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Chapter (1) Rapidly progressive glomerulonephritis

Chapter (1)Rapidly progressive glomerulonephritis (RPGN)

RPGN is one of the nephrology emergencies which need special

attention. RPGN is a clinical description which determines by symptoms

and signs of glomerulonephritis (GN); edema, hypertension and gross

hematuria, and evidence of acute renal failure (severe decrease in

glomerular filtration rate presents as oliguria or anuria, and increased

serum levels of BUN and creatinine) (George et al., 2015).

Definite diagnosis of the disorder is based on kidney biopsy's

findings. Early diagnosis and appropriate treatment plays a critical role in

renal saving and preventing permanent glomerular damage (George et al.,

2015).

RPGN is defined as a syndrome with abrupt or insidious onset of

hematuria, proteinuria, anemia, and rapidly progressing acute renal

failure(ARF), and special findings on light microscopy examination of

kidney biopsy's specimen; crescentic lesions which usually involved most

glomerular architectures . It also characterized by rapid loss of renal

function (GFR<50% within 3 months) with histological findings of

crescent lesions which usually involves>50 % of glomeruli (Tarzi et al.,

2011).

Histologically, RPGN is characterized by a crescentic

glomerulonephritis (CGN), which is due to severe glomerular injury,

resulting in rupture of the glomerular capillary loops (Figure 1), with

accumulation of leucocytes and blood constituents in Bowman’s space,

which in turn induces visceral epithelial cell proliferation, together

forming a cellular crescent (Smeets et al., 2011).

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Fig. (1): Glomerulus showing crescentic glomerulonephritis due to pauci- immune ANCA-associated vasculitis, with a segmental area of thrombosis, tuft disruption and cells in Bowman’s space (Haematoxylin and eosin×400) (Smeets et al., 2011).

CGN is defined pathologically (for most glomerular diseases)

when >50% of glomeruli have crescents, which are identified on light

microscopy by the presence of at least two layers of cells in Bowman’s

space. However, this cut-off is arbitrary and clearly severe glomerular

injury can occur and result in a rapid decline of renal function with a

lower proportion of crescents, There are other conditions that can lead

to a clinical syndrome of RPGN, which are not caused by severe

glomerular. These include thrombotic microangiopathies and rarely

cases of tubulointerstitial nephritis, making it important to make a firm

diagnosis based on clinical, haematological, serological and renal

biopsy data (George et al., 2015).

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Causes of rapidly progressive glomerulonephritis

Table (1): Diagnostic Causes of Rapidly Progressive Renal Failure 1. Primary Renal Diseases

a. Glomerular diseasesi. Renal limited Vasculitis: Microscopic polyangiitis, ANCA neg. pauci-immune GN,

Goodpasture’s diseaseii. Post-infective crescentic glomerulonephritisiii. Idiopathic Collapsing glomerulopathyiv. IgA nephropathy, Membrano-proliferative glomerulonephritisv. Fibrillary glomerulonephritis

b. Tubulo-interstitial diseasesi. Acute interstitial nephritisii. Acute tubular necrosis

c. Vascular diseasesi. Atheromatous and thrombo-embolic renovascular diseaseii. Bilateral renal vein thrombosis

2. Systemic diseases affecting the kidneya. Systemic vasculitis

i. Wegener’s granulomatosisii. Churg-Strauss Syndromeiii. Goodpasture’s syndromeiv. Henoch-Schonlein Purpurav. Cryoglobulinemiavi. Drugs- hydrallazine, allopurinol, rifampicin, propylthiouracil,

carbimazolevii. Rheumatoid vasculitis, paraneoplastic vasculitis

b. Multiple myelomac. Systemic Lupus Erythematosus

i. Class IV lupus nephritisii. Antiphospholipid antibody syndrome

d. Thrombotic microangiopathyi. HUS / TTPii. Malignant hypertensioniii. Systemic sclerosis

e. Infectionsi. Infective endocarditisii. Occult viscera sepsisiii. Hepatitis C

f. Sarcoidosisg. Obstructive nephropathy

i. Retroperitoneal fibrosisii. Pelvic malignancy eg carcinoma cervix

(Dipankar et al.,

2011)

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RPGN can be primary or secondary. Secondary forms occur in any

form of severe glomerulonephritis including membranoproliferative GN,

IgA nephropathy, post infectious GN, and systemic lupus erythematous

(SLE) (Appel et al., 2010).

