Glomerular Structure and Mechanisms of Disease

Question 1

Name 9 places in a glomerulus that disease can be located.

Answer 1

1. Arterioles 2. Capillaries
2. Subendothelial 4. GBM
3. Subepithelial 6. Slit pore diaphragm
4. Podocytes 8. Bowman space/capsule
5. Mesangium

Question 2

Name 8 primary glomerular diseases.

Answer 2

1. Minimal change disease
2. Focal segmental glomerulosclerosis
3. Membranous nephropathy
4. Acute post-streptococcal glomerulonephritis
5. Membranoproliferative glomerulonephritis
6. IgA nephropathy (Berger disease)
7. Hereditary nephritis (Alport syndrome)
8. Congenital nephrotic syndrome

Question 3

Name 5 secondary glomerular diseases.

Answer 3

1. Hypertensive nephropathy
2. Diabetic nephropathy
3. Lupus nephritis
4. Amyloidosis
5. Goodpasture syndrome

Question 4

Name the three most common types of glomerular disease.

Answer 4

1. Hypertensive
2. Diabetic
3. Immune-mediated

Question 5

What do supra-normal glomerular capillary pressures result in?

Answer 5

GBM thickening
Mesangial cell hypertrophy/hyperplasia,
Mesangial matrix production
Hyaline sclerosis of afferent arterioles

Question 6

What is the term for global sclerosis of glomeruli?

Answer 6

Arterionephrosclerosis

Question 7

Why is arterionephrosclerosis more common in African Americans?

Answer 7

Mutation of apolipoprotein L1 (normally confers Trypanosoma resistance)

Question 8

What two conditions are a mutation in apoL1 associated with?

Answer 8

Arterionephrosclerosis

Focal segmental glomerulosclerosis

Question 9

What are the symptoms/signs of malignant hypertension?

Answer 9

BP > 200/120
Headache
Hematuria / Proteinuria
Scotomas
Vomitting
Onion-skin appearance (proliferation of intimal cells in arteries; hyperplastic arteriosclerosis)

Question 10

What does malignant hypertension produce?

Answer 10

Fibrinoid necrosis of arterioles

Question 11

What category of disease does injury to glomerular capillary endothelium cause?

Answer 11

Thrombotic microangiopathies

Question 12

What are the layers of the glomerular basement membrane?

Answer 12

Lamina rara (or lucida) interna
Lamina densa (double usual thickness)
Lamina rara externa

Question 13

What are the major components of the basement membrane?

Answer 13

Type IV collagen
Perlecan
Entactin
Fibronectin
Laminin

Question 14

What is the composition and function of perlecan?

Answer 14

Highly charged proteoglycan w/ heparan sulfate keeps proteins (ie albumin) from being filtered

Question 15

What is the function of entactin?

Answer 15

Glycoprotein with calcium binding properties

Question 16

What is the function of fibronectin?

Answer 16

Glycoprotein binds collagen, heparan sulfate, and integrins

Question 17

What is the function of laminin?

Answer 17

Binds collagen, entactin, heparan sulfate, and cells (integrins)

Question 18

What heterotrimers are present in adult type IV collagen?

Answer 18

alpha3, alpha4, alpha5

alpha5, alpha5, alpha6

Question 19

What is a cause of glomerulonephritis with hematuria?

Answer 19

Antibody against epitope in the NC1 domain of the alpha3 chain

Question 20

Which gender has a thicker glomerular basement membrane?

Answer 20

Men

Question 21

Which gender has a higher incidence of anti-GBM disease?

Answer 21

Men

Question 22

What happens to podocytes during nephrotic syndrome?

Answer 22

Effacement

Question 23

What causes crescentic glomerulonephritis and what is the pathology?

Answer 23

Nephrotic syndrome with inflammatory stimuli lead to proliferation of parietal epithelial cells

Question 24

Name 4 proteins involved in the slit pore diaphragm.

