Glomerular disease

introduction
 Characterized by a group of similar clinical
manifestations, such as proteinuria, hemoturia,
edema, and hypertension
 But etiology, pathogenesis, pathology, and
prognosis are different
 Primary: pathology confined to the kidney, any
systemic features are a direct consequence of
glomerular dysfunction
 Secondary: are clasified as secondary when be
manifestation of systemic diseases, vascular,
metabolic or genetic disorders
 Primary glomerular disease is the main cause of
chronic renal failure in china, and is the most
common in renal diseases
 Clinical classification
According to their characters of clinical
symptoms, gromerular diseases divide
to five types
 Acute GN
 Rapidly progressive GN
 Nephrotic syndrome
 Latent GN
 Chronic GN
Pathological classification
 According to pathological standards of the
glomerular diseases, published by WHO in 1982
1.Minimal changes GN
2.Focal segmental glomerular lesions
3.Diffuse GN
4.Unclassified GN
>50% of the glomerulus are affected diffused
<50% of the glomerulus are affected focal
>50% of the capillary are affected global
<50% of the capillary are affected
segmental
 Pathological classification
Diffused glomerulonephritis
a.Membranous
nephropathy
a.mesangial proliferative GN
b.endocapillary proliferative
b.Proliferative
GN c.Mesangial capillary G
glomerulonephritis
d.Dense deposit GN
e.Crescentic GN
c.Sclerosing GN
 Classification of glomerulopathies

 Clinical: primary and secondary

 According time period: acute or subacute and

chronic

 According renal biopsy: focal or segmental and

diffuse

 According number of cells: non-proliferative and

proliferative

 According imunofluorescence: IgA and IgM

nephropathy
Normal Kidney:
 Minimal change disease

 Always be normal
in light microscopy
 Without depositing
of immune
complex
 Minimal change disease

 On electron
microscopy,
there is a
characteristic
fusion of the
epithelial foot
processes
 Focal
glomerulosclerosis

 Light microscopy
shows the lesions
of focal
segmental
glomerular
sclerosis
 IgAN
 Light
microscopy
shows
mesangial
expansion by
increased cells
and matrix
 IgAN

 Detected by
immunofluoresc
ence
microscopy, IgA
deposit in
mesangium
 Membranous
nephropathy
 Immune
complex deposit
in the
subepithelial
cells, GBM
become thick
and distorted
 Membranoproliferative
glomerulonephritis
 Be
characterized
by a diffuse
increase in
mesangial cells
and matrix, and
by thichness of
the GBM
 Crescentic
glomurulonephritis

Fibrins deposit in the capsule

Relationship between clinical
and pathological classification
 Definite relation exists between the clinical
feature and histopathological type of the
glomerular disease
 Different clinical manifestations can have
similar histopathology while different
histopathologies can have present with
similar manifestation
 Renal biopsy is necessary method to judge
pathological classification of glomerular
diseases
 When diagnose a disease, both clinical and
pathological classifications should be take
into considerarion
 pathogenesis

Damage of kidney depend on:

- mechanism and intensity of immune reaction
Mechanisms:
- Damage by immunocomplexes
 Damage by cytotoxic antibodies (Ab)
 Cell-mediated immune injury
 Damage by complement and proinflammatory
mediators
 Genetic and immune-factors have shown to play
an important role on the severity and treatment
reaction of the disease
 Autoimmunnity leading to nephritis
 Inherited glomerular
diseases
1.alports syndrome
X-linked dominant trait, mutation in the
COL4A5 gene that encode the type IV
collagen located on the X chromosome
2.thin basement membrance disease
is also called benign familial hematuria,
whose mean thickness of GBM <280nm
3.nail-patella syndrome
4.Partial lipodystrophy
 Cytotoxic (Type I) reaction
– antibody mediated cytotoxicity
(ADCC)
These occur when antibodies
interact with antigens found
on
cell surface

2 mechanisms of cytotoxicity:

7. Ab mediate cell
destruction via
mechanism ADCC (cell
cytotoxicity dependent
on Ab)

9. Ab directed against cell-

surface antigens mediate
cell destruction via
complement activation
Type II reaction – immune complex-mediated
hypersensitivity
- The reaction of antibody
with antigen generates
immune complexes. In
some cases, large amounts
of immune complexes can
lead to tissue damage
They deposited in
various
tissues
⇓
induce complement
activation and ensuing
inflammatory response

Antigens can be:

h) Endogenous – for example
DNA in SLE
i) Exogenous – bacteria,
Location of immune deposits in the glomerular capillary wall
 The magnitude of the reaction depends on the quantitity of immune
complexes as well as distribution within the wall of glomerular capillary
 Delayed – type hypersensitivity (Type III)