Primary RPGN is an autoimmune disease which is divided into three

immunopathologic categories :

-Type 1 RPGN: glomerulonephritis with antibodies directed against the

glomerular basement membrane (GBM) (anti-GBM mediated GN) .

-Type II RPGN: immune-complex induced glomerulonephritis

-Type III RPGN: Antineutrophil cytoplasmic antibody associated

glomerulonephritis (ANCA-associated glomerulonephritis or pauci-

immune GN) (Appel et al., 2010).

Type 1 account for only 10% of crescentic GN. Goodpasture

syndrome is the typical example of this category. In normal GBM, alpha

3, alpha 4, and alpha 5 type IV collagen have a hexamer structure and are

cross-linked to adjacent NC1 domains to form dimers (D isoform).In

patients with Goodpasture syndrome, there are linear deposits of

immunoglobulins G (IgG) directed against the non-collagenous 1(NC1)

domain of the alpha-3 chain of type IV collagen in the GBM and in the

membrane of pulmonary alveoli. Antibodies against alpha 5(IV)NC1

have also been identified in anti GBM disease (Pedchenko et al., 2010).

The etiology of Goodpasture syndrome is still unknown. Genetic

and environmental factors may predispose patients to the development of

the Goodpasture syndrome. It has been shown that autoimmunity to the

NC1 domain of the alpha3-chain of type IV collagen is strongly

associated with HLA-DR15. However, alpha3 (IV) NC1 presentation to

T cells seems to be determined more by “processing factors” than by the

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preferences of relatively indiscriminate DR15 molecules . Smoking, viral

respiratory infection or exposure to hydrocarbon solvents may be

frequently associated with Goodpasture syndrome and may contribute to

its development. (Pedchenko et al., 2010).

Other defined Goodpasture syndrome as an autoimmune

“conformeropathy”. Accordingly, the disease is triggered by a

perturbation of the quaternary structure of the alpha345NC1 hexamer,

inducing a pathogenic conformational change in the alpha3NC1 and

alpha5NC1 subunits, which in turn elicits autoantibody formation

(Dammacco et al., 2013).

The injury caused by antibodies can produce gaps in the glomerular

capillary wall that allow the entrance of coagulation factors and

inflammatory cells in the Bowman space, where they promote crescent

formation Although direct injury involving local production of

complement and polymorph nuclear activation is probably the main cause

for activating parietal epithelial cells, it is likely that T cell response and

regulation may also play a pathogenetic role (Tarzi et al., 2011).

Almost all cases of Goodpasture syndrome present with rapidly

progressive GN. The nephritic syndrome is often associated with anemia,

pulmonary hemorrhage and dyspnea. The diagnosis can be confirmed by

detecting anti-GBM antibodies in the blood and by immunofluorescence

analysis of kidney tissue showing linear deposits of IgG along the

GBM .In 10 to 38% of patients, anti-myeloperoxidase cytoplasmic

antibodies (p-ANCA) or, more rarely, anti-proteinase-3 neutrophil

cytoplasmic antibodies (c-ANCA) may also be detected (Lahmer et al.,

2012).

Rare cases of membranous nephropathy preceding or following

recovery from Goodpasture syndrome have been reported, suggesting the

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possibility of increased antigen synthesis, exposure of cryptic epitopes,

and/or capping and shedding of antigen–antibody complexes ( Troxell et

al., 2006).

