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Glomdis - Ganlin
Glomdis - Ganlin
Glomdis - Ganlin
Vasculitis
Clinical manifestation of GN
initiation hematuria proteinuria Edema,hyp Renal
ertention failure
Acute GN acute 100% 100% frequent resumable
Nephrotic syntrome
Minor glomerular abnormalities
Membranous nephropathy
Mesangial proliferative
glomerulonephritis
endocapillary proliferative
glomerulonephritis
Diffuse proliferative glomerulonephritis Mesangial capillary
glomerulonephritis
Crescentic and necrotizing
glomerulonephritis
Sclerosing glomerulonephritis
Immunopathologic mechanisms
Mechanisms:
Damage by immunocomplexes
Damage by cytotoxic antibodies (Ab)
Cell-mediated immune injury = delayed-type
hypersensitivity
Damage by complement and proinflammatory mediators
Cytotoxic (Type II) reaction
– antibody mediated cytotoxicity (ADCC)
These occur when antibodies interact
with antigens found on cell
surface
2 mechanisms of cytotoxicity:
inflammation
Glomerular diseases
• Immune mechanisms
deposits of immuno- complex(IC)
antigen+antibody
kidney deposits
• Extrinsic
drug:nonhomologous serum,penicilin
Foods:xenogenic protein
Pathogens:specific serotypes streptococci,HBV,HCV
• Intrinsic
Nucleus(SLE)
Cytoplasm(ANCA)
Cellular membrane
Antigen of tumor
Antigen of thyroid
Why does IC deposit in the glomeruli
• Persistence of antigen
• Clearance dysfunction of mesangial cells
• Disability of mononuclear macrophage
• Component or function defect of
complements
IC deposit>clearance
• Non immune mechanisms
Glomerular hypertension
Hyperlipidemia(LDL-Cho)
Advanced glycosylation end products
protein
glomerulosclerosis
inflammation
• Mediators of inflammation
A group of molecules which act as mediators of
inflammation and complicated biological function
• Original mediators in kidney
Extrinsic cells in kidney
Infiltrative neutrophil,lymphocyte,mononuclear
macrophage,platelet
intrinsic cells in kidney
Mesangial cells,tubular cells,endothelial cells
Mediators of inflammation
• Active oxygen and active nitrogen
• Lipids
• Complements
• Cytokines
• Adhension molecules
• Growth factors
• Vasoactive substances
Effects of inflammation
mediators
• To arouse or promote
Proliferation of cells
Accumulation of extracellular matrix
Changes of histological structure
Expression of immunomodulating
molecules and adhension molecules
Mechanism of primary GN
Immune Non immune
Essential in the progressive period
Essential in the initiation
inflammation
Inflammation cells
Inflammation mediators
Active oxygen and active nitrogen,cytokines,growth factors,chemotatic factors,
complments,vasoactive subtances,coagulation and fibrolysis system,enzyme
Glomerular injuries
Sites of pathological changes
• Mesangium
mesangial cell
mesangial matrix
• Basement membrane
Podocyte
Endothelial cell
Pathogenesis
Normal glomerular structure
• Glomerular tuft composed 4 major components
– Endothelial cells
– Visceral epithelial cells or Podocytes
– Mesangium
– Capillary loop basementmembrane
• Capillary wall
– carries a net negative charge
– acts as both
– charge-selective
– size-selective filter
Glomerular capillary wall:
Size selective filter
The capillary wall restricts the passage of large molecules into Bowman's space, while
there is less restriction of smaller molecules.
As radii increase, filtration decreases, approaching zero at radii > 4.2 nm
Glomerular capillary wall:
Charge-Selective Filter
The capillary wall restricts the passage of negatively charged molecules such as albumin
while neutral substances pass more freely and are restricted by size from passing into
Bowman's space.
Pathological changes
• LM
Mesangial cells,matrix of mesangium
Endothelial cells
Epithelial cells
Basement membrane
Loops of glomeruli
• EM ( Electron microscope )
• Foot process
Basement membrane
Hyperplasy of mesangium(electron dense deposits)
• IF
Sites,appearances,type of deposits ( IG or C )
Basical changes
• Proliferation
• Fibrosis and sclerosis
• Necrosis
• Infiltration of inflammation cells
Extents of injury
• Primary GN:glomerular injury-only or dominating
injury
• Secondary GN: glomerular injury-a part of systematic
diseases
• Diffuse:impaired glomeruli>50%
• Focal: impaired glomeruli>50%
• Global:impaired capillary loops of a glomerule>50%
• Segmental:impaired capillary loops of a
glomerule<50%
Pathological types of primary
GN
• Minimal change of glomerulonephritis
• Focal segmental lesions
• Diffuse glomerulonephritis
• Unclassified glomerulonephritis
Minimal Change Disease (MCD)
• Most common cause of nephrotic syndrome in childhood
– In a prospective study of untreated children with N.S.:
• minimal change disease was found in 76.6%.
