Download Glomerular Diseases

Glomerular Diseases
Prof C V Raghuveer.
21st ,23rd and 27th March 2013
II MBBS Regular Batch
Classification
• 1. Primary Glomerulonephritis :
Glomeruli are primarily involved.
• 2. Secondary glomerular diseases:
Glomeruli affected secondarily in some
systemic diseases.
• 3.Hereditary Syndromes:
Alports, Fabrys, Nail patella,s Syndromes
Primary Glomerulonephritis (1ᴼGN)
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1 Acute GN.
A) Post-streptococcal.
B) Non-streptococcal.
2. RPGN.
3. Minimal Change Disease.
4. MGN.
5. MPGN.
6. Focal Proliferative GN.
7. FSGS.
8. IgA Nephropathy.
9. Chronic GN.
Secondary/Systemic Glomerular
Diseases.
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1. Lupus Nephritis.
2. Diabetic Nephropathy.
3. Amyloidosis.
4. PAN.
5. Wegeners Granulomatosis.
6. Goodpastures Syndrome.
7. H S Purpura.
8. Systemic Infections e.g, SBE,
HBV,HCV,HIV,F.Malaria,Filariasis.
• 9. Idiopathic mixed cryoglobulinemia.
Hereditary Nephritis
• 1. Alports Syndrome.
• 2. Fabry,s Disease.
• 3. Nail-patella Syndrome.
Clinical Manifestations of GN
• Clinical manifestation is variable.
• Four features in general are seen in different
combinations.
• 1. Acute Nephritic Syndrome.
• 2. Nephrotic Syndrome.
• 3. Asymptomatic proteinuria.
• 4. Asymptomatic hematuria
• 5. A R F.
• 6. C R F.
Acute Nephritic Syndrome
• 1. Hematuria : Smoky urine.
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Microscopy RBC+ and casts +
• 2. Oliguria.
• 3. Hypertension : Mild.
• 4. Proteinuria : Mild <3 g/24hrs. Non-selective.
• 5. Oedema : Mild- due to Na & H₂O retention.
Causes of acute nephritic syndrome
I. Primary GN.
1.Acute GN
• Acute Post streptococcal GN
• Acute non-streptococcal GN.
2.RPGN.
3.MPGN.
4.Focal GN.
5. IgA nephropathy.
II Systemic Disease 2ᴼ G N.
1. SLE.
2. PAN
3. W G
4. HS P
5. Cryoglobulinemia.
Nephrotic Syndrome
• 1. Massive proteinuria. > 3g/24 hrs.
• 2. Hypoalbuminemia :
1-3 g/dL (N;3-5g/dL), Reversal of A /G Ratio.
• 3.Oedema : generalised (Anasarca)
• 4. Hyperlipidemia.
• 5. Lipiduria.
• 6. Hypercoagulability.
Causes of Nephrotic Syndrome.
• I.1ᴼ G N.
MCD, MGN, MPGN, FSGS, Focal GN, IgA nephropathy.
• II. Systemic Diseases.
DM, Amyloidiosis, SLE.
• III. Systemic infections.
HBV,HCV,HIV,SBE,F.malaria,Filaria.
• IV. Hypersensitivity. Bee sting.
• V. Malignancy. Myeloma.
• VI. Pregnancy. Toxemia.
• VII. Circulatory disturbances. RVT.
• VIII. Hereditary. Alports, Fabrys, Nail patella.
Pathogenesis of Glomerular Injury
• 1. Immunologic Injury:
Most 1ᴼ & some 2ᴼ GN have immunologic
pathogenesis.
Evidence: deposits of immunoglobulins and
complement seen by IF.
Mostly antibody mediated “immune complex”
some cell mediated, some non-immune, some
even by secondary mechanisms.
Immunologic Mechanism.
• A. Antibody mediated glomerular injury:
1.Immune Complex Disease.
Immune complex contains IgG/IgM/IgA and Cᴈ
Deposited as irregular/granular deposits by IF.
Three areas of deposition:
Subendothelial.
Subepithelial.
Mesangial.
How are these immune complexes
formed ?
• i) Local immune complex deposits: In situ
formation due to planted antigens on glomeruli.
• Antigens could be :
• Brush border antigens-Heyman nephritis -rat
model, MGN in humans
• Cationic proteins- lectins, DNA, bacterial
products ( e.g, a protein of group A streptococci
in acute GN ) viral and parasitic products.
How are the immune complexes
formed ?