Detection of antibodies to phospholipase A2 is crucial to

discriminate between patients with primary MN and those with a

secondary form of the disease, as both forms require different diagnostic

approaches and treatment strategies (Schlumberger et al., 2014).

Rarely, type 1 crescentic GN may develop in patients with Alport's

syndrome who receive a kidney transplant. The presence in the

transplanted kidney of antigenic epitopes that are lacking in the native

kidneys can trigger the production of antibodies. In most cases there is a

transient IgG linear deposition along the GBM without circulating anti-

GBM antibodies, but in 3% to 12% of patients anti-GBM antibodies can

produce severe crescentic glomerulonephritis (Byrne et al., 2002). The

epitopes recognized by the anti-GBM antibodies in X-linked Alport’s

syndrome are non-cryptic intact hexamer of the alpha5NCI, unlike those

of the classic Goodpasture syndrome in the native kidneys (Pedchenko et

al., 2010).

Type 2 accounts for 15–20% of crescentic GN. It is a

heterogeneous group of rapidly progressive GN characterized by

granular deposits of immunoglobulins. Different immune-complex

diseases may contribute to develop type II crescentic GN, including post-

infectious acute GN (Nasr et al., 2008), lupus nephritis (Borchers et al.,

2012), Henoch–Schonlein Purpura, mixed cryoglobulinemia (Kawasaki

et al., 2004), IgA nephritis, immune-complex mediated membrano-

proliferative glomerulonephritis, diabetic glomerulosclerosis and

primitive or secondary amyloidosis (Nasr et al., 2008).

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The occurrence of crescentic GN has been estimated to range around 16%

for post infectious GN, 8% for lupus nephritis, 2.7% for adults with

Henoch–Schonlein Purpura, and 11% for cryoglobulinemic nephritis

(Moroni et al., 2002).

In these diseases the deposition of circulating immune complexes

in the GBM or in situ formation of immune complexes within the

glomerular capillaries activates inflammatory cells and complement

causing damage to the GBM .Moreover the glomerular injury may trigger

inflammation and activate the innate immune response with recruitment

of macrophages, natural killer cells, granulocytes and maturation of

dendritic cells which stimulate the adaptive immune response with

production of TH1 and TH17 cell. (Summers et al., 2014).

Type 3 is the most common form of crescentic GN accounting for

around 60–80% of all cases. It was the most frequent cause of acute renal

kidney injury reported in the Italian registry of kidney biopsies. This type

of crescentic GN is characterized by the absence of immune glomerular

deposits and is now considered to be a small-vessel renal vasculitis.

Actually, although in a few patients who present the typical clinical

and pathological features of crescentic GN without immune deposits the

signs of vasculitis are absent, most of the afflicted patients have

circulating ANCA and signs of systemic vasculitis. type 3 crescentic GN

classified as ANCA-associated vasculitis (AAV) .This term includes

microscopic polyangiitis (MPA), granulomatosis with polyangiitis

(GPA), eosinophilic granulomatosis with polyangiitis (EGPA) (Jennette

et al., 2012).

In study of 89 patients with AAV and renal involvement crescentic

GN developed in 70% of patients with GPA and in 65% of patients with

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MPA. Crescentic GN was rarer in EGPA with renal involvement

accounting for only 13.8% of cases (Sinico et al., 2006).

All these conditions, although with difference in prevalence, share

renal lesions characterized by diffuse extra capillary proliferation and

necrotizing inflammation of capillaries, venules, arterioles and small

arteries (Lyons et al., 2012).However, the accompanying signs and

symptoms are different. In all the three diseases lesions of skin,

gastrointestinal system and neurologic system may be present . In GPA

the renal lesions are usually associated with granulomatous involvement

of the respiratory tract, ear, nose and throat. EGPA is associated with

asthma, eosinophilia and granulomatous inflammation. In MPA asthma

and granuloma are generally absent while pulmonary capillaritis often

occurs. Around 75% of patients with GPA have circulating cANCA, 20%

have pANCA and only 5% have negative ANCA. In MPA around 10% of

patients have undetectable ANCA, while around 50% of patients are

pANCA positive and 40% cANCA positive. About 1/3 of patients with

EGPA do not have circulating ANCA, 60% are positive for pANCA, in

particular those with renal involvement and only 10–20% are cANCA

positive. The majority of patients with pauci-immune GN are pANCA

positive (Jennette et al., 2012).