• Only 10% to 30% of adult cases of nephrotic syndrome
– Percentages vary in different parts of the world
• The clinical onset of nephrotic syndrome associated with:
– upper respiratory infection
– with routine prophylactic immunizations
– Other genetic and environmental factors may also be
important
Morphologic Features (LM & IF)
• LM: focal and segmental glomerular sclerosis with capillary loop collapse, hyaline and lipid deposition and often adhesion to Bowman's capsule
– The remainder of the glomerular tuft is normal in appearance; thus the term 'segmental'. The lesions are considered to begin or to be more common near the corticomedullary junction.
• IF: Deposition of IgM and C3 in the mesangium or in the areas of segmental sclerosis may be seen, but no immune complex deposition is present.
• EM: effacement of podocyte foot processes. Podocyte denudation may be present focally as an early lesion, and segmental sclerosis may also be seen
Clinical Course
• FSGS may be :
– primary (idiopathic)
– secondary to a number of etiologic agent :
• Unilateral renal agenesis
• Renal ablation
• Sickle cell disease
• Morbid obesity (with or without sleep apnea)
• Congenital cyanotic heart disease
• Heroin nephropathy
• HIV nephropathy
• Aging kidney
Membranous Glomerulonephritis ( MG
N)
• Antibody mediated disease
– ICs localize to subepithelial of the capillary loop
• between outer aspect of GBM and podocyte
• Immune complexes
– develop in situ
– deposition of circulating ICs (less likely)
– antibody may bind to
• intrinsic glomerular antigen
• exogenous antigen planted on the capillary wall
– Serum complement level was normal
Clinical Manifestation
• more common in adults (peak 40-50 y/o)
• mostly older than 30 years at diagnosis
• 35-50% of cases of adult nephrotic syndrome
• Most patients present with:
– heavy proteinuria: most commonly in nephrotic
range
– insidious in onset
– few patients accompanying microscopic hematuria
Morphologic Features
LM
Electron microscopy
• Proteinuria
Urinary protein test—positive
Urinary protein excretion
rate>150mg/24h
• Quantity:
• Mild:<1.5g/d
• Moderate:1.5-3.5g/d
• Severe:>3.5g/d
• Hematuria
RBC>3/HP(fresh,10ml/sample,1500rmp
centrifuge for 5min,sediment observation)
• Gross hematuria
Red color of urine,1ml blood/1L urine
RBC from glomeruli
Dismorphic RBC
Phase contrast
microscopy Urinary RBC volume distribution curve
Dismorphic Dissymmetry curve
RBC>50%,hypothesis MCV of urinary
of glomerular bleeding RBC<that in blood
Dismorphic
RBC>50%,final
diagnosis of glomerular
bleeding
edema
Glomerular diseases
edma
Vessoactive substances
dependent
hypertension
Clinical types of GN
• Glomerulonephropathy
Confined concept
Leading manifestation: proteinuria /hematuria
Extensive concept
Glomerular diseases
• Glomerulonephritis
Leading manifestation:hematuria /proteinuria
Clinical manifestation of GN
initiation hematuria proteinuria Edema,hyp Renal
ertention failure
Acute GN acute 100% 100% frequent resumable
• Etiology:streptococcus
others:bacteria
viruses
parasites
• antigen:components of cytoplasm/ membrane
• frequently CIC
•
Pathological changes
• Endocapillary proliferative GN
Acute phase
Proliferation of endothelial
/mesangium
Recovery phase
Only mesangium
proliferation,sometimes minor injure
Clinical manifestation
• Epidemiology:primarily children,sometimes
adult/aged
• Preliminary infection
Frequently tonsillitis,upper respiratory
infection
• Latent period:1-3w
Occasionally skin infection
Latent period:longer,less than 4w
Nephritis syndrome
• Points:
• Preliminary infection/latent period
• Acute onset
• Surely hematuria,frequently edema and
hypertention
• ASO↑c3↓--dynamic change
• Self limitation
Indications of renal biopsy
• Oligouria>1w,except
ECBV,insufficient,urinary tract
obstruction,etc
• Progressive renal failure
Unresolved in 2 months
Untypical manifestation,or with NS
treatment
• Supportive treatment
• Rest
• Food and water
• Restrictive intake of NaCL<5g/d
If moderate to severe edema or hypertention
• Water
If decreased urine volumn
• Protein
Renal failure,but not dialysis yet
Treatment of infection
• Penicilin for 2w
• Tonsillectomy if recurrent attacks of tonsillitis
• Patient is stable:U pro<1g/d,Urbc<10/HP
• Penicilin for 2w before and after the surgery
• Symptomatic treatment
Diuresis
Antihypertention
dialysis
prognosis
• Hematuria,proteinuria
Usually reduce in one month,resolve in
2-3 months
Some resolve in 6-12months
• 1% ARF death
• 6-18% CGN?
