PATHOGENESIS
PATHOGENESIS OF GLOMERULAR DISEASES

At the end of these two lectures (Pathogenesis of the glomerular diseases and Pathology
of specific glomerular diseases) students should have understanding of:

(1
(1)) Ul
Ultr
tras
astr
truc
uctu
ture
re and
and ffun
unct
ctio
ions
ns ooff gl
glom
omer erul
ular
ar capi
capill llar
ary
y wa
wallll
(2
(2)) Pa
Path
thog
ogen
enet
etic
ic mec
mecha
hani
nism
smss of
of gglo
lome
meru rula
larr da
dammag agee
(3
(3)) Cl
Clas
assi
sifi
fica
cati
tion
on of th
thee glo
glome
merurula
larr d
dis
isea
ease
sess
(
()) Cl
Clin
inic
ical
al e!p
e!preress
ssio
ions
ns of
of th
thee gl
glom
omer erul
ular
ar dis
disea
easesess
("
(")) Pat
Pathol
holog
ogic
ical
al nomen
nomencl clat
ature
ure of the
the gglo
lome
merurula
larr d
dis
iseas
eases
es
(#
(#)) $om
$omee of the
the com
commo
mon n sp
spececif
ific
ic gglo
lome
merurula
larr di
dise
seas
ases
es aand
nd tthe
heir
ir out
outco
come
me

%lomerular disease encompasses a spectrum of morphological changes resulting

from a wide variety of etiological factors& 'aority of the glomerular diseases are
immunemediated&

PATHOGENESIS OF GLOMERULAR DISEASE

10 Immunopathogenetic mechanim! " *nitiator of the disease process +y

deposition,formation of immune comple!es
(1) Anti+ody mediated
(2) -cellmediated

#0 immunopathogenetic mechanim! " Actual mediation of the disease

(1) .ole of complement

(2) .ole of neutrophils
(3) .ole of monocytes,macrophages
() .ole of coagulation systems

10  Immunopathogene
Immunopathogenetic
tic mechanim!

Anti$o%& me%iate%!

Circulating immune comple! deposition

o

  (granular immunofluorescent pattern)

o *nsitu immune comple! formation
(*) *ntrinsic fi!ed glomerular
glomerular antigen
(1) /orma
/ormall component of glomerul
glomerular
ar +asement mem+r
mem+rane0
ane0 linier immunofluor
immunofluorescent
escent
 pattern:
 Anti"g'ome(u'a( $aement mem$(ane"anti$o%& %ieae

(2) Podocy
Podocyte
te antigen0 granular
granular immunoflu
immunofluoresce
Immune comp'e) g'ome(u'oneph(iti
orescent
nt pattern
pattern

1
 

(**) *ntrinsic and,or e!trinsic nonglomerular

nonglomerular nonfi!ed antigen
 Plante
Plantedd aanti
ntigen
gen00 g
gran
ranula
ularr immunof
immunoflor
loresc
escent
ent pat
patter
tern
n
Int(inic i&e& endogenous proteins
E)t(inic i&e& products of +acteria0 viruses0 parasites0 foreign proteins etc&
Immune comp'e) g'ome(u'oneph(iti

T"ce''"me%iate%!

-lymphocytes are essential for cellmediated and anti+ody

mediated immune response& -hus it is responsi+le for +oth induction and
an d
mediation of renal disease that are caused +y immune responses& -his may occur
through regulation of cell differentiation and anti+ody production or +y local
cellmediated immunity i&e& delayedtype hypersensitivity reaction& -he later is
initiated +y C4 cells +y activating monocytes,macrophages which produces
cyto5ines: *6120 *620 */78 and -/7 α which are powerful inflammatory
mediators causing inury&
C94 cells acts +y their cytoto!ic a+ility&

#  Immunopathogene
Immunopathogenetic
tic mechanim!
*1+ Ro'e o
o,, comp'eme
comp'ement!
nt!
Complement is activated +y immune comple!es (classic pathway) or +y
comple! polysaccharides (alternate pathway)& C 3  C" are chemoattractant for
leu5ocytes0 neutrophils in particular which causes damage +y releasing proteolytic
en;ymes and +y generating reactive o!ygen meta+olites& -erminal complement
components C"  +<0
+<0 mem+rane attac5 comple! ('AC) causes inury +y +asement
mem+rane lysis&

*#+ Ro'e o
o,, neut(op
neut(ophi'!
hi'!
 /eutrophils can cause damage to the mem+rane and cause proteinuria +y
generating reactive o!ygen meta+olites and +y releasing of proteolytic en;ymes&
-hey can also mediate acute changes in glomerular hemodynamics i&e& alter
glomerular filtration +y mechanical o+struction of capillary lumens0 attaching
themselves to the endothelium and in tern stripping the same from the underlying
 +asement mem+rane reducing the availa+le surface areas for filtration&
filtration&