Symptoms and Signs

• General fatigue, slight fever, appetite loss, flu-like symptoms, and

abnormal body weight loss are also frequently observed.

• Microscopic, or occasionally macroscopic, hematuria is observed

accompanied by dimorphism of red blood cells and cellular cast

formation.

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• Proteinuria is frequently present; however, nephrotic syndrome

accompanying systemic edema is rare. Asymptomatic cases found

through urinary screening during sporadic health checks are increasing

(Matsuo et al., 2011).

When the causative disease of RPGN is systemic (vasculitis,

systemic lupus erythematosus, etc.), a variety of extra renal symptoms are

observed, such as:

disorders of the upper respiratory tract, lung (pulmonary

bleeding, interstitial pneumonitis),

skin (purpura, erythema),

Digestive organ (melena, abdominal pain), or neurons (Matsuo et

al., 2011).

In blood chemistry tests:

• Elevation of serum creatinine

• Decrease of estimated glomerular filtration rate

• Elevation of C - reactive protein (CRP)

• Rapidly progressive anemia, gradual elevation of neutrophil-

dominant white blood cells, and thrombocytes are frequently observed.

• Complement levels tend to be elevated in RPGN because of

systemic vasculitis; in contrast, systemic lupus erythematosus

(SLE) decreases complement levels.

Autoantibodies for detecting the causative disease of RPGN, anti-

glomerular basement membrane (GBM) antibody, ANCA, and

anti-dsDNA antibody are highly specific.

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Concerning signs in renal imaging, renal atrophy on echography

is relatively rare.

Renal pathology frequently reveals crescentic glomerulonephritis

(Matsuo et al., 2011).

Histopathology characteristics of RPGN :

1- Light microscopy findings

Histopathologically, RPGN is characterized by a vasculitis which

involves glomerular capillaries, and results in formation of cellular

crescents within most glomeruli .The hallmark histologic lesions are

crescents; a morphologic expression of severe glomerular injury. In

severe glomerular injury rupture of the glomerular capillaries allows

inflammatory mediators to spill into Bowman's space, resulting in

epithelial cell proliferation and invasion of monocyte and macrophage to

Bowman's space (Thomas et al., 2001).

Crescents are divided into cellular, fibro cellular or fibrous types.

Hallmarks of irreversible glomerular or tubulointerstitial injuries are

glomerular sclerosis, fibrous or fibro cellular crescents, and interstitial

fibrosis. The lesions usually are seen in various stages of activity or

resolution. Necrotizing inflammation in small cortical arteries is reported

in 10 % of biopsy specimens .Inflammation of medullary vasarectae with

papillary necrosis is another finding that may be found (Lionaki et al.,

2007).

In acute pauci-immune glomerulonephritis (RPGN type III)

fibrinoid necrosis accompanies crescents. These lesions occur at the same

frequency irrespective of the presence or absence of associated

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vasculitis .Acute lesions range from focal segmental fibrinoid necrosis

affecting less than 10 %of glomeruli to severe diffuse necrotizing and

crescentic glomerulonephritis that may injure all glomeruli.

Periglomerular granulomatous inflammation may occur, but is not

specific for pauci-immune glomerulonephritis (Lionaki et al., 2007).

2-Histopathology characteristics on immunoflurecent microscopy:

Anti-GBM glomerulonephritis characterized by linear staining for

IgG and usually C3 along the glomerular capillary. Immune complex-

mediated glomerulonephritis, which is found in severe forms of various

types of glomerulonephritis such as PSGN, IgA nephropathy, and lupus

nephritis, characterized by granular glomerular staining for one or more

immunoglobulins and/or complement components, and pauci-immune

glomerulonephritis characterized by mild or absent glomerular tuft

staining for immunoglobulins and/or complement (Rutgers et al., 2005) .

