Dr Mohamed Alameen

Glomerular
Injury

Practical Classification

Nephritic vs Nephrotic
Nephritic

Nephrotic

Hematuria
Azotemia

Proteinuria > 3.5 gm

Hypoalbuminemia

Variable Proteinuria
Oliguria

Edema
Hyperlipidemia

Edema
Hypertension

Lipiduria

Nephrotic
Mechanism
Injury to
podocytes
Changed
architecture
Scarring
Deposition
of matrix

Nephritic
Mechanism
Inflammation
Reactive cell
proliferation
Braks in GBM
Cresent
formation

Glomerulopathies
Nephrotic Glomerulopathies

Nephritic Glomerulopathies

1ry

1ry

1.
2.
3.

MCD
FSGS
MN

IgA nephropathy
MCGN
Alport
Idiopathic RPGN

2ry

2ry
1.
2.
3.

1.
2.
3.
4.

DM
Amyloidosis
Multiple Myeloma

1.
2.
3.
4.

PIGN
SLE
Anti-GBM
Small Vesels vasculitis

Diabetic Mellitus
Diabetes
Most common cause
of NS in adult.
Most common cause
of ESRD worldwide.

Diagnostic criteria of DN

In diabetic patient (>10

DM-1, may be at
diagnosis in DM-2)
development of:
Persistent proteinuria
>300mg/24h
In presence of HTN, P.
retinopathy, RF and
absense of other causes

Diabetic Mellitus
Pathology

Wide spread thickening of the GBM

Diffuse glomerulosclerosis (increase

in mesangial matrix & mild
proliferation of mesangial cells)

Nodular glomerulosclerosis ( hyaline

mass within mesangial coreKimmelsteil-Wilson disease)

Hyalinization of arteriolar walls. IF may

demonstrate immunoglobulins and complement
in the glomeruli. EM regularly shows marked
thickening of the GBM and increased mesangial
matrix material.

Pathogenesis
Advanced glycosylation end

products accounts for

thickening of GBM &
increased mesangial matrix
(seen in all patients)
Hemodynamic effects
associated with glomerular
hypertrophy leads to
glomerulosclerosis

Diabetic Mellitus

Nodular glomerulosclerosis
(Kimmelstiel-Wilson
lesion) of diabetes mellitus.

Nodules of pink hyaline

material form in regions of
glomerular capillary loops in
the glomerulus.

This is due to a marked

increase in mesangial
matrix from damage as a
result of non-enzymatic
glycosylation of proteins.

Diabetic Mellitus:
Stages

<30mg/day

30-300mg/day

>300mg/d

Nodular glomerulosclerosis (Kimmelstiel-Wilson disease) in a patient with longstanding diabetes mellitus. Note also the markedly thickened arteriole at the lower right
which is typical for the hyaline arteriolosclerosis

Amyloidosis
Amyloidosis is due to the systemic extracellular

deposition of:

Antiparallel, -pleated sheet

Nonbranching
8- to 12-nm fibrils
Stain positive with Congo red (green birefringence
with polarized light).

Amyloidosis is frequently confirmed by biopsy of

the abdominal fat, kidney, or, in the case of AL

amyloidosis bone marrow

Amyloidosis
Primary (AL) amyloidosis:
kidneys are affected in 50% of patients.
Patients are typically older than 50 years.
Common renal manifestations include proteinuria, nephrotic

syndrome (25% of patients), and renal failure.

Immunofluorescence generally demonstrates light chains in
the glomeruli (75% of patients).
For patients with cardiac involvement, the prognosis is poor,
with a median survival of less than 2 years.
Treatment with prednisone and melphalan can be beneficial in
some patients. In selected cases, high dose melphalan followed
by bone marrow transplantation has led to resolution of the
disease.

Amyloidosis
Secondary (AA) amyloidosis
Most common in patients with rheumatoid arthritis,

inflammatory bowel disease, chronic infection, or

familial Mediterranean fever and in subcutaneous
drug users (heroin).
Treatment of AA amyloidosis is directed at the
underlying inflammatory process. Colchicine is
helpful in patients with familial Mediterranean fever.

Amyloidosis

Amyloidosis
The amorphous

pink depositis
of amyloid may
be found in and
around arteries,
in interstitium,
or in glomeruli,
as seen here
with H&E stain.