Rapidly progressive glumerulonephritis
• Acute onset
• Rapidly progressive
• Renal failure within a few weeks to a few
months
• Acute renal failure-chronic renal failure
Treatment-early!!!
• Renal failure
Balance of fluid,electrolytes and acid
base
Dialysis
• Infection
• hypertension
prognosis
• Hardly relieve
• Mostly CRF-death
• Risk factors:type1 worst,type2 worse,type
3 bad
Treatment:not
progressive,not prompt
Age:the aged
Chronic glomerulonephritis
• Pathological properties
• Treatment
• Hypertension
• Infection,prerenal factors(hypertension
etc)
• Nephrotoxic drugs
Point of diagnosis
• Chronic onset
• proteinuria and/or hematuria
• Protracted and progressive
AGN CGN
age children Young/middle-aged
• SLE:sysmetic presentation
Immune abnormality
Pathological changes
Treatment
• Glucocorticoid
Four major pathogenetic forms of glomerular
injury
In non-proliferative glomerulopathy:
Damage by antibodies
Damage mediate by complement
In proliferative glomerulopathy:
• According imunofluorescence:
Pathogenic mechanisms of glomerular diseases
NEPHRITIC
NEPHROTIC
Chronic
glomerulonephritis
Pathogenesis of nephritic diseases
Histologic pattern
• Various histological
types of
glomerulonephritis
B: “Minimal changes” GN = lipoid nephrosis: some mesangial proliferation,
edematous podocytes, fusion (“loss”) of their foot processes
GN in infection endocarditis
- different etiology:
IgA nefropathy
Nephritis in systemic lupus erythematodes (SLE)
Nephritis in bacterial endocarditis
Henoch-Schölein purpura
Rapidly progressive glomerulonephritis
(RPGN)
Heterogeneous group of diseases, it is characterised by intense proliferation
of glomerular/capsular epithelial cells in the form of a crescent.
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)
Three forms of RPGN
GN with creation of antiobdies (IgG, IgA) agains
GBM (anti-GBM)
- linear deposits of Ig
(+ alveolocapillary BM) Goodpastures´ syndrome
Especially in children
Pathogenesis ambiguous – connection with
viral infections, vaccination, atopy,
application some drugs (antiphlogistics etc.),
Association with several HLA antigens
(DRw7, B8, B12 …)
Therapy: corticoids
Focal (segmental) glomerulosclerosis
Histologic pattern:
WHO classification – normal glomerules (typ I)
- mezangial GN (typ II)
- focal proliferative GN (typ III)
- diffuse proliferative GF (typ IV)
- membranous GN (typ V)
- glomerular sclerosis (typ VI)
Vasculitis
Pathogenesis:
- damage by immunocomplexes
- ANCA (pauciimmune form)
- damage by cells (IV. typ)
Henoch-Schönlein purpura
alterations are similar to finding in IgA nephropathy
Polyarteritis nodosa
Wegener´s granulomatosis
glomerulonephritis
90% of such patients have a positive ANCA
ANCA – react with neutrophils
respiratory burst of phagocytic cells
release of free radicals
degranulation
injury to endothelial cells
Diabetic nephropathy
= diabetic intracapillary glomerulosclerosis (sy Kimmelstielův-Wilsonův)
proliferation of cells
glomerulosclerosis
Alport syndrom
- Hereditar nephritis with deafness (X chromosome)
- Pathogenesis: congenital defect of collag synthesis
GMB very slight or with more layers