*-+ Ro'e oo,, monoc&te.mac

monoc&te.mac(ophage
(ophage!!
-hese groups of cells play maor part in acute as well as chronic
inflammatory process +y producing various cyto5ines0 reactive o!ygen
meta+olites0 plasminogen activator etc& -he resident macrophages may participate
in the local presentation of antigen in delayedtype hypersensitivity reaction& -hey
are also responsi+le for hypercellularity of the glomerular tuft particularly in
diffuse proliferative glomerulonephritis0 crescentic glomerulonephritis etc&

2
 

*/+ Ro'e oo,, coagu'ation

coagu'ation &tem!
%lomerular deposition of fi+rin is important factor in causing proliferation
of parietal epithelial cells forming crescent& *ntraglomerular fi+rin deposition
may lead to glomerulosclerosis&

OMMONEST IMMUNE"MEDIATED GLOMERULAR DISEASE IS

IMMUNE"OMPLE GLOMERUONEPHRITIS

'inica' e)p(eion o, the g'ome(u'a( %ieae!

Patients can present with any one of the following or com+ination of more than one:

(1) Asymptom
ptomatatiic pro
proteinuri
uria
(2) 'icroscopic hematuria
(3) Acute renal failure
() Chronic re
renal ffaailure
(") Acute n
neephritic ssyyndrome
(#) /ephrotic syndrome

Acute nephritic $yndrome comprises of:

- =ematuria
- A;otemia
- Proteinuria
- >dema
- =ypertension

-he /ephrotic $yndrome is characteri;ed +y:

- Proteinuria ? 3&" gms,2 hrs

-- =ypoal+uminemia @ 2" g,l

>dema
- =yperlipidemia
- 6ipiduria

$ome of the common causes

cau ses of nephrotic syndromes are:

- 'inimal change disease (common in children)

- 'em+ranous glomerulonephropathy (common in adults)
- 'esangiocapillary (mem+ranoproliferative) %/
- 7ocal  $egmental glomerulosclerosis
- $ystematic diseases including:

- ia+etes mellitus

3
 

- $ystematic lupus erythematosus (lupus nephritis)

- Amyloidosis etc&

Te(mino'og& ue% in g'ome(u'a( %ieae

iffuse  A lesion involving all or nearly all glomeruli (? 9B)

7ocal  A lesion involving some +ut not all glomeruli (@ "B)
$egmental  A lesion involving portion of glomerulus (i&e& some
capillary loops remain uninvolved)
$clerosis  A lesion of the glomerulus where there is increase in
fi+rillary material laid within mesangial areas with
collapse of capillary loops and condensation of
o f +asement
mem+rane&
Crescent:
Cellular  A le
lesion co
consisting o off cceellular pr
proliferation o
off parietal ep
epithelial
cells filling part of owmans space&
7i+rocellular  A lesion which is similar to cellular crescent +ut with
varia+le amount of fi+rillar material&
7i+r
7i+rou
ouss  A le
lessio
ion
n with
withiin o
owm
wman ans space
pace wh
whiich is pr
pred
edomomin
inan
anttly
composed of fi+rous tissue i&e& scarred cellular,
fi+rocellular crescent&

'ai,ication o, G'ome(u'a( Dieae

 Clinical
 'orphological
 >tiological
 *mmunopathological

2ai o, 'ai,ication

- *mmune comple! glomerulonephritis

- Anti%'anti+ody diseases

Immune comp'e) g'ome(u'oneph(iti

- Associated with infection

  Poststreptococcal %/
  Postinfections %/
- Associated with systemic diseases
  $ystemic lupus erythematosus i&e& lupus nephritis
- Primary %lomerular diseases
  *diopathic mem+ranous %/
  'esangiocapillary (mem+ranoproliferative) %/

Anti"G2M"anti$o%& %ieae


 

 
%oodpasture syndrome

Dieae 3ith immune mechanim 3ithout I ,o(mation o( anti"G2M"anti$o%&

%e4e'opment

'inimal change disease

7ocal  segmental glomerulosclerosis&

PATHOLOG5
PATHOLOG5 OF SPEIFI GLOMERULAR
DISEASES 

Acute *%i,,ue p(o'i,e(ati4e

p(o'i,e(ati4e++ g'ome(u'oneph(iti
g'ome(u'oneph(iti

*t is also descri+ed as poststreptococcal , postinfectious glomerulonephritis& *t is

a form of immunecomple! glomerulonephritis and is characteri;ed histologically +y
diffuse proliferation of glomerular cells with or without influ! of polymorphs& -he
disease is more common in children  young adults and usually presents as acute
nephritic syndrome& Dne can elicit h,o preceding infection i&e& sore throat or s5in sepsis&
-he most common organism responsi+le is group A βhemolytic streptococci +ut other
organisms have +een identified& $erological investigation shows rising titers of A$D and
low levels of C3& >lectron microscopic e!amination of the glomeruli will show electron
dense su+epithelial immune comple! deposit classically 5nown as su+epithelial EhumpF&
-his disease is usually self limiting and only less then "B ofo f the patients may either
 progress to rapidly progressive glomerular disease (crescentic
(crescentic glomerulonephritis) or to
chronic renal disease&