• ii) Circulating immune complex deposits:
• Antigens may be Endogenous- e.g, DNA in SLE.
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Exogenous- e.g,HBV,
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T.pallidum,
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P.falciparum,
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Tumors.
• Antigen+Antibody complexes formed in
circulation, trapped in glomeruli and cause
injury after complement activation.
Examples for Immune complex
glomerular diseases.
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Acute diffuse proliferative GN.
MGN.
MPGN.
Ig A Nephropathy.
RPGN- some cases.
Focal GN.
Systemic diseases- SLE, malaria, syphilis,HS
purpura etc.
Antibody mediated glomerular injury
(contd.)
• 2. Anti-GBM disease:
• Here GBM components act as antigens
• E.g, type 4 collagen.
• Antibodies are formed against this and they
• get deposited as interrupted linear deposits
on IF along GBM-Goodpastures syndrome.
• Some cases of RPGN.
Antibody mediated injury (contd.)
• 3. Alternate pathway disease:
• Here alternate pathway of complement
activation occurs – Cᴈ and properdin get
• deposited in glomerulus without immunoglo.
• There is a circulating CᴈNeF – an IgG auto
antibody to Cᴈ-convertase, leading to
persistent alternate pathway activation.
• E.g, Type 2 MPGN, RPGN, Acute diffuse GN,
IgA nephropathy, SLE.
B. Cell Mediated Injury.
• Delayed type hypersensitivity.
• E.g, pauci immune type 3 RPGN.
• Activated T cells ( CD⁴/ CD⁸/NK Cells), release
cytokines which injure glomerulus.
C. Secondary mechanisms causing
glomerular injury.
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1. Neutrophils.
2. Mononuclear phagocytes.
3. Complement itself. MAC (C⁵ᵇC⁶⁷⁸⁹) causes
injury.
4. Platelets.
5. Mesangial cells.
II. Non-immunological mechanisms.
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1. Metabolic- DM.
2. Hemodynamic- HT, FSGS.
3. Deposition disease- Amyloidosis.
4. Infections- HBV,HCV,HIV.
5. Drugs- NSAIDs
6. Inherited- Alports, Nail-patellar syndrome.
Normal Structure of Glomerulus
Normal Glomerulus.
E M -Normal Filtration Membrane
Normal Glomerulus & Filtration
membrane.
Immunological Pathogenesis
Planted Antigens
Acute Diffuse Proliferative GN
• 1. Post streptococcal. Following Infection by
nephritogenic streptococci.
12, 4, 1 & Group A β-hemolytic streptococci.
• Immune complex disease.
• Clinically Nephritic Syndrome.
• 2. Non-streptococcal.
• Following infection by other bacteria, viruses,
parasites.
Clinical Features and Lab findings
• Children• Sudden onset.
• Past H/O sore
throat/skin infection.
• Acute Nephritic
Syndrome
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Urine- smoky.
RBCs and RBC casts +
Mild non selective
proteinuria.
S G high.
Pathogenesis of Acute GN
• Glomerular lesions are due to immune complex
deposition.
• Evidences:
• Strep.inf 1-2 wks before.
• Latent period to build antibodies.
• Elevated ASO, DNase,ASkinase.
• Hypocomplimentemia.
• Antigenic component- endostreptosin can be
identified.
Morphology.
• Gross: Both kidneys
enlarged.
• Cortex- petechial
spots.(Flea bitten)
Normal Glomerulus
Acute G N Light microscopy.
E M Sub-epithelial hump
granular I F
Prognosis
• Excellent 95 % recover on their own.
• 5 % may get complications:
• RPGN, Chronic GN, Uremia, CRF.
R P G N (Crescentic G N )
• Presents with acute reduction in Renal
Function – ARF.
• Characterised by crescents due to parietal
epithelial cell proliferation
• Caused by fibrin deposition in Bowmans
space.
• Common in adults
• Slight male predominance.
Aetipathogenesis
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Based on aetiopathogenesis 3 types of RPGN .
1.RPGN-seen in systemic disease( anti-GBM type)
2.Post-infectious RPGN( Immune complex type)
3.Pauci- immune RPGN.
• 3 serologic markers are seen in above.
• 1) anti-GBM antibody.
• 2)serum C3.
• 3) ANCA
Type-1 RPGN- Anti-GBM disease.
• Systemic diseases which produce RPGN due to
anti-GBM pathogenesis :
• Goodpastures syndrome- classic example
• SLE vasculitis.
• Wegeners granulomatosis.
• H S purpura.
• Idiopathic mixed cryoglobulinemia.