T lymphocytes may also recognize

antigen

When they do, a mononuclear cell

infiltrate may accumulate at the
site of Ag concentration and
lead to the elaboration of toxic
products and tissue injury
Four major pathogenetic forms of glomerular
injury
In non-proliferative glomerulopathy:

 Damage by antibodies
 Damage mediate by complement

In proliferative glomerulopathy:

 Damage by circulating proinflammatory cells

(especially neutrophils and macrophages)
 Damage by local activating resident cells (for
example mesangial cells)
Pathogenic mechanisms of glomerular diseases
Nonimmunologic glomerular
injury
 Metabolic injury 1.Interactions of anvanced glycosylation
end-products
 Carbohydrate
2.Direct effects of high glucose on renal
 Lipid metabolism cells mediated through the genaration of
reactive oxygen species

 hyperglycemia 3.High glucose-triggered glomerular

hypertension
4.Mesangial cell hypertrophy, increased
mesangial cell martrix, and
glomerulosclerosis
Nonimmunologic glomerular
injury
Glomerular hypertension
 Is an independent risk factor for
glomerular injury
 Increase workload in the
remaining functioning nephrons
 Is a stimulus for increased
mesangial matrix production and
glomerulosclerosis
Miscellaneous mechanisms of
nonimmunologic glomerular injury

 In addition to the major immune,

metabolic, and mechanical
mechanisms, glomerulopathy can be
precipitated by a variety of infectious
and toxic agents, include both
exogenous (eg.drugs) and
endogenous (eg. Fibril deposition)
toxin
 Fianl common pathways:
a.focal segmental
Clinical manifestation

 Proteinuria
a.Both charge and size selectivity normally
prevent virtually all of plasma albumin,
globulin, and other large-molecular-weight
proteins from the glomerular wall
b.Normal individuals excrete less than
150mg/g of total protein and only about
30mg/d of albumin
c.The remainder of the protein in the ruine is
secrete by the tubules:Tamm-horsfall, IgA,
and beta-microglobulin
Clinical manifestation

 Proteinuria
d.The endocelial cell forms a barrier
penetrated by pores of about 100nm
that hold back cells and other
particles
e.The glomerular basement membrane
traps most large proteins
f.The foot processes of epithelial cells
allow molecular passage of small
solutes and water
Clinical manifestation

Proteinuria
g.Disruption of the basement
menbrane and slit diaphragms,
resulting in large amounts of
protein
h.The fusion of foot process
causes increased pressure
across the capillary basement
membrane, resulting in
Clinical manifestation

 Hematuria
a.Isolated hematuria without proteinuria,
other cells, or casts is often indicative of
bleeding from the urinary tarct
b.Gross hematuria with blood clots is almost
suggests a postrenal source in the urinary
collecting system
c.Isolated painless hematuria
(nondysmorphic RBCs) often indicate
urogenital neoplasms
d.In the pediatric population, isolated
hematuria is more likely to be idiopathic
or congental anomaly
Clinical manifestation

 Hematuria
e.Isolated hematuria with dysmorphic RBC
examined by phase-contrast microscopy
always indicated glomerular disease
f.The most etiologyies of glomerular
hematuria are IgA nephritis, hereditary
nephritis, and thin basement menbrane
disease.
g.Even in the absence of azotemia, these
patients should undergo serologic
evaluation and renal biopsy
Clinical manifestation

 Edema
Glomerulopathy
a.First found in body parts with low tissue
tention
b.With heavy proteinuria(>3.5g/d)
c.With hypoalbuminemia and hyperlipidemia
d.With diminished colliod oncotic pressure
due to losses of large quantities of protein
into the urine, the salt and water retained
can not be restrained within the vascular
compartment
Clinical manifestation

 Edema
Glomerulonephritis
a.Assosiated with hematuria, proteinuria,
and hypertension
b.Especially evident in the very soft tissue of
the eyelids and face, and tends to be most
pronounced in the morning because of the
recumbent posture during the night
d.Fluids retention is due to increased
capillary permeability, and primary
retention of sodium and water by the
kidneys owing to renal insufficency
Clinical manifestation

 Hypertension
a.Fifty percent of patients have
hypertension
b.cause: salt and water retention,
hyperreninemic states and
exogenous erythropoietin
administration
c.Must be meticulously controled, fail
to do so can accelerate the
progression of renal damage and
congestive heart failure
Clinical manifestation

 Renal function damage

a.Unware because remain
asymptomatic until their disease has
significantly progressed
b.Reduction in the renal mass leads to
hypertrophy of the remaining
nephrons with hyperfiltration,
increased GFR
c.place a burden on the remaining
nephrons and leads to progressive
Clinical manifestation

