Glomerular diseases

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Glomerular diseases

• 1. Normal anatomy
• 2. Pathogenesis
  21 Hypersensitivity reactions
  22 Pathogenetic mechanisms
  of glomerular diseases
  23
  Mechanisms of vascular injury

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1 Normal
anatomy Fig. 1 Anatomy of the glomerulus and the
juxtaglomerular apparatus
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Fig. 2 A podocyte surrounding a glomerular
capillary All three layers
(endothelium, glomerular basement membrane, slit
pores between podocytes) are negatively charged
Mesangium is contractable ? F
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Fig. 3 Glomerular basement membrane (GBM)
GBM
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2 Pathogenesis 21 Hypersensitivity
reactions Mast cells covered with IgE
antibodies bind parasite antigens ? inflammatory
response, attraction of eosinophils ? killing
worms
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Type I Immediate hypersensitivity
(anaphylaxis) 1st exposure to antigen ?
production of specific AB ? their binding
to mast cells (sensitization). Next
exposure ? allergen degranulates mast
cells ? release of histamine (immediate
response) ? ?vascular permeability, ?airways,
hives, conjunctivitis, rhinitis. Later
? leukotriens, prostaglandins, PAF,
proteases (late phase) ? localized anaphylaxis
atopy (asthma,
hay fever, eczema, hives)

systemic anaphylaxis circulatory shock,

dyspnea, laryngospasm Ts activity ?
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Type II Antibody-dependent cellular cytotoxicity
(ADCC) Cell-mediated cytotoxicity that requires
prior binding of antibodies to target
cells K(iller) cells Lymphocyte-like cells (not
B or T) that kill a variety of tumor cells and
virus-infected cells but only after previous
immunization Errant or uncontrolled plasma cells
produce antibodies against selfantigens Drugs
combine with body antigens (e.g., on
erythrocytes) anchor and activate K-cells ?
ADCC AB attach to the
surface of cells, bind
(via Fc receptors) and activate GBM etc.
neutrophils
and macrophages
activate complement cascade
damage of the cells, GBM etc.


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Type III Immune-complex-mediated-hypersensitivity
Fig. 4 Immunologic reactions after injection
of heterologous protein
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ANTIGEN EXCESS ? SMALL COMPLEXES
(PERSISTENT INFECTION,
AUTOIMMUNITY, REPEATED CONTACT WITH ENVIRON-
MENTAL ANTIGEN)
DEFECT IN SYSTEMS REMOVING IMMUNE
COMPLEXES (PHAGOCY- TES COMPLEMENT)
?
? CLEARANCE OF COMPLEXES
?
THEIR DEPOSITION IN TISSUES
?
ACUTE INFLAMMATORY RESPONSE
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Deposition of complexes may reflect hemodynamic
factors (glomeruli) Type IV Cell-mediated
immune injury delayed-type hypersensitivity Res
istant (intracellular) bacterium, foreign tissue
etc. ? activation of TH cells ? ? TC, ?angry
macrophages, ?K cells, ?N(atural) K(iller) cells
(do not require prior immunization) ?
indiscriminate phagocytosis, exudation ?
granulomatous inflammation, contact dermatitis,
transplant rejection 22 Pathogenetic mechanisms
of glomerular diseases Three typical syndromes
nephritic, nephrotic and chronic
glomerulonephritis
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Fig. 5 Etiology of glomerular injury - survey
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Histology May not correlate with the clinical
presentation Fig. 6, 7 Various
histological types of glomerulonephritis
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B Minimal changes GN lipoid nephrosis some
mesangial proliferation, edematous podocytes,
fusion (loss) of their foot processes C
Intracapillary mesangial proliferative GN
proliferation of endothelia and mesangium,
peeling off of enthelial cells from the GBM,
duplication of GBM, humps formed by
immunocomplexes D Crescentic GN proliferation
of all components (aggressive white cells, endo-
and epithelia, mesangium, epitheloid and giant
cells), leakage of fibrin. Hypersensitivity
reaction type II or IV E Membranous GN
Precipitation of immunoglobulins on the outer
surface of the GBM (spikes ? complete
incorporation of Ig into the membrane) F
Proliferative sclerotizing GN advanced mesangial
proliferation ? narrowing and destruction of
capillaries
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221 Visceral epithelial cell ( podocyte)
injury Minimal change disease lipoid
nephrosis (Fig. 7 B)
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Focal segmental glomerulosclerosis
(FGS) Focal ?50 of glomeruli
are affected by light microscopy
Diffuse ?50 affected Segmental
only a part of the glomerular tuft is involved
Glomerulosclerosis obliteration of
capillary lumens Nephrotic syndrome.
Edematous podocytes, fusion (loss) of
their foot processes. Unclear
podocyte damaging toxin some lymphokine? React
on glucocorticoids
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222 Immune complex formation immune complex
disease Glomerulus is highly susceptible to the
entrapment or formation of immune
complexes Detection electron microscopy,
immunofluorescence (granular appearance) Location
of the complexes ? type of injury and clinical
manifestations Fig. 8 Porosity versus
permeability
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2221 Subepithelial deposits Fig. 9 left
side
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Circulating complexes cannost pass through GBM ?
in situ immune complex formation -
circulating cationic antigen, afterwards enter
the corresponding antibodies -
filtered autoantibody antigen present in situ
(glycoprotein on podocyte cell
membrane).
CATIONIC ANTIGEN
AUTOANTIBODIES
POSTINFECTIOUS GN
(MOSTLY A, ?-HEMOLY-
TIC STREPTOCOCCI)
HUMPS (FIG. 6C)
AMORPHOUS DEPO- SITS ? MEMBRANOUS NEPHROPATHY.
SPIKES (FIG. 6E)
SYSTEMIC DISEASES LUPUS NEPHRITIS HEPATITIS B
IDIOPATHIC
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Injury to the podocytes membrane attack complex
C5b-9 ? fusion of the foot processes Clinical
manifestations of exclusively subepithelial
deposits typically nephrotic. Distortion
of slit diaphragms ? proteinuria
Activated complement is not in contact with
circulating inflammatory cells ?
lack of inflammatory cell
infiltration ? proteinuria lasts for a long time
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Nephrotic syndrome Fig. 10 Pathogenesis of
symptoms
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2222 Subendothelial and mesangial
deposits Fig. 9 right side
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Typically caused by passive entrapment
of preformed circulating immune complexes. The
nature of the antigen ? whether subepithelial or
subendothelial deposition Lupus
nephritis Postinfectious GN Streptococci,
bacterial endocarditis, hepatitis B,
malaria Berger Schönlein-Henoch Inflammatory
response - Complexes in contact with
circulation generate C3a and C5a -
Activation of Hageman factor ? ?coagulation
cascade - Damaged endothelium ?
cytokines and autocoids (local hormones) ?
?adhesion molecules ? activation of endothelial
and inflammatory cells
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• Clinical manifestations inflammatory and
  proliferative response ? typically nephritic
  syndrome
• active urine sediment red cells, white cells,
  cellular and granular casts
• ?GFR
• Recovery more rapid, but severe inflammation ?
  irreversible cell injury ? glomerulosclerosis
• Hypersensitivity reaction type III

