Glomerular Structure and Mechanisms of Disease Flashcards
Name 9 places in a glomerulus that disease can be located.
- Arterioles 2. Capillaries
- Subendothelial 4. GBM
- Subepithelial 6. Slit pore diaphragm
- Podocytes 8. Bowman space/capsule
- Mesangium
Name 8 primary glomerular diseases.
- Minimal change disease
- Focal segmental glomerulosclerosis
- Membranous nephropathy
- Acute post-streptococcal glomerulonephritis
- Membranoproliferative glomerulonephritis
- IgA nephropathy (Berger disease)
- Hereditary nephritis (Alport syndrome)
- Congenital nephrotic syndrome
Name 5 secondary glomerular diseases.
- Hypertensive nephropathy
- Diabetic nephropathy
- Lupus nephritis
- Amyloidosis
- Goodpasture syndrome
Name the three most common types of glomerular disease.
- Hypertensive
- Diabetic
- Immune-mediated
What do supra-normal glomerular capillary pressures result in?
GBM thickening
Mesangial cell hypertrophy/hyperplasia,
Mesangial matrix production
Hyaline sclerosis of afferent arterioles
What is the term for global sclerosis of glomeruli?
Arterionephrosclerosis
Why is arterionephrosclerosis more common in African Americans?
Mutation of apolipoprotein L1 (normally confers Trypanosoma resistance)
What two conditions are a mutation in apoL1 associated with?
Arterionephrosclerosis
Focal segmental glomerulosclerosis
What are the symptoms/signs of malignant hypertension?
BP > 200/120 Headache Hematuria / Proteinuria Scotomas Vomitting Onion-skin appearance (proliferation of intimal cells in arteries; hyperplastic arteriosclerosis)
What does malignant hypertension produce?
Fibrinoid necrosis of arterioles
What category of disease does injury to glomerular capillary endothelium cause?
Thrombotic microangiopathies
What are the layers of the glomerular basement membrane?
Lamina rara (or lucida) interna Lamina densa (double usual thickness) Lamina rara externa
What are the major components of the basement membrane?
Type IV collagen Perlecan Entactin Fibronectin Laminin
What is the composition and function of perlecan?
Highly charged proteoglycan w/ heparan sulfate keeps proteins (ie albumin) from being filtered
What is the function of entactin?
Glycoprotein with calcium binding properties
What is the function of fibronectin?
Glycoprotein binds collagen, heparan sulfate, and integrins
What is the function of laminin?
Binds collagen, entactin, heparan sulfate, and cells (integrins)
What heterotrimers are present in adult type IV collagen?
alpha3, alpha4, alpha5
alpha5, alpha5, alpha6
What is a cause of glomerulonephritis with hematuria?
Antibody against epitope in the NC1 domain of the alpha3 chain
Which gender has a thicker glomerular basement membrane?
Men
Which gender has a higher incidence of anti-GBM disease?
Men
What happens to podocytes during nephrotic syndrome?
Effacement
What causes crescentic glomerulonephritis and what is the pathology?
Nephrotic syndrome with inflammatory stimuli lead to proliferation of parietal epithelial cells
Name 4 proteins involved in the slit pore diaphragm.
Cadherin and FAT - bind adjacent pedicles
Nephrin and podocin - play a role in filtration
What is a potential cause of congenital nephrotic syndromes?
Mutations in nephrin and podocin
What causes IgA nephropathy?
Reduced glycosylation in the hinge region of IgA1
What can IgA form immune complexes with?
IgA
IgG
Fibronectin
CD89 (soluble IgA receptor)
What do the immune complexes bind to that triggers phagocytosis?
CD71 (transferrin receptor on mesangial cells)
What produces the injurious inflammation in IgA nephropathy?
Complement activation
75% Alternative - 25% Lectin
Define deposited and in situ immune complexes.
Deposited - originated in circulation
In situ - formed in glomerulus
Define intrinsic and planted antigens.
Intrinsic - fixed in glomerulus
Planted - from circulation
What mechanisms typically cause damage in immune-mediated glomerular disease?
Complement activation and leukocyte mechanisms
How do leukocytes cause glomerular injury?
Lysosomal proteases
ROS
Arachidonic acid metabolites
How do platelets cause glomerular injury?
Aggregation
Arachidonic acid metabolites
How do endothelial cells cause glomerular injury?
Cytokines (IL-1) Arachidonic acid metabolites Growth factors Nitric oxide Endothelin
How do glomerular epithelial and mesangial cells cause glomerular injury?
Cytokines (IL-1)
Arachidonic acid metabolites
Growth factors
What is a hallmark histopathology of lupus nephritis?
Subendothelial deposits thickening capillary walls that resemble “wire loops.”
What location do poststreptococcal glomerulonephritis antigens plant?
Subepithelium (characteristic “humps”)
What do antibodies against phospholipase A2 receptors of podocytes cause?
Membranous glomerulonephritis
What are the antibodies in post-streptococcal glomerulonephritis against?
Streptococcal exotoxin B
Streptococcal GAPDH
Endostroptosin
What three forms of microscopy are needed to diagnose kidney immune complex disease?
Light microscopy
Immunofluorescence
Electron microscopy
What stains are used in light microscopy when studying immune glomerular disease?
H&E
Jones methenamine silver (GBM)
periodic acid Schiff (cytoplasmic inclusions)
trichome (collagen)
The largest subset of crescentic glomerulonephritis is described as what?
Pauci-immune (typically ANCA+)
What are P-ANCA and C-ANCA associated with?
P-ANCA - microscopic polyangiitis or Churg-Strauss syndrome
C-ANCA - granulomatous with polyangiitis or Wegener’s
What does hyperglycemia cause in the blood and GBM?
Glycosylation of proteins
Thickening of GBM
Deposits on GBM
What causes the characteristic effect of diabetes mellitus on organs throughout the body?
Metabolization of glycosylated proteins to advanced glycation end-products (AGE)
What activate/induce NADPH oxidases (producing ROS)?
Advanced glycation end-products (AGE)
Advanced oxidation protein products (AOPP)
Renin Angiotensin System (RAS)
TGF-beta
What does activated NADPH oxidases (and ROS) cause in the kidney?
Mesangial cell hypertrophy / hyperplasia
Mesangial matrix production
Podocyte injury / apoptosis
What does hypertension cause in the glomerulus?
GBM thickening
Mesangial cell hypertrophy / hyperplasia
Mesangial matrix production
