Rapidly progressive glomerulonephritis


 Rapidly progressive glomerulonephritis (RPGN) is a syndrome
of the kidney that is characterized by a rapid loss of renal
function.
 usually a 50% decline in the glomerular filtration rate (GFR)
within 3 months with glomerular crescent formation seen in at
least 50% or 75% of glomeruli seen on kidney biopsies.
 In 50% of cases, RPGN is associated with an underlying
disease such as Goodpasture syndrome, systemic lupus
erythematosus or granulomatosis with polyangiitis; the
remaining cases are idiopathic.
 RPGN involves severe injury to the kidneys' glomeruli, with
many of the glomeruli containing characteristic glomerular
crescents (crescent-shaped scars)
INTRODUCTION


 Proliferative extracapillary glomerulonephritis (GN) or crescentic
GN is not a specific disease, but a histologic manifestation of
severe glomerular damage.
 The term “extracapillary proliferation” is used to designate the
cellular and/or fibrous proliferation that occupies the Bowman’s
space, arising from its capsule.
 Extracapillary indicate that proliferation occur outside of
capillary tuft.
 Definition of crescent is the presence of at least two layers of
cells that are filling totally (circumferential) or partially
(circumscribed) the Bowman’s space.
CRESCENTIC GLOMERULONEPHRITIS


 Crescents are formed by a variable proportion of epithelial cells
and monocytes (macrophages); according to the evolution of
crescent the predominant cells are monocytes (earlier phase) or
epithelial cells (later phases).
 In cases with segmental necrosis and/or rupture of the Bowman’s
capsule usually there are more monocytes, and in cases of
immune complexes disease there are more epithelial cells.
 Crescents are associated to rupture of capillary walls and fibrin in
the urinary space. This fibrin and other proteins of the plasma
seem to have the capacity to stimulate epithelial cells so that they
proliferate, in addition, the mediators released by monocytes and
platelets would contribute to the cellular proliferation and, probably,
to posterior fibrosis.
 Crescents may evolve to fibrosis (fibrous crescent) or disappear
(by apoptosis). Fibrosis is mediated by infiltration of fibroblasts
from the periglomerular interstitium through spaces in the
Bowman’s capsule.
 When the crescents contain only cells, without collagen, is
called: epithelial crescent
 when cellular components are mixed with collagen the lesion is
called: fibroepithelial crescent


 Hematuria
 Red blood cell casts in the urine
 Proteinuria - sometimes exceeding 3 g protein/24 h,
a range associated with nephrotic syndrome.
 Hypertension
 Edema
 Oliguria or anuria
SIGN AND SYMPTOMS


 In the pathophysiology of RPGN the anti-neutrophil
cytoplasmic antibodies (ANCA) interact with antigens
in cytoplasm of neutrophils.
 It is thought that ANCA causes an early
degranulation giving way to release of lytic enzymes
at site of injury.
 ANCA are linked to the pathogenesis of
glomerulonephritis, anti-neutrophil cytoplasmic
antibodies specificity is determined via (ELISA), with
pANCA(antibody) directed against MPO
PATHOPHYSIOLOGY


 RPGN can be classified into three types, based upon
the immunofluorescence patterns:
 Type I– Anti-glomerular basement
membrane antibody associated RPGN.
 Type II – Immune complex RPGN
 Type III-- Pauci immune associated
RPGN
CLASSIFICATION


 Accounting for approximately 20% of RPGN, type I RPGN is
characterized by the presence of autoantibodies directed
against the glomerular basement membrane (GBM).
 It is also called anti-GBM glomerulonephritis.
 The antibodies are directed against a particular protein found
in the GBM, type IV collagen.
 some cases of type I RPGN are also associated with antibodies
directed against the basement membrane of lung alveoli,
producing Goodpasture syndrome.
TYPE 1


 RPGN caused by the deposition of immune complexes accounts
for 25% of RPGN and is classified as type II.
 These diseases include systemic lupus erythematosus, acute
proliferative glomerulonephritis, Henoch–Schönlein purpura
and IgA nephropathy.
TYPE 2