Goodpastures Syndrome
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Produces RPGN , presents with ARF.
Common in males 3rd decade.
Damage to GBM by anti-GBM antibodies
which cross-react with alveolar BM.
RPGN + Pulmonary hemorrhages occur
Linear deposits of IgG+ Complement along GBM
Goodpastures :antigen appears to be collagen-4
RPGN
R P G N- IF : Type -1 on the right,
crescent on the left
Anti-GBM Disease
Type-2 RPGN. Immune Complex
Disease
• A few post-streptococcal acute GN in adults
• develop RPGN, as a complication.
• Show granular IF of IgG and C3 along capillary
walls.
Type-3 RPGN- Pauci immune RPGN.
• A few cases of Wegeners granulomatosis,PAN
• develop RPGN .
• They are ANCA +, implying defect in humoral
immunity
• Serum complement is normal, no immune
deposits seen in glomeruli.
• Anti-GBM antibody is negative.
Morphology of RPGN
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Gross : Kidneys are large pale.
C/S pale cortex and congested medulla.
LM:
Glomeruli –Hypercellular, Crescent formation+
Fibrin deposition along the crescents.
Tubules-hyaline droplets, casts, RBCs, fibrin.
Interstitium- oedema, fibrosis, LC and PC.
Vessels- no changes.
IF in RPGN.
• Linear pattern in Type-1 RPGN.
• Granular pattern in Type-2
• No pattern in Type-3..
Clinical features of RPGN
• Acute GN with ARF.
• Type-1 present with ARF and pulmonary bleed
• Prognosis is uniformly bad.
Minimal Change Disease.
(Lipoid Nephrosis)
• Presents as Nephrotic Syndrome.
• L M :No apparent change in glomeruli.
• Accounts for 80 % cases of N S in children
< 16yrs.
• More in boys.
Aetiopathogenesis of MCD
• 1. Idiopathic in majority cases.
• 2. Some associated with HD, HIV, NSAID ,
Rifampicin, interferon etc..
• Evidences for Possible immune mechanism :
• Presence of circulating immune complexes in
• some cases.
• Response to corticosteroids.
• Increased suppressor T-cell activity- IL 8 released
causes foot process flattening and loss of charge.
Clinical features of MCD
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N S in children- selective massive proteinuria.
No hypertension.
Past H/O- URI/ atopic allergy/ immunisation +
In adults with NS- non selective proteinuria.
Morphology of MCD
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L M : no apparent changes in glomeruli.
Tubules- fine lipid droplets.
E M- fusion of foot processes.
IF- no deposits.
Disease responds to corticosteroids
EM- Morphology Normal & MCD
Prognosis of MCD
• Mostly patients are children < 16yrs.
• Respond to corticosteroids.
• Remissions may be there, but overall
prognosis is excellent.
Quiz -1
• An 8 yrs old boy brought to Paediatrics OPD with
H/O having passed high colored small quantity of
urine past 2 days.
• The boy is tired. Past H/O itching skin lesions
which started oozing about a month back.
• Urine examined microscopically and pt. admitted
after noting his BP & some blood chemistry tests.
• Unfortunately the pt. took 6 weeks to recover
necessitating kidney biopsy.
• Eventually there was good recovered.
Quiz -1 What is your diagnpsis?
What is the IF pattern in this condition ?
Quiz -2
• A 10 yrs old boy admitted for persistent
hypertension of 1 week duration after having
had “some kidney problem” according to the
mother. His urine showed RBC casts and
protein. His serum creatinine was mounting.
• He had to be admitted and evaluated.
Quiz -2.What is your diagnosis ?
What is the EM appearance ?
QUIZ-3
• A 10 YRS OLD GIRL PRESENTED WITH
GENERALISED OEDEMA OF 2 WEEKS
DURATION. SHE WAS VACCINATED ABOUT 4
WEEKS BACK.
• SHE WAS ADMITTED AND GIVEN STEROIDS TO
WHICH SHE RESPONDED WELL.
• RENAL BIOPSY HAD TO BE DONE.
Quiz-3.What is your diagnosis ?
MGN
• Widespread thickening of capillary wall.
• Most common cause of Nephrotic Syndrome
in adults.
• 85 % cases-MGN is truly idiopathic.
• 15 % cases-secondary to underlying cause
• E.g, SLE, Malignant tumors, HBV, HCV, Syphilis
• Malaria, drugs.
Aetiopathogenesis of MGN
• Idiopathic MGN is due to in situ immune
complex
• No neutrophilic infiltrate.