Anti-neutrophil cytoplasmic antibodies (ANCAs) associated

glomerulonephritis are usually pauci immune; however,

immunofluorescence microscopy often reveals a low level of staining

(less than +2, in the 0–4 scale Figure2

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Fig. (2): Histopathologic findings in light and immunoflurecent microscopy a/left; light microscopic demonstration of ANCA-associated necrotizing GN (with a crescent), arrows; (alveolar capillaritis with intra-alveolar hemorrhage); arrow; middle (and pulmonary necrotizing granulomatous inflammation with a multinucleated giant cell) arrow; right b/middle; Immunofluorescence microscopy can separate crescentic glomerulonephritis into anti-GBM with linear IgG staining, ( left) immune complex with granular staining, (right); or pauci-immune categories with little or no immunoglobulin staining(Lionakiet al., 2007).

3-Electron microscopy findings:

On electron microscopy examination absence of electron-dense immune

complex deposits (type I RPGN), multiple electron-dense deposits (type

II RPGN), and few or no electron-dense deposits (typeIII RPGN) are

main findings (figure 3) (Haas et al., 2004).

Fig. (2): Electron microscopy findings

C: Electron microscopy showing multiple sub-epithelial electron-dense deposits, some appearing partially resorbed, with extension of the glomerular basement membrane (GBM) around the deposits (uranyl acetate and lead citrate stain, original magnification ×6300)

F: Electron microscopy showing a large sub epithelial deposit in a “notch” area (arrow), as well as mesangial deposits (uranylacetate and lead citrate stain, original magnification×3800(Haas &Eustace, 2004).

Anti-neutrophil cytoplasmic and anti-GBM antibodies:

Anti-neutrophil cytoplasmic antibodies (ANCAs )are characteristic

markers of small vessel vasculitides; Wegener’sgranulomatosis(WG),

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Microscopic polyangiitis(MPA), Churg-Strauss Syndrome(CSS), and

idiopathic pauci-immune necrotizing glomerulonephritis for them the

term ANCA associated vasculitides(AAV) has long being used (Seo et

al., 2004).

The standard approach for detection of ANCA is indirect

immunofluorescence (IIF) technique followed by antigen-specific

quantitative assays .Myeloperoxidase (MPO) and proteinase3 (PR3) are

major ANCA antigens (Hauer et al., 2002).

In patients with RPGN, there are two major sub classes of ANCA,

namely perinuclear (p -ANCA) and cytoplasmic (c -ANCA) .The main

epitope of p-ANCA is myeloperoxidase(MPO), and that of c-ANCA is

proteinase-3 (PR3) (Lionaki et al., 2007).

MPO-ANCA is a useful serum marker for MPA and idiopathic

pauci-immune crescentic GN, and PR3-ANCA is regarded as a serum

marker for Wegener’s granulomatosis and MPA (Lionaki et al., 2007).

Approximately80- 85% of cases of pauci-immune crescentic

glomerulonephritis are ANCA positive. Greater than 95% of cytoplasmic

ANCA are PR3-ANCA and >95 %of perinuclear ANCA are MPO-

ANCA (Lionakiet al., 2007).

Anti-GBM antibodies which are directed to the non-collagenous

part of the α 3 chain of type IV collagen, can also be evaluated by both

IIF and ELISA(Rutgers et al., 2005) .The ANCA-GBM dot-blot is a

qualitative assay that uses nitrocellulose strips on which purified antigens

are blotted at preset spots .MPO and PR3 antigens that are used in these

tests are produced from human leukocytes .The GBM-ANCA dot-blot

assay has been revealed reactivities that had not been detected by

ELISA(Table 2) (Rutgers et al., 2005).

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Table (2): Characteristics of the GBM-ANCA Dot-Blot Assay

(Rutgers et al., 2005).

