Glomerulonephritis

Dr G.O Ogun
Department of Pathology,
College of Medicine
University of Ibadan
1
 INTRODUCTION
Disorder of glomerular structures and
functions.
Constitute major problems in nephrology.
Most common cause of CRF/ESRD.
$8 Billion expenditure on dialysis alone by
US Government.

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 INTRODUCTION…Contd
Glomerulonephritis is an inflammation of
glomerulus.
Glomerulopathy is all-embracing term for
the disorders affecting this structures.
Diagnosis hinges on identification of
derangement of normal glomerular
configuration.
These changes are recongnised by LM,
IM, EM.
3
 Structure Of Glomerulus
Anastomosing capillary network
Renal artery > A&P >ILA > AA > ILBA > AFA.
An afferent arteriole branching from an
interlobular artery supplies the glomerulus with
blood.
Within the glomerulus are many capillary loops
supported by mesangium.
The mesangium can function both for filtration
and phagocytosis.
The glomerular capillaries have a fenestrated
endothelium for filtration.

4
 GLOMERULAR CELLS

Epithelial cells
i. Visceral (podocytes)
ii. Parietal
Mesangial cells
Endothelial cells 5
Structure of Glomerulus

6
Structure Of Glomerulus
The capillary loops are surrounded by
podocytes that have foot processes
forming slits.
A negative (anionic) charge on podocyte
foot processes helps keep negatively
charged proteins from filtering through.
The urine consisting of water and waste
products (and some solutes to be
recovered later) collects initially in
Bowman's space in the glomerulus.
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STRUCTURE OF NORMAL GLOMERULI

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9
Structure of Glomerulus

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 Structure of BM
GBM- Lamina rara externa, Lamina densa, Lamina
rara interna.
Collagen Type IV, laminin,polyanionic proteoglycans,
fibronectin, entactin
The buiding block (monomer) is a triple helical
molecule that are made up of three α chains,
composed of one or more of six α1-α6 (COL4A1-
COL4A6).
Triple helix 3α. α1- α2- α1combination (common)
Each molecule has 3 parts
6. 7s domain (amino terminus)
7. Triple helical domain (middle)
8. Globular NC1 domain (carboxyl terminus).
Antigen in the NC1 domain are the main target of 11anti
GBM nephritis and Goodpasture syndrome.
THE GLOMERULAR SYNDROMES
Acute nephritic syndrome Hematuria, azotemia, variable
proteinuria, oliguria, edema,
and hypertension
Rapidly progressive GN Acute nephritis, proteinuria, and
acute renal failure
Nephrotic syndrome >3.5 gm proteinuria,
Hypoalbuminemia
hyperlipidemia, lipiduria
Chronic renal failure Azotemia uremia progressing
over the years
Asymptomatic hematuria Glomerular hematuria;
or proteinuria subnephrotic proteinuria

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 CLASSIFICATION
AETIOLOGICAL
Primary (Renal)
Secondary (Systemic disorders)
To exogenous Antigens (eg Poststrep.,
drug-related)
To endogenous Antigens (eg SLE)

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 CLASSIFICATION
WHO
Distribution
When many glomeruli are involved.
• Focal – affecting some glomeruli
• Diffuse – most glomeruli
When single glomeruli is considered
• Segmental – involving parts of
glomerulus
• Global – involving entire glomerulus 14
15
 AGENTS INVOLVED IN RENAL
GLOMERULAR DISEASES
1. Infectious and Post Infectious (Bacteria,
Viruses, Spirochetes, Protozoa, Parasites, ?
Fungi)
2. Tissue Antigens (DNA, RNA)
3. Intravascular Coagulation
4. Chemical Agents
5. Physical Agents
6. Mechanical Factors
7. Metabolic
8. Genetic
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 Immune Mechanism of Glomerular Injury
1. Antibody- Mediated Injury
In situ immune complex Deposition
Fixed intrinsic tissue antigens
NC1 domain of collagen Type IV antigen ( anti-GBM induced
nephritis)
Heymann antigen ( membranous glomerulopathy)
Mesangial antigens
others
Planted antigens
Endogenous antigens (e.g DNA, nulcear proteins, Ig,
immmune complexes, IgA)
Exogenous antigens (e.g infectious agents, drugs) 17
Anti-GBM Antibody- Induced Nephritis

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 HEYMANN-MODEL

Experimental GN (Rats)
Induced in rats by injection of an antigen
preparation (megalin/LDLP) derived from
tubular brush borders. The rats develop
antibodies to this antigen and
membranous GP resembling human
MGP, subepithelial granular deposits.