Amyloidosis
Amyloid

deposits
are seen in
glomeruli
at the left
and in
arteries at
the right

Amyloidosis

Nephritic
Glomerulopathies

Primary
Mesangicapillary GN

Secondary

Postinfectious GN

(Membranoproliferative GN)

Ig A Nephropathy
Alport Syndrome
RPGN (Idiopathic)

PSGN
Endocarditis
Shunt nephritis
Viseral absesses

SLE
Cryoglobulinemia
Anti-GBM
Vasculitides

Three Tests Classified GN

IC-GN
Granular
Deposits
Anti GBM
Linear
Deposits
ANCA+ve
Vasculitis
PauciImmune

Complement Low: 1- APSGN 2- IE 3- SN 4- MPGN 5- SLE 6-

Cryo
Complement Normal: 1- IgAN 2- HSP 3- Fib GN
Anti-GBM +ve With Lung Hage GPS
Anti-GBM +ve Without Lung Hage Anti-GBM disease
ANCA +ve C-ANCA with Granuloma WG
ANCA +ve P-ANCA with Granuloma Microscopic

polyangitis
ANCA +ve P-ANCA without Granuloma +Asthma
Churge-Strauss S

Acute Post-infectious GN
Acute post-streptococcal GN is the prototype but Non

strep infections is the most common.

Bacterial endocarditis: common in subacute rather than acute
endocarditis. S aureus is now the most common pathogen recognized.

Shunt nephritis: This may be associated with ventriculovascular,

ventriculoperitoneal, peritoneovascular, or vascular shunts.

Visceral abscesses: These may occur with abdominal, pulmonary,

or retroperitoneal abscesses.

Syphilis,HBV, HCV, HIV, CMV, Parvovirus B19, Hantavirus,

Malaria, Schistosomiasis, Leishmaniasis, Filariasis, Hydatid
disease Toxoplasmosis, Aspergillosis.

Acute Post-streptococcal GN

Neutrophils

Increased
number and
proliferation

Subendotelial
deposits

Subepithelial (humplike) deposits

Acute Post-streptococcal GN
Rapid onset of (95% have at least 2) (40% full blown picture)
Hematuria (smoky or Cola urine) e` RBCs casts in the urine)
It is universal, in 30% it is gross
Edema (Periorbital) presenting symptoms in 60%
Na&H2O retention
Subnephrotic proteinuria, 5-10% NS
HTN (60-80%) may be severe but most often trabsient)
Normalisation of BP with resolution
If persist, it is progressed to chronic or not PSGN
HTN encephalopathy in 5-10%
Oliguria: (10-50%) indicates severe cresent, resolved in 1-2 weeks
Left Ventricular Dysfunction in rare cases
Subclinical, microscopic hematuria may be four
times more common as overt acute PSGN, as
documented in studies of family members of affected

Age: it is
disease of
children peak 26y
15% of
patients: <2y
&>40 years
Male/Female:
2/1

Acute Post-streptococcal GN
Group A beta hemolytic streptococci
Nephritogenic strain (12, Throat) (49, Skin)

Latent period: 1-2 weeks throat, 3-6 weeks skin

Ab titers +ve in 80-90% (at 1 wpeak at 1mafter months)

ASO, anti-nicotinamide adenine dineoclitide (anti-NAD),

antihyaluronidase, anti-DNAseB, antizymogen .

Azotemia: transient, failure to normalise at 2 weeks alternative

diagnosis
5% present with RPGN

Low C3: to normal after 6-8W, if not alternative dx

C 4: usually in the low normal

Acute Post-streptococcal GN
Indication of biopsy: Failure of normalisation of:

Renal function at 1 month

Complement at 2 months
Proteinuria at 6 months
Hematuria at 18 months

Pathology
LM: diffuse proliferative (endothelial, mesangial and migrant PNL)
PNL are present in large # (exudative GN)
EM: subepithellial electron dense deposits (humps)
IF: granular deposits Lumpy-bumby of IgG and C3.
Starry Sky: small and irregular

Treatment: Bed rest, symptomatic, streptococcal inf, throat

culture for family members (erythromycin 250mg qid X7-10
days)

Acute Post-streptococcal GN
Complications:
Encephalopathy
HF
ARF

Prognosis:
General
85% recover
5% die-in the acute phase
10% develop CRF

Children
Excellent Prognosis
Less than 1% CKD after
10 years

Adult
50% recover
25% die-in the acute
phase
25% develop CKD

This glomerulus is hypercellular and capillary loops are

poorly defined.