RPGN, Pulmonary–renal syndrome (PRS), and ANCA-associated

vasculitis (AAVs):

The ANCA-associated vasculitis(WG, MPA, and CSS) are a group

of autoimmune conditions characterized by the development of

necrotizing vasculitis .They share a number of clinical features and are

therefore treated using similar treatment protocols.The AAVs are rare

with an annual incidence of 20/million in Europe, with WG as the most

common and CSS the least frequent (Ntatsaki et al., 2011).

In far-east, MPA is more common than WG .It's thought that they

arise from interaction between an environmental factor and a genetically

predisposing agent(Ntatsaki et al., 2011).

Pulmonary–renal syndrome (PRS) is defined as combination of

diffuse alveolar hemorrhage (DAH) and glomerulonephritis(Seo et al.,

2004).

This syndrome is caused by different diseases, including various

forms of primary systemic vasculitis especially WG and MPA, ANCA-

associated systemic vasculitis(AAV), Good pasture's syndrome, SLE, and

infection-associated or drug induced glomerulonephritis (Mitra Naseri,

2011).

Immunologic injuries or non-immunologic mechanisms are

involved in pathogenesis of PRS .Immunologic mechanisms such as

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production of anti-GBM antibodies, ANCA, immune complexes

mediated injuries and non-immunologic mechanisms such as thrombotic

microangiopathy have been suggested .Pulmonary involvement in the

majority of cases is the result of small-vessel vasculitis that involves

arterioles, venules and alveolar capillaries (necrotic pulmonary

capillaritis). These lesions are clinically expressed with diffuse alveolar

haemorrhage (DAH)(Jayne et al., 2000).

In the majority of cases the underlying renal pathology is a form of

focal proliferative glomerulonephritis with fibrinoid necrosis, as well as

micro vascular thrombi, and extensive crescent formation accompanies

glomerular tuft disease (Walters et al., 2010).

According to results of ANCA pulmonary renal syndrome can be

categorized into two sub-groups:

1. ANCA-positive Pulmonary–renal syndrome

2. ANCA-negative Pulmonary–renal syndrome

Majority of cases of pulmonary-renal syndromes are related to ANCA

associated vasculitis (Mitra Naseri, 2011).

Pulmonary–renal syndrome in ANCA-negative systemic vasculitis

is very rare and has been reported in Behçet’s disease, HSP, IgA

nephropathy and in mixed cryoglobulinaemia and rarely in thrombotic

thrombocytopenic purpura(TTP) (Mitra Naseri, 2011).

Wegener's granulomatosis (WG): Their diagnosis was based on

upper and lower respiratory tract complications, renal disease, and

variable involvement of other organs with disseminated vasculitis .Tissue

biopsies confirmed the characteristic clinical findings , Pathologically

Wegener’s granulomatosis was characterized by small-vessel necrotizing

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vasculitis and granulomatous inflammation involving mostly the upper

and lower respiratory tracts and the kidneys (Mitra Naseri, 2011).

Diffuse alveolar hemorrhage (DAH) is the most serious

complication in small-vessel vasculitis. Respiratory symptoms including

cough and hemoptysis. CXR or chest CT-scan may reveal diffuse lung

infiltrate. Clinical manifestations, pathologic and serologic findings play

important role in the diagnosis of WG. 75- 90 %of patients with active

disease have PR3-ANCAs (Ozaki et al., 2007).

The role of PR3-ANCA in the pathogenesis of the disease is not clear, but

in vitro evidence suggests that PR3-ANCA can directly or indirectly

damage endothelial cells (Mitra Naseri, 2011 ).

ANCA-positive patients with clinical presentations of WG such as

sinusitis, pulmonary infiltrates, nephritis, and documented necrotizing

vasculitis, but without biopsy-proven granulomatous in flammation. Both

classic Wegener’s granulomatosis and Wegner's vasculitis are different

manifestations of the same disease process. (Mitra Naseri, 2011 ).