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 Immune Mechanism of Glomerular Injury
1. Antibody- Mediated Injury
In situ immune complex Deposition
Circulating Immune Complex Deposition
Endogenous antigens (e.g DNA, tumour antigens)
Exogenous antigens (e.g infectious products)
6. Cytotoxic Antibodies to glomerular cells
7. Cell mediated Immunity
8. Activation of Alternate Pathway of complement

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 Mediators of Glomerular Injury
Cells- Neutrophils, Monocytes,T-cell, NK cells, Platelets,
Resident glomerular cells- especially mesangial cells
Soluble mediators-
3. Complement- C5b-C9, also stimulate mesangial cells
4. Ecosanoids, NO, angiotensin and endothelin- involved in
haemodynamic changes
5. Cytokines- IL1, TNF
6. Chemokines and growth factors- PDGF- involved in
msangial proliferation and TGF-β and FGF are critical for
ECM deposition and glomerulosclerosis in chronic injury
7. Coagulation system- Fibrin leak serve as stimulus for the
formation of crescents

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24
 MORPHOLOGY

HYPERCELLULARITY (cellular
proliferation, inflammation)
BASEMENT MEMBRANE THICKENING
(BM proper, IC deposits)
HYALINIZATION (BM, protein,
mesangial matrix)
SCLEROSIS (loss of structure)
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Mechanism of Progression- FSGS-
Renal ablation

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 FACTORS AFFECTING
LOCALIZATION
Size and charges
Charge
 Highly cationic tend to cross the BM to
subepith
 Highly anionic molecules are located
subendothelially/non-nephrogenic.
 Neutral charge accumulates in the
mesangium.

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 IMMUNE DEPOSITS
SUBEPITHELIAL (DPGN, MPGN1,
SLE, Memb)
ANTI-GBM (GPS)
SUBENDOTHELIAL (SLE, MPGN1,
cryo, HUS)
INTRAMEMBRANOUS (MPGN2, late
Memb)
MESANGIAL (IgA, IgM, SLE, MPGN2) 28
 Glomerulonephritis
Acute- Is characterised by inflammatory
alterations in the glomeruli and clinically
by syndrome of acute nephritis

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 GLOMERULOPATHIES-
Primary
Acute diffuse proliferative GN
2. Poststreptococcal
3. Non –post streptococcal
Rapidly progressive (crescentic) GN
Membranous glomerulopathy
Minimal change disease
Membrano-proliferative GN
Focal segmental glomerulosclerosis
IgA Nephropathy
Chronic glomerulonephitis 30
 Nil Disease (lipoid nephrosis,
minimal change
glomerulonephropathy)
Characterized by
Acute nephrotic syndrome on presentation
Normal renal function
• ATN if present must be related to Rx (diuretics or NSAID Rx)
Hypertension – typically absent
Haematuria – typically absent
Selective proteinuria in children
Good response to steroid Rx
Excellent prognosis

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 Minimal Change Disease
LM: few if any changes (other than
changes secondary to proteinuria
( swollen visceral epithelial cells)
IF: usually negative; may have mesangial
IgM
EM: only “fusion” of foot processes, other
nonspecific changes
Course: 85% responsive to steroids

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 This is minimal change disease (MCD) which is characterized by
effacement of the epithelial cell (podocyte) foot processes and loss of
the normal charge barrier such that albumin selectively leaks out and

proteinuria ensues. By light microscopy, the glomerulus is normal

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 Focal Segmental
Glomerulosclerosis
Although similar to MCD it differs in many important respects. It is more
likely to:
Have Haematuria
Have hypertension, HGFR, Non-selective Proteinuria
Exhibit poor response to steroid Rx.
Progress to ESRD in 10yrs in 50% of cases, rate is increased to
70% if initial presentation is NS.
SCD, Obesity, Congenital 19q13
Primary/Secondary – HIV, Heroin/Reflux Nep.
Focal/Segmental
Pathological lesion is sclerosis/Fibrosis e.g. glomerulus
Hyalinization of the feeding arterioles
Early lesion show a mesangial matrix and mesengial
hypercellularity.

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35
 Focal Segmental
Glomerulonephropathy (focal
sclerosis)
LM: some glomeruli (esp. juxtamedullary ones)
with segmental sclerosis (mesangial matrix
material, collapse, basement membrane-like
material) hyalinosis
IF: Usually negative except in sclerotic segment
which may have Ig M, C3.
EM: Just accumulation of matrix-like material in
collapse loops
Course: 15% responsive to steroids; over 1/3
progress to end stage renal disease.

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 This is focal segmental glomerulosclerosis (FSGS). An area of collagenous
sclerosis runs across the middle of this glomerulus. In contrast to minimal
change disease, patients with FSGS are more likely to have non-selective
proteinuria, hematuria, progression to chronic renal failure, and poor response

to corticosteroid therapy.