 Also known as pauci-immune RPGN, type III RPGN accounts
for 55% of RPGN and features neither immune complex
deposition nor anti-GBM antibodies.
 the glomeruli are damaged in an undefined manner, perhaps
through the activation of neutrophils in response to ANCA.
 Type III RPGN may be isolated to the glomerulus (primary, or
idiopathic) or associated with a systemic disease (secondary).
 The systemic disease is an ANCA-associated vasculitis such as
granulomatosis with polyangiitis, microscopic polyangiitis or
eosinophilic granulomatosis with polyangiitis
TYPE 3


 Goodpasture syndrome (GPS) is a rare autoimmune
disease in which antibodies attack the basement
membrane in lungs and kidneys, leading to bleeding
from the lungs and kidney failure.
 It attack the alpha-3 subunit of type IV collagen.
 Goodpasture syndrome may quickly result in
permanent lung and kidney damage, often leading to
death.
GOODPASTURE
SYNDROME


 60 to 80% of those with the condition experience both
lung and kidney involvement; 20-40% have kidney
involvement alone, and less than 10% have lung
involvement alone.
 Lung symptoms usually antedate kidney symptoms and
usually include: coughing up blood, chest pain (in less
than 50% of cases overall), cough, and shortness of
breath.
 Kidney symptoms usually include blood in the urine,
protein in the urine, unexplained swelling of limbs or face,
high amounts of urea in the blood, and high blood
pressure. oliguric or anuric renal failure, macro or
microhematuria, and other unspecific general symptoms.
According to sodium retention and volume expansion,
hypertension may be detected.
SIGN AND SYMPTOMS


HISTOPATHOLOGY
 Histopathological presentation in renal tissue is similar for anti-
GBM and pauci-immune crescentic GN. There is glomerular
inflammation with necrotizing lesions; GN is usually focal and
segmental, but it may be global and diffuse.
 Necrotizing lesions are invariably accompanied by crescents.
 In the tuft (in addition to necrosis) capillary collapse, mesangial
matrix increase, and karyorrhexis can be identified.
 Frequently there is segmental or extensive destruction of
Bowman’s capsule in these cases it is usual to find granulomas
and multinucleated cells surrounding the glomerulus.

Figure 1. This case corresponds to a 58-years-old
patient with rapidly progressive GN. See proliferation
of cells occupying the entire Bowman’s space (green
arrows) and compressing the tuft (red arrows). The
Bowman’s capsule is indicated by the blue arrows. This
is the characteristic aspect of an epithelial crescent, in
this case circumferential. Cells forming the crescent
may be epithelial, monocytes or other inflammatory
cells

In epithelial crescents the proliferating cells are not
accompanied by fibrous or collagen tissue.
Methenamine-silver stain emphasizes the compressed
tuft and rupture of capillary walls (arrows). This
capillary damage is an important pathogenic
phenomenon in the generation of the extracapillary
proliferation. (Methenamine-silver, X400).

In fibroepithelial crescents we can see a mixture of
large cells, with cleared nucleus, prominent nucleolus,
and ample cytoplasm, that are mixed with fibrous or
collagen tissue that is highlighted with the silver stains
(like in this photo) and with the trichrome stains. The
blue arrows indicate the tuft compressed and distorted;
the red arrows indicate large, active, proliferating cells,
and green arrows mark the fibrosis replacing many
areas of this crescent; this combination of lesions
indicates a process that evolves to chronicity.
(Methenamine-silver, X400).

. When advancing the destructive process of
glomeruli the crescent becomes more fibrous (or
scarred) and the cells composing it diminish
progressively until disappearing, being replaced
by fibroblasts. Stains for fibrous tissue, like
trichrome and silver, emphasize this component
(green arrows), in this case without epithelial
component; the blue arrows indicate remains of
glomerular tuft. (Methenamine-silver, X400).