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Nephritic diseases (Survey, Fig. 11)
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Fig. 12 Mechanisms causing reduction of GFR in
the nephritic syndrome
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223 Antibodies directed against GBM
antigens Antigen noncollagenous portion of the
?3 chain of type IV collagen Complement and
mediators ? focal glomerular necrosis, crescent
formation ? end-stage renal failure Anti-GBM
antibodies bind in a linear pattern to the GBM
(without electronoptically dense
deposits) Hypersensitivity reaction type
II Goodpasture syndrome
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224 Crescent formation and cell-mediated
immunity Fig. 6D
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• Severe damage of capillary wall ? leaks (rents)
  in GBM ? fibrinogen and other plasma components
  enter Bowmans space
• Crescents accumulation and proliferation of
  extracapillary cells
• ? compression of the glomerular tuft ? rapid
  renal failure
• Crescentic glomerulonephritis (?50 glom.) ?
  rapidly progressive GN
• Etiology
• any severe GN
• anti-GBM antibody disease
• ANCA-positive disorders
• Hypersensitivity reaction type II or IV (?)
• 225 Alport syndrome
• Congenital defect of collagen

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23 Mechanisms of vascular injury 231 Systemic
vasculitis and antineutrophil cytoplasmatic
antibodies Acute systemic process of arteries.
- Large vessel arteritides, e.g.
polyarteritis nodosa ? distal
glomerular ischemia (no inflammation) ? ?GFR
- Glomerular tuft, e.g. polyarteritis
nodosa, Wegeners granulomatosis ?
focal glomerular necrosis, crescents,
active urine sediment Novel circulating
autoantibody antineutrophil cytoplasmic
antibody ANCA Highly specific for
systemic necrotizing vasculitides ANCA ?
respiratory burst of phagocytic cells ? release
of free radicals ? degranulation ? injury to
endothelial cells
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232 Thrombotic microangiopathies Injured
endothelial cell loses its natural
thromboresistance ? platelet activation ? thrombi
in the lumen ? possibly fibrinoid necrosis and
fibrin deposition into media Hemolytic-uremic
syndrome thrombocytopenia, microangiopathic
hemolytic anemia, ?renal function Pathogenesis
- verotoxin-producing Escherichia coli ?
damage to endothelia (infantile
diarrhea) also immunosuppresives and
chemotheraputics - ?Willebrand factor ?
?platelet aggregation autoantibody
against inhibitors of platelet aggregation
- antibody-mediated endothelial injury in
hyperacute renal transplant rejection
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Hematuria, azotemia, hypervolemia. Mild to
moderate proteinuria Primary and secondary
(systemic with renal involvement) diseases The
majority is of immunologic etiology
hypersensitivity reactions type II or III
Local glomerular inflammation ? breaking
filtration membrane
? ?porosity,
hematuria,
proteinuria
blocking
of glomerular
capillaries ?
?permeability
? hypervolemia,
uremia Membranous GN (type E) ?
proteinuria, rather slow Proliferating GN
(type C and D) ? hypertension, more acute