The deposits are seen here with bright breen fluorescence in a

granular, bumpy pattern because of the focal nature of the immune

Acute Post-streptococcal GN

PNL

GBM

Epithellial

Humps

Post- infectious
glomerulopathies
HBV

1.
2.
3.

MN (most common)
Mesangiocapillary GN type I
Cryoglobinemia

HCV
1. Mesangiocapillay GN type I
2. Essential mixed cryoglobinemia

Ig-A Nephropathy

Increaing number and

proliferation of
mesangial cells

Mesangial deposits of
IgA

Ig-A Nephropathy
The most common primary GN worldwide
Abnormally glycosylated IgA1
A portion of IgA1 secreted by IgA1-producing cells in patients with
IgAN is galactose-deficient and consequently recognized by antiglycan IgG or IgA1 antibodies.
Some of the resultant immune complexes in the circulation escape
normal clearance mechanisms, deposit in the renal mesangium, and
induce glomerular injury.

Characterised by:
by
Deposition of IgA1 in the mesangium and less frequently of C3, IgG
and IgM,
Mesangial cell proliferation
Matrix expansion.

Ig-A Nephropathy

Ig-A Nephropathy
Long-term prognosis
1/3 achieve clinical remission with resolution of
Hematuria
Proteinuria
1/3 develop more benign disease
Urinary protein excretion < 1g/24hrs
1/3 have progressive decline in renal function

Negative prognostic Factors

Clinical: hypertension, proteinuria (> 1 g/24 h),

GFR

at the

time of diagnosis

Histological: glomerulosclerosis, interstitial fibrosis, vascular

sclerosis

Ig-A Nephropathy
Secondary causes:

Advanced chronic liver disease

Celiac disease
Dermatitis herpetiformis
Ankylosing spondylitis.

Ig-A Nephropathy
1.

Strict control of hypertension (ACE inhibitors, ARBs)

2.

Fish oil (Omega 3 Fatty acids) in patients with slow

progression of renal insufficiency.

3.

Corticosteroids in patients with proteinuria, which

do have preserved renal functions.

4.

Tonsillectomy might be beneficial.

5.

Cytotoxic agents in patients progressing renal

insufficiency

IgAN- histological
findings

Light microscopy (LM): Focal (here) or diffuse mesangial

proliferation. Rarely picture of crescentic GN, more frequently
picture of sclerotisating GN. Vasculitic lesions occur in HSP.

Immunofluorescence (IF): diffuse mesangial

deposits of IgA,

Electrone microscopy (EM):

demonstation of deposits in mesangium

Henoch-Schnlein purpura

Systemic Face of IgA

Nephropathy
HSP is usually self-limited
with a good eventual
outcome.
if urine protein exceeds 1 g/d

and/or renal insufficiency is

present), the risk of
developing chronic renal
failure is approximately 18%
in children and 28% in adults

Mesangiocapillary GN
Ab against C3 convertase
stability of C3 convertase, become resistant

to degradation
the half life C3 convertase to 10 folds.
Stimulate C3 amplification loop

This Ab is called C3

Nephritic factor

Mesangiocapillary GN
MPGN is defined as the diffuse proliferation of the mesangium and

thickening of glomerular capillary walls.

Secondary forms of MPGN tend to predominate in adults (>90%).

The main cause of secondary MPGN is cryoglobulinemia in a patient with

hepatitis C virus (HCV) infection.

Other secondary causes include

shunt nephritis, malaria, SLE, congenital complement deficiency (C2 and C3), sickle
cell disease, partial lipodystrophy (only type II), and 1-antitrypsin deficiency.

Type-I:
10% of all renal biopsies.
affects mainly children of both sexes between the ages of 8 and 16 years.

Type-II:
Rare disease < 1% of all renal biopsies

Mesangiocapillary GN
1/3 of the patients: combination of

asymptomatic hematuria and proteinuria.

1/3 of patients: nephrotic syndrome and
preserved renal function.
Some patients (10%-20%) present with
nephritic syndrome.
Hypertension is common (50%-80% of
patients).

Mesangiocapillary GN
In Type I: C3 and C4 are low (reflecting

activation of both complement pathways.

In MPGN type II, the alternative pathway is
activated, with patients having a
persistently low level of C3 but a normal
level of C4.
C3 nephritic factor is often present.