 Systemic lupus erythematosus (SLE), also known simply as
lupus, is an autoimmune disease in which the body's immune
system mistakenly attacks healthy tissue in many parts of the
body.
 Symptoms vary between people and may be mild to severe.
Common symptoms include painful and swollen joints, fever,
chest pain, hair loss, mouth ulcers, swollen lymph nodes,
feeling tired, and a red rash which is most commonly on the
face.
 The mechanism involves an immune response by
autoantibodies against a person's own tissues. These are most
commonly anti-nuclear antibodies and they result in
inflammation.
SYSTEMIC LUPUS ERYTHEMATOSUS


 Kidneys
 Painless passage of blood or protein in the urine may often be the only
presenting sign of kidney involvement. Acute or chronic renal
impairment may develop with lupus nephritis, leading to acute or
end-stage kidney failure. Because of early recognition and
management of SLE, end-stage renal failure occurs in less than 5%of
cases; except in the black population, where the risk is many times
higher.
 The histological hallmark of SLE is membranous glomerulonephritis
with "wire loop" abnormalities. This finding is due to immune
complex deposition along the glomerular basement membrane,
leading to a typical granular appearance in immunofluorescence
testing.

Example of a glomerulus that contains a
focal cellular crescent and expanded
mesangium. Thickened capillary loops
suggest double contouring of the basement
membrane


 Membranoproliferative glomerulonephritis ("MPGN"), also known as
mesangiocapillary glomerulonephritis, is a type of glomerulonephritis
caused by deposits in the kidney glomerular mesangium and
basement membrane (GBM) thickening, activating complement and
damaging the glomeruli.
 MPGN accounts for approximately 4% of primary renal causes of
nephrotic syndrome in childreN and 7% in adults.
 Membranoproliferative glomerulonephritis involves deposits at the
intraglomerular mesangium.
 It is also the main hepatitis C associated nephropathy.
 The GBM is rebuilt on top of the deposits, causing a "tram tracking"
appearance under the microscope. Mesangial cellularity is increased.
MEMBRANOPROLIFERAIVE
GLOMERULONEPHRITIS


 Type I
 Type I the most common by far, is caused by immune
complexes depositing in the kidney. It is characterised by
subendothelial and mesangial immune deposits.It is believed to
be associated with the classical complement pathway.
 Type II
 The preferred name is "dense deposit disease".Most cases of
dense deposit disease do not show a membranoproliferative
pattern, A 2012 review considers DDD to be in a continuum
with C3 glomerulonephritis,
 Type III
 Type III is very rare, it is characterized by a mixture of
subepithelial deposits and the typical pathological findings of
Type I disease.

Glomerulus from a case of MPGN type I
with crescent.


 Henoch–Schönlein purpura (HSP), also known as IgA
vasculitis, anaphylactoid purpura, purpura rheumatica,and
Schönlein–Henoch purpura.
 is a disease of the skin, mucous membranes, and
sometimes other organs that most commonly affects
children.
 In the skin, the disease causes palpable purpura (small,
raised areas of bleeding underneath the skin), often with
joint pain and abdominal pain.
 With kidney involvement, there may be a loss of small
amounts of blood and protein in the urine (hematuria and
proteinuria)
HENOCH SCHONLEIN PURPURA


 HSP is a systemic vasculitis and is characterized by deposition
of immune complexes containing the antibody immunoglobulin
A (IgA);
 it usually resolves within several weeks and requires no
treatment apart from symptom control but may relapse in a
third of cases and cause irreversible kidney damage in about
one in a hundred cases.
 Henoch–Schönlein purpura is a small-vessel vasculitis in which
complexes of immunoglobulin A (IgA) and complement
component 3 (C3) are deposited on arterioles, capillaries, and
venules.
 HSP is more predominant among children.
 HSP involves the skin and connective tissues, scrotum, joints,
gastrointestinal tract and kidneys

Glomerular arteriole showing a
vasculitis with fibrinoid necrosis of
the vessel wall (arrow) and
swelling of the endothelial cells (E).
Surrounding the vessel there is
granulomatous inflammation (G)

.
Renal biopsy. (A) The glomerulus shows segmental necrosis with fibrin
exudation and a small cellular crescent (arrow). Note also endocapillary
hypercellularity and neutrophil polymorph exudation. Haematoxylin & eosin
(H&E). (B) There is fibrin within several capillary loops and Bowman's space
(arrows). The remaining capillary loops on the left show mild hypercellularity
only. Silver trichrome. Direct immunofluorescence microscopy for IgA (C)
and C3 (D) shows strong granular mesangial and peripheral capillary wall
staining.


