B70. Pathogenesis of glomerular disease

Question 1

What are the components of the filtration barrier in the glomerulus, ie what are the structures surrounding the glomerular capillary?

Answer 1

• Fenestrated endothelial cells of the capillary
• The glomerular basement membrane (GBM).
• The visceral epithelial cells also known as podocytes. Podocytes possess interdigitating processes embedded in and adherent to the basement membrane.
• Adjacent foot processes are separated by 20‐30nm wide filtration slits, which are bridged by a thin diaphragm composed in large part of nephrin.

Question 2

What is the more common name for glomerular disease?

What are the different clinical classifications of glomerular disease?

Answer 2

Glomerulonephritis

1. Nephritis syndrome
2. Nephrosis syndrome
3. Rapidly Progressing Glomerulonephritis
4. Asymptomatic hematuria or proteinemia
5. Chronic glomerulonephritis

Question 3

What is the end stage of glomerular disease?

Answer 3

Chronic glomerulonephritis

Question 4

What are the histology/pathology based groups of glomerular disease?

Answer 4

1. Glomerular hypercellularity
   
   • proliferative
     
     • endothelial cells
     • epithelial cells (crescents)
     • mesangial cells
   • infiltrative,
     
     • leukocytes
2. Basement membrane thickening
   
   • linear
   • granular
     
     • subepithelial
     • subendothelial.
3. Sclerosis and hyalinization
   
   • diffuse or focal
   • and
   • segmental or global

Question 5

What are the groups based on immunological manifestation

Answer 5

1. Circulatory Immune Complex GN
2. In-Situ Immune Complex GN
3. Heyman’s nephritis, experimental model of GN.

Question 7

What are the 3 layers of the glomerular basement membrane?

What are its main components?

Answer 7

Lamina Rara Interna

Lamina Densa

Lamina Rara Externa

Collagen 4, laminin, fibronectin, and polyanionic porteoglycans,

Question 8

Describe the pathogenesis of Circulatory Immunce Complex GN

Answer 8

Circulating ICs form as part of a type 3 HSR (antibodies against circulating antigens) and deposit in the glomerulas as granular deposits.

• Large sized IC’s –> deposit in the subendothelium. (bigger, get trapped earlier in the filter)
• Smaller IC’s –> deposit in the supepithelium, or can slip through and deposit in the mesangium.

They cause damage by:

• activating complement system and recruiting leukocytes, causing inflammatory damage.
• Leukocyte Fc receptors binding deposited IC’s and becoming cross linked, activating the leukocyte and causing degranulation irrespective of complement activation.

The leukocyte infiltration and degranulation causes increased permeability, and can cause proliferation of endothelial, mesangial, or parietal epithelial cells (bowman’s capsule cells).

Question 9

Describe the pathogenesis of In-Situ Immune Complex GN

Answer 9

In-situ implies that the complexes form within the glomerulus

two types:

1. Anti-basement membrane nephritis
   
   • antibodies are directed against fixed components of the GBM.
   • produces a linear deposition
   • Anti-collagen IV is the most common type.
     
     • this is the type seen in Goodpasture Syndrome,
     • which also reacts against collagen in alveolar basement membranes of the lung, producing lesions in both the kidney and lungs.
   • Causes:
     
     • Goodpasture syn.
   • Experimental model is Mashugi nephritis, uses rat GBM homogenate to generate antibodies in rabbits, antibodies then injected into rats.
2. Antibodies against planted antigens.
   
   • Circulating antigens that are not of glomerular origin get trapped, planted, in the GBM, and are only then bound by antibodies.
   • It is usually granular, but depending on the antigen can be linear, or mixed.
   • causes
     
     • ​Nucleosomal antigens in SLE
     • Endostroptosin of S. Pyogenes
     • IgG aggregations
   • Experimental model is Heyman’s nephritis, uses proximal tubule brush border antigen to make antibodies.

Question 10

Describe the clinical nephritis syndrome

Answer 10

Acute development of:

• Painless macroscopic hematuria, with dysmorphic RBC casts in urin
• Mild hypertension - from decreased GFR and RAS activation.
  
  • periorbital edema
• Oliguria
• Azotemia
• Mild proteinuria, <3.5 g/day

Is caused by inflammatory leukoctyic infiltration and inflammatory capillary injury, causing increased permeability.

Question 11

What are infections that can cause post-infectious GN?