 Renal function damage

d.Reduction in the effective glomerular
capillary surface available for filtration
leads to endothelial mesagial and
epithelial cell dysfunction
e.Lesions ensued include capillary
microthrombosis, mesangial expansion,
microaneurysm formation, and basement
menbrane thickening
f.These alteration lead to segmental and
eventually global glomerulosclerosis,
closing the loop of a positive feedback
mechanism that perpetuates and
Acute poststreptococcal
glomerulonephritis
 Etiology
 Is commonly caused by infection
of certain strains of group A
beta-hemolytic Streptococci
(pharyngitis, pyoderma)
 nephritis develop after a latent
period of about 2-3 weeks, often
with pharyngitis or a skin
infection
 Acute poststreptococcal
glomerulonephritis
 Pathology
intracapillaryproliferation of
mesangial and endothelial cells
 with subepithelial („humps“)
and subendothelial deposits
 (C3, or IgG)

Acute diffuse proliferative GN

Acute poststreptococcal
glomerulonephritis
Clinical presentations
 Is often encounter in children of 2-6years
age with pharyngitis or cutaneous
infections
 Oliguric acute renal failure, gross
hematuria, proteinuria, and generalized
symptoms: anorexia, nausea, vomiting,
and malaise
 Swelling of the kidney can cause flank or
back pain
 Physical examination reveals
Acute poststreptococcal
glomerulonephritis
Laboratory findings
 Urinary sediment: dysmorphic red blood cells, red
cell casts, leukocytes, leukocytes casts, and
subnephrotic proteinuria
 Serum examination: elevated creatitine, C3 CH50
are depressed within 2 weeks, and return to
normal within 6-8 weeks
 75% of the patients have transient hypergamma-
globulinemia and mixed cryoglobulinemia
 90% have circulating antibodies against
streptoccal exoenzymes auch as
antistreptolysin(ASO)
Acute poststreptococcal
glomerulonephritis
Treatment and prognosis
 Eliminating the streptococcal infection with
antibiotics
 Providing supportive therapy until
spontaneous resolution of glomerular
inflammation
 Diuretics to control extracellular fluid
volume
 Antihypertensive agents to control blood
pressure
 Most of prognosis are excellent, rarely
cause end-stage renal disease, 20% of the
patients may have persistent proteinuria
 Rapidly progressive glomerulonephritis
(RPGN)
 A group of diseases, characterised by intense proliferation
of glomerular/capsular epithelial cells in the form of a
crescent.

 crescemt = accumulation and proliferation of extracapillary

cells.

 The glomerular capillaries collapse and are bloodless, and

fibrin can be identified within the capsule
⇓
it can stimulate proliferation of parietal epithelial
cells
⇓
deposits of fibrin compress the glomerula capillaries
tuft
(↓ GFR and destruction of glomerulus)
 Rapidly progressive
glomerulonephritis (RPGN)
Causes of rapid progressive glomerulonephritis

1.Infection diseases 3.drugs

a.posttreptococcal glomerulonephritis
b.infective endocarditis
c.hepatitis B infectin
2.Mutisystem disease
disease
a.systemic lupus erythematosus
b.systemic necrotizing vasculitis
c.goodpastures syndrome
a.penicillamine
b.hydralazine
c.allopurinol
4.idiopathic or primary glomerular
a.anti-GBM antibody-mediated
b.immune complex-mediated
c.pauci-immune
d.antineutrophil cytoplasmic
 Three forms of RPGN
 GN with creation of antiobdies (IgG, IgA)
agains GBM (anti-GBM)
- linear deposits of Ig
Goodpastures´ syndrome

 GN with granular deposits of Ig and

complement
- formation of crescent is complication less
serious
intracapillary proliferative GN
(IgA nefropathy, SLE

 GN with ANCA antibodies

- ANCA ab (Ab agains cytoplasma of Crescent GN
neutrophiles)
2 forms – systemic disorders
(Wegener granulomatosis)
- only renal disease
Rapidly progressive
glomerulonephritis (RPGN)

Clinical presentations
• develop renal failure over weeks to months
•With nephritic urinary sendiment: gross hematuria,
proteinuria, oliguria, hypervolemia, edema,
hypertension
•Headache, malaise, anorexia, weight loss, fever,
arthralgias, and myalgias
Rapidly progressive
glomerulonephritis (RPGN)

Laboratory findings
•The urinary is nephritic
•Ccr decreases progressively
•anti-GBM autoantibodies detectable by
immunoassay
•Pauci-immune glomerulonephritis have ANCA be
detected
Rapidly progressive
glomerulonephritis (RPGN)