 Also known as IgA nephritis, Berger disease or
synpharyngitic glomerulonephritis, is a disease of the
kidney (or nephropathy); specifically it is a form of
glomerulonephritis or an inflammation of the
glomeruli of the kidney.
 IgA nephropathy is the most common
glomerulonephritis worldwide.
 IgA nephropathy is characterized by deposition of
the IgA antibody in the glomerulus.
IgA NEPHROPATHY


 Hematuria- which usually starts within a day or two of a non-
specific upper respiratory tract infection.
 proteinuria
 IgA nephropathy may show mesangial widening and focal and
segmental inflammation.
 Diffuse mesangial proliferation or crescentic
glomerulonephritis may also be present.
 Immunoflourescence shows mesangial deposition of IgA often
with C3 and properdin and smaller amounts of other
immunoglobulins (IgG or IgM)
 In IgA nephropathy, there is abnormally glycosylated IgA1.
Anti-glycan antibodies form and lead to immune complexes
deposited within the mesangium of the glomeruli. These
complexes attach to fibronectin or type IV collagen in the
extracellular matrix and activate mesangial cells to produce
extracellular matrix, leading to mesangial hypercellularity,
segmental glomerulosclerosis or adhesion, tubular atrophy, and
interstitial fibrosis.

The IgA is deposited mainly
within the mesangium,
which then increases
mesangial cellularity as
shown at the arrow.


 Formerly known as Wegener's granulomatosis (WG) is a long-
term systemic disorder that involves both granulomatosis and
polyangiitis.
 It is a form of vasculitis that affects small- and medium-size
vessels in many organs but most commonly affects the upper
respiratory tract and the kidneys.
 The signs and symptoms of GPA are highly varied and reflect
which organs are supplied by the affected blood vessels.
 Typical signs and symptoms include nosebleeds, stuffy nose
and crustiness of nasal secretions, and inflammation of the
uveal layer of the eye. Damage to the heart, lungs and kidneys
can be fatal.
GRANULOMATOSIS WITH POLYANGITIS


 Kidney: rapidly progressive glomerulonephritis (75%), leading to
chronic kidney failure.
 Upper airway, eye and ear disease:
 Ears: conductive hearing loss due to auditory tube dysfunction,
sensorineural hearing loss
 Oral cavity: strawberry gingivitis, underlying bone destruction
with loosening of teeth, non-specific ulcerations throughout oral
mucosa.
 Lungs: pulmonary nodules (referred to as "coin lesions"), infiltrates
(often interpreted as pneumonia), cavitary lesions, pulmonary
haemorrhage causing haemoptysis, and rarely bronchial stenosis.
 Arthritis: Pain or swelling (60%), often initially diagnosed as
rheumatoid arthritis
 Skin: subcutaneous nodules (granulomas) on the elbow, purpura,
various others (see cutaneous vasculitis)
 Nervous system: occasionally sensory neuropathy (10%) and rarely
mononeuritis multiplex
 Heart, gastrointestinal tract, brain,


 Classic microscopic features of GPA include
inflammation of blood vessels associated with poorly
formed granulomas, necrosis, and many giant cells.
 It is now widely presumed that the anti-neutrophil
cytoplasmic antibodies (ANCAs) are responsible for
the inflammation in GPA. The typical ANCAs in GPA
are those that react with proteinase 3, an enzyme
prevalent in neutrophil granulocytes.
 ANCAs can activate neutrophils, increase their
adherence to endothelium, and induce their
degranulation that can damage endothelial cells.