Answer 24

Cadherin and FAT - bind adjacent pedicles

Nephrin and podocin - play a role in filtration

Question 25

What is a potential cause of congenital nephrotic syndromes?

Answer 25

Mutations in nephrin and podocin

Question 26

What causes IgA nephropathy?

Answer 26

Reduced glycosylation in the hinge region of IgA1

Question 27

What can IgA form immune complexes with?

Answer 27

IgA IgG Fibronectin CD89 (soluble IgA receptor)

Question 28

What do the immune complexes bind to that triggers phagocytosis?

Answer 28

CD71 (transferrin receptor on mesangial cells)

Question 29

What produces the injurious inflammation in IgA nephropathy?

Answer 29

Complement activation | 75% Alternative - 25% Lectin

Question 30

Define deposited and in situ immune complexes.

Answer 30

Deposited - originated in circulation | In situ - formed in glomerulus

Question 31

Define intrinsic and planted antigens.

Answer 31

Intrinsic - fixed in glomerulus | Planted - from circulation

Question 32

What mechanisms typically cause damage in immune-mediated glomerular disease?

Answer 32

Complement activation and leukocyte mechanisms

Question 33

How do leukocytes cause glomerular injury?

Answer 33

Lysosomal proteases ROS Arachidonic acid metabolites

Question 34

How do platelets cause glomerular injury?

Answer 34

Aggregation | Arachidonic acid metabolites

Question 35

How do endothelial cells cause glomerular injury?

Answer 35

``` Cytokines (IL-1) Arachidonic acid metabolites Growth factors Nitric oxide Endothelin ```

Question 36

How do glomerular epithelial and mesangial cells cause glomerular injury?

Answer 36

Cytokines (IL-1) Arachidonic acid metabolites Growth factors

Question 37

What is a hallmark histopathology of lupus nephritis?

Answer 37

Subendothelial deposits thickening capillary walls that resemble "wire loops."

Question 38

What location do poststreptococcal glomerulonephritis antigens plant?

Answer 38

Subepithelium (characteristic "humps")

Question 39

What do antibodies against phospholipase A2 receptors of podocytes cause?

Answer 39

Membranous glomerulonephritis

Question 40

What are the antibodies in post-streptococcal glomerulonephritis against?

Answer 40

Streptococcal exotoxin B Streptococcal GAPDH Endostroptosin

Question 41

What three forms of microscopy are needed to diagnose kidney immune complex disease?

Answer 41

Light microscopy Immunofluorescence Electron microscopy

Question 42

What stains are used in light microscopy when studying immune glomerular disease?

Answer 42

H&E Jones methenamine silver (GBM) periodic acid Schiff (cytoplasmic inclusions) trichome (collagen)

Question 43

The largest subset of crescentic glomerulonephritis is described as what?

Answer 43

Pauci-immune (typically ANCA+)

Question 44

What are P-ANCA and C-ANCA associated with?

Answer 44

P-ANCA - microscopic polyangiitis or Churg-Strauss syndrome | C-ANCA - granulomatous with polyangiitis or Wegener's

Question 45

What does hyperglycemia cause in the blood and GBM?

Answer 45

Glycosylation of proteins Thickening of GBM Deposits on GBM

Question 46

What causes the characteristic effect of diabetes mellitus on organs throughout the body?

Answer 46

Metabolization of glycosylated proteins to advanced glycation end-products (AGE)

Question 47

What activate/induce NADPH oxidases (producing ROS)?

Answer 47

Advanced glycation end-products (AGE) Advanced oxidation protein products (AOPP) Renin Angiotensin System (RAS) TGF-beta

Question 48

What does activated NADPH oxidases (and ROS) cause in the kidney?

Answer 48

Mesangial cell hypertrophy / hyperplasia Mesangial matrix production Podocyte injury / apoptosis

Question 49

What does hypertension cause in the glomerulus?

Answer 49

GBM thickening Mesangial cell hypertrophy / hyperplasia Mesangial matrix production