Mesangiocapillary GN
In Type I MPGN:
LM:
Diffuse global thickening of capillary walls and endocapillary
hypercellularity, giving the glomeruli a lobular appearance.
The interposition of mesangium between the GBM and the
endothelium triggers the production of neomembrane and results in
developing a double contour or tram-track appearance, best seen
with silver staining.
IF:
Granular deposition of IgG and C3 in the mesangium and outlines
the lobular contours.
EM
Immune deposits in the subendothelial space and mesangium.and
subepithellial.

Mesangiocapillary GN -I

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

Mesangiocapillary GN - II
In Type II MPGN: also known as dense

deposit disease
Electron-dense deposits replace the lamina

densa and produce a smooth, ribbonlike

thickening.
IF: Intense capillary wall staining for C3 (NO
IgG).

DENSE DEPOSIT DISEASE (Type-II)

C3 PERIPHERAL LOOPS (Type-I & II)

C3 Peripheral Loops & Signet Rings

Mesangiocapillary GN
Treatment in children:
long-term corticosteroid therapy has been helpful.
The use of dipyridamole (225 mg/d) and aspirin (975

mg/d) may temporarily slow the rate of progression of

type I MPGN, but results are not lasting.

Treatment in adults: is unknown.

Prognosis:
MPGN type I usually has a slowly progressive course, with

40% to 50% of patients reaching ESRD in 10 years.

Worse with hypertension, poor renal function, and
proteinuria >3 g/1.73 m2 per 24 hours.

Recurrence after transplantation: 30%

Mesangiocapillary GN
Prognosis of MPGN type II:
Worse prognosis
clinical remission rates are less than 5%.

Predictors of poor outcome:

impaired renal function at presentation
nephrotic-range proteinuria (>3 g/1.73 m2 per 24

hours),
Hypertension
Number of crescents (>50%)
Degree of tubulointerstitial damage.

Recurrence after transplantation: 90%

Alport Syndrome

(Hereditary Nephritis)

Defects in genes encoding different domains

of collagen type IV situated on chromosome

2 have been identified

Alport Syndrome

(Hereditary Nephritis)

Alport syndrome is nephritis associated with:

Nerve deafness

Various eye disorders (lense dislocation, posterior

cataracts and corneal dystrophy).

Males tend to be affected more frequently

and more severely than females and are more
likely to develop renal failure.

Patients present at age of 5-20 years with

gross or microscopic hematuria and
proteinuria and overt renal failure occurs
between 20 and 50 years of age.

Alport Syndrome

(Hereditary Nephritis)

Defects in genes encoding different domains

of collagen type IV situated on chromosome

2 have been identified
Alpha (IV)
Chain

Genes

Chromosomal
Location

Mutation

Alpha-1 (IV)

COL4A1

13

Unknown

Alpha-2 (IV)

COL4A2

13

Unknown

Alpha-3 (IV)

COL4A3

ARAS, ADAS

Alpha-4 (IV)

COL4A4

ARAS

Alpha-5 (IV)

COL4A5

XLAS

Alpha-6 (IV)

COL4A6

Leiomyomatosis

RPGN

RPGN
Clinicopathological syndrome in which

glomerular damage is accompanied by rapid

and progressive decline in renal functions. It
is characterized by severe oliguria or anuria
usually resulting in irreversible renal failure
in weeks or months.

RPGN
Type I CrGN-12% (anti-GBM disease):

shows linear deposits of IgG and C3 on GBM,

some show presence of Ab against alveoloar capillary BM (Good
pastures syndrome)
Anti-GBM Abs are diagnostic and these patients respond to
plasmapheresis.

Type II CrGN-44% (immune complex mediated):

IF reveals characteristic granular pattern of staining seen in poststrepGN, SLE and IgA nephropathy.

Type III CrGN-44% (pauci-immune type):

IF & EM findings are negative and serum

shows presence of ANCA associated with systemic vasculitis, mostly
idiopathic.

RPGN
LM:

Glomeruli show focal necrosis and thrombosis

Diffuse or focal endothelial proliferation
Mesangial proliferation
Formation of crescents (proliferation of parietal cells,
migration of T cells macrophages & fibrin strands in
the Bowman s space, eventually obliterating it).

EM:

Rupture of GBM in all cases.

 Type I CrGN-LINEAR IgG

 Type III RPGN Pauci Immune

Cresecent

Diabetes

Renal Biopsy

Renal Biopsy

MCD
FSGS
MN
APSGN
MPGN
Cryo
TMA

Glomerul
ar
Injury

IgA
MPGN

GPS
Pauci Immune
MN
MPGN

Lupus Nephritis