Well-developed cellular crescent with
collapse of small amount of remaining
glomerular tuft with segmental fibrinoid
necrosis and extracapillary fibrin and
necrosis in pauci-immune crescentic
glomerulonephritis, consistent with
Wegener's granulomatosis or microscopic
polyangiitis. Immunofluorescence studies
were negative

Electron microscopy shows the absence of
deposits along the capillary wall in a case of
pauci-immune crescentic glomerulonephritis,
consistent with Wegener's granulomatosis. The
glomerular basement membrane break, which is
the unit lesion leading to exudation of plasma
proteins which stimulates proliferation of parietal
epithelial cells, leading to crescent formation, is
illustrated

FOCAL SEGMENTAL PROLIFERATIVE,
NECROTIZING AND SCLEROSING PAUCI-IMMUNE
GLOMERULONEPHRITIS WITH FOCAL (30%)
CRESCENT FORMATION.
NECROTIZING GRANULOMATOUS ARTERITIS
INVOLVING INTRALOBULAR SIZED ARTERIES
AND ARTERIOLES.
FOCAL ACUTE TUBULAR INJURY WITH
INTERSTITIAL EDEMA AND PATCHY ACUTE AND
CHRONIC INTERSTITIAL INFLAMMATION


 Microscopic polyangiitis is an ill-defined autoimmune disease
characterized by a systemic, pauci-immune, necrotizing, small-
vessel vasculitis without clinical or pathological evidence of
necrotizing granulomatous inflammation.
 Clinical features may include constitutional symptoms like fever,
loss of appetite, weight loss, fatigue, and kidney failure. A
majority of patients may have blood in the urine and protein in
the urine. Rapidly progressive glomerulonephritis may occur
 The process is begun with an autoimmune process of unknown
cause that triggers production of p-ANCA. These antibodies will
circulate at low levels until a pro-inflammatory trigger — such as
infection, malignancy, or drug therapy. The trigger upregulates
production of p-ANCA.
MICROSCOPIC POLYANGITIS


 The large number of antibodies make it more likely
that they will bind a neutrophil. Once bound, the
neutrophil degranulates. The degranulation releases
toxins that cause endothelial injury.
 Results from blood vessel inflammation that can
result in damage to organ systems. Areas most
commonly affected by MPA include the kidneys, lung,
nerves, skin, and joints.
 Have common features with another form of
vasculitis called granulomatosis with polyangiitis

The case of this microphotography corresponds
to a 62-year-old man with microscopic
polyangiitis. In an intrarenal artery we
demonstrated this vascular lesion. The arterial
wall is pointed with green arrows, and the lumen
with asterisks. In the central zone we can see an
area with fibrinoid necrosis of the wall,
polymorphous and cellular detritus (blue
arrows). These lesions are not very frequent in
intrarenal arteries, but its presence helps much
in the vasculitis diagnosis.

Crescentic glomerulonephritis.

Focal segmental glomerulonephritis.


 Also known as Churg-Strauss syndrome (CSS) or allergic
granulomatosis, is an extremely rare autoimmune condition that
causes inflammation of small and medium-sized blood vessels
(vasculitis) in persons with a history of airway allergic
hypersensitivity (atopy).
 The early (prodromal) stage is marked by airway inflammation;
almost all patients experience asthma and/or allergic rhinitis.
 The second stage is characterized by abnormally high numbers of
eosinophils (hypereosinophilia), which causes tissue damage,
most commonly to the lungs and the digestive tract.
 The third stage consists of vasculitis, which can eventually lead to
cell death and can be life-threatening.
EOSINOPHILLIC GRANULOMATOSIS WITH
POLYANGITIS


 It is a type of systemic necrotizing vasculitis.
 An EGPA-like syndrome is a rare complication that develops in
steroid-dependent patients with asthma who have their oral
steroid dose reduced after they start treatment a leukotriene
receptor antagonist (eg, montelukast, zafirlukast).
 The vasculitic phase usually develops within 3 years after the
onset of asthma, although it may be delayed for several
decades. The most prominent symptoms and signs are those
related to pulmonary, cardiac, dermatologic, renal, and
peripheral nerve involvement. Mononeuritis multiplex is a
major clinical finding.
 Asthma is one of the cardinal features of EGPA.
 Kidney--Glomerulonephritis
 Kidney-- Hypertension

Micrograph showing an eosinophilic vasculitis
consistent with Churg–Strauss syndrome. H&E
stain. One of the American College of
Rheumatology criteria for Churg–Strauss
syndrome is extravascular eosinophil infiltration
on biopsy.


 http://www.kidneypathology.com/English_version
/Crescentic_GN.html
 Wikipedia
 Google images
 Medscape
REFERENCES

Rapidly progressive glomerulonephritis

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