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This trichrome stain of a glomerulus in a patient with focal segmental
glomerulosclerosis (FSGS) demonstrates blue collagen deposition.
FSGS accounts for about a sixth of cases of nephrotic syndrome in
adults and children.

38
 Membranous GN
Usually presents as NS in adults
Proteinuria is non-selective
Assoc. with higher incidence of renal vein thrombosis
than any other cause of NS.
Macro haematuria rare but micro haematuria is
common
A cause may be readily found – SLE, Hepatitis,
Malaria, Neoplasm (in elderly) of lungs, bowel,
drugs.
Relatively high spontaneous remission in
idiopathic form
Effective Rx is controversial though steroids &
cytotoxic drugs have been tried.
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 Membranous
Glomerulonephropathy
LM: Normal to extreme diffuse thichkening of the
capillary wall “tuft hypercellularity, foam cells in
interstitium”
IF: Finely granular diffuse capillary wall staining
– IgG, C3.
EM: Numerous subepithelial deposits, spikes of
GBM between capillaries
Course: 1/3 progress, 1/3 remit, 1/3 proteinuria
only.

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41
 Here is the light microscopic appearance of membranous
glomerulonephritis in which the capillary loops are thickened and
prominent, but the cellularity is not increased. Membranous GN is the

most common cause for nephrotic syndrome in adults.

42
A silver stain of the glomerulus highlights the proteinaceous basement
membranes in black. There are characteristic "spikes" seen with
membranous glomerulonephritis seen here in which the black
basement membrane material appears as projections around the
capillary loops

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 Membranous glomerulonephritis is an immunologically mediated
disease in which deposits of mainly IgG and complement collect in the
basement membrane and appear in a diffuse granular pattern by

immunofluorescence, as seen here.

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 Diffuse Mesangial Proliferative
GN
Ig A nephropathy is the prototype of this
histopathological variant.
Recurrent macro haematuria – characteristic
presentation; often assoc. with URT inf.
(haematuria occurs at the peak of the illness)
Other presenting syndromes include:
Chronic GN
RPGN
ARF
Dysuria with loin pain (may confuse with haem cystitis)

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 Diffuse Mesangial Proliferative GN
(Contd)
Other findings include:
Proteinuria – usually mild < 1gm/day
Elevated plasma Ig A in up to 50% of cases
Pericapillary depo of Ig A and C3 on skin biopsy
Clinical indicators of poor prognosis include:
Decrease GFR at presentation
Persistent heavy proteinuria
Persistent heavy haematuria
Severe hypertension

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Diffuse Mesangial Hypercellularity
in Nephrotic Syndrome
LM: 3 or more cells in a mesangial region
in a thin section away from the vascular
pole
IF: IgM in mesangial regions
EM: mesangial deposits
? Part of nil disease
? Relationship to IgM nephropathy

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 Diffuse Proliferative GN
Poststrep GN is the prototype and is one of the
few cases where the cause, clinical and
pathological features correlates sufficiently to
justify labelling the disease by aetiology.
Diffuse Post-infectious GN (Post-streptococcal GN)
LM: Proliferative, exudative (PMNs) “ cresents
IF: Granular lumpy-bumpy cap, wall-IgG C3
EM: Subepithelial humps, small
subendothelial/mesangial deposits
Course: Resolves in vast majority of cases.
DX: ASO up, complement down, nephritic syndrome,
hypertension

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This glomerulus is hypercellular and capillary loops are poorly defined.
This is a type of proliferative glomerulonephritis known as post-

streptococcal glomerulonephritis.

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 Post-streptococcal glomerulonephritis is immunologically mediated,
and the immune deposits are distributed in the capillary loops in a
granular, bumpy pattern because of the focal nature of the deposition

process.

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 Membranoproliferative GN
Clinical presentation
NS – with significant haematuria, hypertension
and impaired renal function
Acute Nephritis or combination with NS
Chronic proteinuria & haematuria
10 MPGN- Type 1 and Type 2( dense-deposit
disease)
Persistently depressed plasma C3
Circ. C3-nephritic factor (Ig G ab to C3-convertase)
10yr renal survival for Type 1 is 40% with
nephrosis and even worse for Type 2

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Membranoproliferative GN, Type 1
(mesangiocapillary GN)
LM: Proliferative, PMNs, lobulation, tram-
tracking
IF: Broad capillary wall deposits – C3 is
deposited in a granular pattern. C1q and
C4 are also deposited
EM: Massive subendothelial electron dense
deposits, mesangial deposits may be
present
Course: progressive (many to renal failure)
DX: low complement, nephritic and/or
nephrotic syndrome. 52
 Membranoproliferative GN Type II
(Dense Deposit Disease)
LM: any glomerular pattern (membranous,
membranoproliferative, normal, crescentic GN,
etc.)
IF: Broad capillary wall deposits – C3 is present in
irregular or linear foci in the BM on either side
but not in the dense deposits,
EM: large electron dense in the GBM proper.
Course:progressive (many to renal failure)
DX: low complement (persistent),
nephritic/nephrotic.
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This is membranoproliferative glomerulonephritis (MPGN).
As seen here, the glomerulus has increased overall
cellularity, mainly mesangial.

