpy bumpy”

Anti-neutrophil Cytoplasmic Antibodies (ANCA)

Robbins book notes

Figure 56. RPGN Type III or pauci-immune type

March 3, 2009 | Tuesday Page 16 of 16

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