Lupu neph(iti

As much as GB of the patient suffering from $ystemic 6upus >rythematosus

($6>) will show renal involvement& -his is an autoimmune disease0 also an e!ample of
immunecomple! glomerulonephritis where the antigen is an endogenous protein& -he
 presence of anti+odies to nuclear protein i&e& antinuclearanti+ody (A/A) to dou+le
stranded /A is a hallmar5 of the disease& -he hallmar5 of the disease in tissue is
Ehemato!ylin +odiesF&
-he disease is more common in women0 particularly of African descent0 in child
 +earing age group with 7:' ratio +eing <1:1&-he patients can present as significant
 proteinuria (H 2mg,2 hr&) nephrotic syndrome acute nephritic syndrome etc& -he
renal prognosis will depend on histological features i&e& diffuse
d iffuse proliferative type of
histology will carry much worse prognosis then diffuse mesangial proliferative type of
histology&

"
 

I%iopathic mem$(anou g'ome(u'oneph(iti

'ost common cause of nephrotic syndrome in adults and is characteri;ed +y

diffuse thic5ening of the capillary walls due to e!tensive su+epithelial immunecomple!

deposition
microscopic which can +e identified
e!aminations& on light0
-he disease electroninand
is insidious immunofluorescence
onset and shows slow progression
to reach to chronic state eventually& -he management of this disease remains
controversial&
Ihen the disease is associated with other systemic diseases0 it is no longer
idiopathic +ut will +e 5nown as secondary type of mem+ranous glomerulonephritis& -his
occurs commonly in following conditions:
   rug therapy0 after prolonged gold therapy0 penicillamine or /$A*s etc&
 $ystemic 6upus >rythematosus i&e& lupus nephritis
 *nfections: =epatitis0 or C etc
 $econdary to malignant tumors0 especially epithelial tumors

Meangiocapi''a(&
Meangiocapi''a(& *Mem$(anop(o'i,e(ati4e+
*Mem$(anop(o'i,e(ati4e+ g'ome(u'onep
g'ome(u'oneph(iti
h(iti

-his disease is also 5nown as hypocomplementemic glomerulonephritis as there is

low levels of C3 in almost all the patients& -his is a disease of children in general +ut can
occur at any age& -he classical presentation of this disease is nephrotic syndrome +ut can
also presents as acute nephritic syndrome and is characteri;ed +y enlarged0 hypercellular
glomeruli with accentuation of the lo+ules0 with mar5ed thic5ening of the capillary wall
which shows Edou+le contour or Etramtrac5F appearance& -here are su+endothelial
electrondense deposits seen on electron microscopy& -he course of this disease is one of
slow progression and is generally not responding to corticosteroid or immunosuppressive
therapy and eventually ends in chronic renal failure&

Minima' change %ieae

*s a commonest cause of nephrotic syndrome in children in whom this disease

occur freJuently& espite massive proteinuria0 the renal function remains normal&
n ormal& Dver
<B of patients are corticosteroid sensitive while small num+ers of patients are
corticosteroid dependent or resistant& -he later can +e treated +y immunosuppressive
agents& -he disease is characteri;ed +y normal appearing glomeruli on light and
immunofluorescence microscopy and the only a+normality detected is effacement of
epithelial cell foot processes which is identified on electron microscopy only&
on ly& /o
immunecomple!es are identified and so the disease
d isease is not an immune comple! in origin
 +ut several associated features suggests immune mediation& -he current hypothesis is
is that

#
 

the cellmediated immunity seems to play an important role where -lymphocytes are
said to produce vascular permea+ility factor which is responsi+le for massive proteinuria&
h(onic g'ome(u'oneph(iti
g'ome(u'oneph(iti

*t is an end stage disease in which there is wide spread (?<B) glomerulosclerosis

associated with e!tensive tu+ular atrophy0 interstitial fi+rosis0 mononuclear cell
infiltration and vascular changes of +enign hypertension& -he pelvis will remain
unaffected (unli5e chronic pyelonephritis)& -his results in mar5ed reduction in glomerular
function leading to chronic renal failure& At this stage no underlying glomerular
 pathology can +e determined&