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This silver stain demonstrates a double contour to many basement
membranes, or the "tram-tracking" that is characteristic of
membranoproliferative glomerulonephritis (MPGN) type I that results
from basement membrane reduplication.

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 Diffuse Crescentic GN
Associated with
Rapidly deteriorating renal function
Macroscopic haematuria
Proteinuria – usually >1g/day
Hypertension is often absent.
Profound oligo-anuria means damage is irrev.
Systemic dis. in 30-50%, Goodpasture’s, SLE or
necrotizing vasculitis.

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 IMMUNOPATHOLOGIC CLASSIFICATION OF
CRESCENTIC GLOMERULONEPHRITIS
I. Crescentic GN with granular immune deposits ~
40%
> 3/4 with well-defined clinical disorders
(e.g., SLE, postinfectious)
< 1/4 apparently idiopathic
(50% of these have small deposits)

II. Crescentic GN with Anti-GBM antibodies ~

5%
> 2/3 with pulmonary hemorrhage
< 1/3 without pulmonary hemorrhage

III. Crescentic GN without “significant” glomerular

deposits ~ 55% 57
 Crescentic GN (Rapidly
Progressive GN)
LM:Over 50% of glomeruli with crescents,
hypercellularity.
IF: 1/3 granular (immune complex GN, e.g. SLE,
postinfectious)
1/3 linear (probably anti-GBM) (Goodpasture’s
disease)
1/3 no deposits (e.g., polyarteritis, Wegener’s,
vasculitis
EM: either glomerular deposits anywhere (immune
complex) or no deposits (either anti-GBM or no
deposit disease)
Course: Terrible (progression to end stage renal
disease, except post infectious)
DX: anti-GBM antibodies in serum 58
(radioimmunoassay)
Seen here within the glomeruli are crescents composed of proliferating
epithelial cells. Crescentic glomerulonephritis is also known as rapidly
progressive glomerulonephritis (RPGN)

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 This immunofluorescence micrograph of a glomerulus demonstrates
positivity with antibody to fibrinogen. With a rapidly progressive GN, the
glomerular damage is so severe that fibrinogen leaks into Bowman's
space, leading to proliferation of the epithelial cells and formation of a

crescent.

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61
 IgA Nephropathy (Berger’s
Disease)
LM: any glomerular pattern (most normal
to focal GN)
EM: always mesangial deposits
Peripheral capillary wall deposit unusual
IF: Mesangial granular IgA by definition (in
absence of SLE, HSP, active liver
disease)
Prognosis: 2%/year to end stage renal
disease
?relationship to Henoch-Schonlein
purpura poorly understood. 62
 LIGHT MICROSCOPIC CHANGES IN IGA
NEPHROPATHY: GLOMERULAR

1) Normal or essentially normal glomeruli

2) Focal/segmental mesangial
hypercellularity

3) Diffuse mesangial hypercellularity

4) Focal glomerulonephritis
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IgA NEPHROPATHY- Mesangial IgA
deposits

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 CHRONIC
GLOMERULONEPHRITIS
End stage glomerular disease by various
specific types of GN.
Post streptococcal (1-2%)
RPGN(90),
MGN(30-60%)
FSGS(50-80%)
MPGN(50%)
IgA(30-50%) and others

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 Morphology- (CGN)
Kidneys are symmetrically contracted
diffuse granular cortex.
Thin cortex with increase in perinephric fat.
MG/MPGN,
Hyaline obliteration of glomeruli/acellular
eosinophilic masses (proteins, matrix, BM-like
material and collagen).
Arterial and arteriolar sclerosis.
Tubular atrophy,
interstitial fibrosis,
mononuclear leucocytic infiltration of intersitium.66
 The microscopic appearance of the "end stage kidney" is similar
regardless of cause, which is why a biopsy in a patient with chronic
renal failure yields little useful information. The cortex is fibrotic, the
glomeruli are sclerotic, there are scattered chronic inflammatory cell
infiltrates, and the arteries are thickened.

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