Answer 11

Group A strep mostly

less commonly:

• S. Pneumo
• S. aureus
• mumps
• measle
• VZV
• HBV
• HCV

Question 12

What are the major types of GN associated with Lupus?

Answer 12

Proliferative GN and Membranous nephropathy.

Question 13

What are major causes of clinical nephritis syndrome?

Answer 13

Note, nephritis syndrome can be caused by either circulating IC GN, or planted in-situ IC GN

Primary glomerulonephritis,

• ie. IgA glomerulonephritis, ie, Berger disease

Postinfectious glomerulonephritis,

• Streptococcus
• Bacterial endocarditis associated GN
• Involves diffuse (all glomeruli are involved) proliferation of mesangial cells and endothelial cells, and in severe cases, bowman epethelial proliferation and crescent formation. ​

Secondary GN associated with systemic disease

• SLE
• Wegener’s granulomatosis
• Goodpasture syndrome

Question 14

What are the clinical symptoms and pathogenesis of Rapidly Progressing Glomerulonephritis?

Answer 14

A clinical syndrome whose symptoms are rapid development of, severe nephritic syndrome, which progresses to acute renal failure in a period of weeks.

• oliguria/anuria
• hematuria
• proteinuria
• hypertension

The common feature is crescent formation due to capillary damage that causes significant fibrin leakage and deposition into bowmans space, which then causes bowmans epithelium to proliferate. This epithelial proliferation, along with monocyte and macrophage invasion produces the crescent that totally occlueds the capsule, which eventually becomes totally atrophic and replaced with scarring.

Question 15

What are the causes of RPGN?

Answer 15

1. Anti-GBM antibody mediated crescentic GN.
   
   • linear deposits of IgG and C3 on the GBM.
   • Seen in goodpasture syndrome.
   • Importantly, Plasmapheresis is effective therapy for anti-GBM antibodies driving RPGN.
   • Crescent proliferation occurs, but mesangial and endothelial proliferation is not significant
2. Immune complex mediated crescentic GN​
   
   • Can occur as a result of any immune complex associated disease,
     
     • SLE,
     • IgA nephropathy
     • Henoch Schonlein purpura
     • unkown cause of IC generation
   • Can be from in situ IC formation against planted antigens, or from circulating antigens
   • Involves crescent, mesangial, and endothelial proliferation.
3. Pauci-immune crescentic GN
   
   • ​​Occurs in the absence of anti-GBM antibodies or immune complex deposition (paucity of imune characteristics)
   • Usually, ANCA antibodies, Anti-neutrophil cytoplasmic antibodies are found in the serum.
   • It is thus often a component of Systemic Vasculitis syndromes
     
     • ​microscopic polyangitis
     • Wegener granulomatosis
   • It can also occur in isolation of these syndromes and is called idiopathic pauci-immune crescentic GN.

Question 16

Morphology of end stage kidney disease, chronic glomerulonephritis.

Answer 16

Classically, the kidneys are symmetrically contracted,
and their surfaces are red-brown and diffusely granular
when the underlying disorder affects blood vessels or glomeruli.
Kidneys damaged by chronic pyelonephritis are typically
unevenly involved and have deep scars. Microscopically,
the feature common to all cases is advanced scarring of the
glomeruli, sometimes to the point of complete sclerosis (Fig.
13–20). This obliteration of the glomeruli is the end
point of many diseases, and it is impossible to ascertain from

such kidneys the nature of the initial lesion. There is also
marked interstitial fibrosis, associated with atrophy and
dropout of many of the tubules in the cortex, and diminution
and loss of portions of the peritubular capillary network. The
small and medium-sized arteries frequently are thick-walled,
with narrowed lumina, secondary to hypertension. Lymphocytic
(and, rarely, plasma cell) infiltrates are present in the
fibrotic interstitial tissue. As damage to all structures progresses,
it may become difficult to ascertain whether the
primary lesion was glomerular, vascular, tubular, or interstitial.
Such markedly damaged kidneys have been designated endstage
kidneys.

Question 17

What disease is associated with linear antibody deposition in RPGN?

Answer 17

Goodpasture syndrome, anti-GBM antibodies

Question 18

What diseases are associated with granular deposition in RPGN?

Answer 18

Post-Strep GN

Diffuse proliferative glomerulonephritis, see nin SLE

Question 19

What disease cause a negative IF staining on the GBM in RPGN?

Answer 19

Wegener granulomatosis,

microscopic polyangitis

Churg-Strauss syndrome