• Damage to GBM is by MAC (C⁵ᵇC⁶⁷⁸⁹)
• Secondary MGN due to circulating immune
• complexes due to endogenous(e.g,DNA in SLE)
• antigens or exogenous antigens (HBV, Tumor
antigen, T.pallidum,drugs)
Morphology of MGN
• L M:
• Glomeruli –diffuse capillary wall thickening.
• Spike & Dome appearance-best seen by silver
stains or PAS.
• No cellular proliferations.
Morphology of MGN
• E M -Immune deposits occur in subepithelial
region
• In between deposits BM material protrudes• SPIKE AND DOME APPEARANCE.
• IF- granular deposits of IgG and C3.
• In secondary MGN particular antigen like HBV
• can be demonstrated.
Morphology of MGN- LM
Morphology of MGN
Clinical Features of MGN
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Insidious onset of N S.
Proteinuria of non-selective type.
Microscopic hematuria & HT may be seen.
Changes in MGN are irreversible in majority.
50 % cases go for Impaired renal function--Azotemia---ESRD in 2-20 years.
Renal vein thrombosis occurs in many cases.
MPGN
• Another imp cause of NS in young adults &
children.
• Characterised by increased cellularity,irregular
• thickening of capillary wall & lobulation.
Aetiopathogenesis of MPGN
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Aetiology is largely unknown, but past H/O
streptococcal infection, in many cases.
Based on EM,IF & pathogenesis 3 types:
Type-1: Comprises > 70 % cases. Classic form.
Immune complex disease.
• Immune deposits in subendothelial space
• Seen in association with SLE, Sjogrens,
• SBE,HIV,HBV, HCV, NHL, leukemias.
Aetiopathogenesis of MPGN
• Type -2 /Dense Deposit Disease ( 30 % cases)
is due to activation of alternate pathway of
complement activation.
• Capillary wall is thickened due to immune
deposits in the lamina densa of GBM.
• It is an autoimmune disease with IgG auto
antibody
Aetiopathogenesis of MPGN
• Type-3 : is rare and shows features of Type-1
MPGN and MGN in association with systemic
diseases or drugs.
Morphology of MPGN
• LM:
• Glomeruli enlarged due to proliferation of
mesangial cells and increased matrix, with
lobular accentuation.
• GBM markedly thickened.
• Silver stain- “double contour”/Split/ Tram
track BM.
• Tubules : vacuolation & hyaline droplets.
Morphology of MPGN
• EM:
• Type- 1 : Electron dense deposits of C3 and IgG in
subendothelial location.
• Type-2 : Deposits in lamina densa of GBM & in
mesangium.
• IF : C3 and properdin in granular patern.
• Immunoglobulins absent.
• Type-3 : Deposits within GBM, sub endothelial
• and sub epithelial locations.
• IF : IgG, IgM, C3.
Morphology of MPGN Type – 1
Morphology of Type -1 MPGN
MPGN-EM
Morphology Type-2 MPGN.
Dense Deposit Disease
Clinical Features of MPGN
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Common between 15 & 20 yrs
50 % pts present with Nephrotic Syndrome.
30 % with asymptomatic proteinuria.
20 % with Nephritic Syndrome.
Proteinuria is non-selective.
Hematuria and Hypertension common.
Hypocomplementemia common.
Prognosis not good. Majority go to CRF.
FSGS
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Sclerosis and hyalinosis- focal & segmental.
Involvement of some glomeruli & portions of
glomeruli.
3 types:
1. Idiopathic: Children, NS, non-selective
proteinuria, steroid resisitant, progress to CRF.
• IF: C3 and IgM in the sclerosed part.
FSGS
• 2. With superimposed primary GN : FSGS with
superimposed MCD or IgA nephropathy.Good
response to C’steroids. CRF late.
• 3. Secondary type- FSGS secondary to diseases
like HIV, analgesic nephropathy.
FSGS Morphology
• LM: Focal and
segmental sclerosis.
• Homogenous PAS +
material.
• Mesangial
hypercellularity.
FSGS Morphology H & E,
Trichrome Stains
IgA Nephropathy
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Aggregates of IgA in mesangium.
C3 and properdin +
Alternate pathway of complement activation +
Association with GIT and respiratory infection.
LM: Looks like FSGS, MPGN and even RPGN.
IF: Deposits of IgA, C3 and properdin in
mesangium.
IgA Nephropathy
IF : Mesangial IgA, properdin & C3
Ig A Nephropathy