Microscopic polyangiitis (MPA):

Renal and pulmonary symptoms are characteristic in MPA, and

interstitial pneumonitis and pulmonary hemorrhage are common clinical

features .MPO-ANCA is positive in 50-75% of patients and biopsy of the

lung and kidney reveals necrotizing vasculitis of arterioles, capillaries,

and venules with few immune deposits necrotizing and crescentic GN

(Ozaki; 2007).

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Table (3): Diagnostic criteria for microscopic polyangiitis(Ozaki, 2007).

Allergic granulomatous angiitis (AGA) or Churg-Strauss

syndrome(CSS)

Churg and Strauss was firstly described allergic granulomatous

angiitis(Churg, & Strauss, 1951). The disease is characterized by

presence of asthma, eosinophilia, and necrotizing granulomatous

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inflammation .Clinical manifestations of small-vessel vasculitis; palpable

purpura of the lower extremities, mononeuritis multiplex, abdominal

pain, and gastrointestinal bleeding develop several years after the onset of

asthma. Positive MPO-ANCA are seen and skin biopsy shows necrotizing

vasculitis of small vessels with massive eosinophilic infiltration and

extravascular granulomatosis(Ozaki, 2007).

SLE and AAV

Systemic lupus erythromatosis is an autoimmune disorder .Variety

of autoantibodies are present in SLE patients including ANCA which

have been reported in 3-69 %of cases( Pradhan et al., 2004).

In Pradhan et al's study predominant ANCA pattern was p-ANCAwhile c-

ANCApattern was not found in any patient(Pradhan et al., 2004).

Their study revealed that ANCA can be used as a serological marker to

differentiate vasculitides in lupus nephritis cases from SLE without

nephritis.

Table (4): presents diagnostic criteria for CSS

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(Ozaki, 2007).

Epidemiology and prognosis

1) Epidemiology:

RPGN is a rare renal disease; however, the number of Japanese

patients with RPGN has increased in last years. Although the precise

incidence of RPGN in Japan or worldwide is not known. Based on a

questionnaire survey of 1,772 Japanese cases collected from1989 to 2007,

the most common clinical form of RPGN in this country is pauci-

immune-type necrotizing glomerulonephritis without systemic vasculitis,

and the second most common form is microscopic polyangiitis. In recent

years, the age at onset has increased (Watanabe et al., 2011).

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Crescentic glomerulonephritis is rare, it accounted for 13% out of

patients submitted to renal biopsy over a period of 7 years in Italy .

Although immune-complex crescentic GN may occur at any age, lupus is

typical of women in childbearing age, Henoch–Schonlein purpura is

more frequent in childhood and adolescence, mixed cryoglobulinemia

and AAV present more frequently between the fifth and the seventh

decades of life (Gabriella et al., 2014).

Goodpasture syndrome may have a bimodal distribution, being

more frequent in the 2nd–3rd decades, when it mainly affects males, and

in the 6th decade of life when it preferentially affects females (Fomegné

et al., 2006).

Post- infectious GN is frequent in underdeveloped countries and in

subjects with poor socioeconomic conditions. Lupus nephritis is more

rare in Caucasian subjects than in Asian populations (Mahr et al., 2004).

2) Prognosis:

The survival and renal prognosis of RPGN or ANCA-associated

RPGN has improved in last years. In contrast, patients with anti-GBM

antibody-associated RPGN show an extremely poor prognosis. Infection

has been, and continues to be, the leading cause of death in

patients with RPGN(Watanabe et al., 2011).

Independently of the original disease, the prognosis of crescentic GN was

ominous until a few years ago. Modern treatment has improved the

outcome .All patients who required immediate dialysis and had 100%

crescents on renal biopsy remained dialysis dependent (Gabriella et al.,

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2014).

Fig. (4): Algorithm for Differential diagnosis of Rapidly progressive

glomerulonephritis (Dipankar et al., 2011)

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