Treatment and prognosis

•High-dose steroids given as intravenous
boluses(10-30mg/d.kg, continuously for 3 days) are
effective on controlling acute glomerular
inflammation
•Followed by oral prednisone at 1mg/d.kg(for 6-
8weeks)
•Cyclophosphamide is important adjuncts to steroid
therapy and appear to afford better long-term
preservation of renal function than steroids alone
Rapidly progressive
glomerulonephritis (RPGN)

Treatment and prognosis

•Azathoiprine and mycophenolate have been used
as a therapeutic option in patients resistant to
cyclophosphamide
•Other medication include intravenous
immunoglobin, antithymocyte antibody, and
humanized monoclonal antibody to CD4 and CD25,
but none of these therapy have been well studied
•50% of patients require dialysis within base of next
6 months of diagnosis
Chronic glomerulonephritis
(RPGN)
Be characterized by
 persistent moderate to heavy
proteinuria and/or hematuria,
 symmetrically contracted kidneys
 renal insufficiency progress slowly
over
years
 Chronic glomerulonephritis

 Common terminal result of many

glomerular diseases
(„end stage kidney“)
 It is charecterised by different degrees
of sclerotization and proliferation

Pathogenesis: damage (loss) of

nephrons
⇓
hyperperfusion
⇓
hyperfiltration
⇓
sclerosis of glomeruli
Chronic glomerulonephritis
(RPGN)
Pathology
1.Be a manifestation of virtually all of the major
glomerulopathies
2.If a kidney biopsy is performed early, it may be
possible to reach a precise diagnosis of the
cause, such as membranous GN, IgA
nephropathy, focal segmental glomerulosclerosis,
mesangial proliferative GN, diabetic nephropathy
3.Tubulointerstitial inflammation and scarring are
frequent additional fingings portend to a poor
prognosis
4.Glomerular hypertension and hyperfiltration
through remnant functioning nephrons can
hasten progression to ESRD
Chronic glomerulonephritis
(RPGN)
Clinical presentations
1.Hematuria proteinuria oliguria
polyuria nocturia edema hypertension
electrolyte disorders anorexia
weight loss dyspnea fatigue pruritus
sleep and taste disturbance
2.The time to progression to ESRD is
variable, hastened by uncontrolled
hypertension and infection
Chronic glomerulonephritis
(RPGN)
Treatment and prognosis
1.Lowering systemic and glomerular
hypertension, usually with an ACE
inhibitor or ARB
2.Controlling extracellular fluid volume
with water and salt restriction and
diuretics
3.EPO to ameliorate anemia
4.Some patients develop ESRD require
renal replacement with dialysis or
Asymptomatic urinary
abnormalities

Diagnosed when asymptomatic

hematuria or proteinuria uncompanied
by edema, reduced GFR, or
hypertension
 Asymptomatic urinary
abnormalities

Cause:
I.Hematuria with or without proteinuria
a.primary glomerular diseases
1.IgA nephropathy
2.mesangiocapillary glomerulonephritis
3.thin basement membrane disease
b.associated with multisystem or hereditary
1.Alports snydrome
2.fabrys disease
3.sickle cell disease
c. associated with infections
1.poststreptococcal glomerulonephritis
2.other postinfectious glomerulonephritis
Asymptomatic urinary
abnormalities

Cause:
II. Isolated nonnephrotic proteinuria
a.primary glomerular diseases
1.orthostatic proteinuria
2.focal and segmental glomerulonephritis
3.membranous glomerulonephritis
b.associated with multisystem or hereditary
1.diabetes mellitus
2.amyloidosis
3.nail-patella syndrome
Asymptomatic urinary
abnormalities

Diagnosis and differential diagnosis

1.Must be distinguished from a variety of renal
parenchymal and extrarenal causes of
hematuria
2.partivularly important to exclude
malignancy of kidney or urinary tract
3.Other potential diagnosis include vascular,
cystic, tubulointerstitial disease, papillary
necrosis, hypercalciuria and renal calculi,
Asymptomatic urinary
abnormalities

Treatment and prognosis

1.The optimal treatment is a subject of
ongoing debate and controversy.Most
authorities advise observation only in
patients whose GFR is not compromised and
whose proteinuria is < 1.0g/day
2.ACEI are usually prescribed for their
renoprotective effect in patients with more
severe disease
Asymptomatic urinary
abnormalities

Treatment and prognosis

4.Other immunosuppressive agents such as
cyclophosphamide and mycophenolate
mofetil are unproved, which only reserved
for the minority of patients presenting with
nephritic syndrome or RPGN, and with
aggressive crescent formation and marked
glomerular inflammation in renal biopsy
5.Asymptomatic hematuria or proteinuria
typically smolders for decades, with patients
often suffering exacerbation of hematuria