Robbins Basic Pathology: Pathogenesis of glomerular injury and disease

Question 1

What is the most common cause of chronic kidney disease in humans?

Answer 1

Chronic glomerulonephritis

Question 2

What are the structures of the glomerulus?

Answer 2

(1) Fenestrated vascular endothelium (70-100nm)
(2) Basement membrane composed of laminia rara interna, lamina densa, and lamina rara externa.
(3) Visceral epithelium (podocytes) with interdigitating foot processes
(4) Mesangial cells and matrix.

Question 3

What protein makes up the major part of the filtration slit diaphragm?

Answer 3

Nephrin

Question 4

What is glomerular barrier function?

Answer 4

The ability of the glomerulus to be permeable to water and small uncharged particles and yet to be impermeable to larger and negatively charged particles such as albumin.

Question 5

What makes the glomerulus impermeable to negatively charged particles?

Answer 5

negatively charged glycoproteins (heparan sulfate) in the GBM prevent the filtration of negatively charged particles.

Question 6

What are secondary glomerular diseases?

Answer 6

Systemic diseases that also happen to affect the kidney.

Question 7

What are primary glomerular diseases?

Answer 7

Diseases in which the kidney is the only or the primary organ affected by the disease.

Question 8

What has been shown to induce glomerulonephritis experimentally?

Answer 8

Antibodies and glomerular deposits of immunoglobulins can cause glomerulonephritis.

Question 9

What are the two categories of antibody associated glomerular injury?

Answer 9

(1) deposition of circulating antibody antigen complexes

(2) In situ reaction of antibodies with intrinsic glomerular antigen or antigen seeded in the glomerulus.

Question 10

What are the three types of glomerulonephritis caused by circulating immune complex?

Answer 10

The antigen is not of glomerular origin, it may be

1) endogenous (as in SLE
(2) Exogenous (post-infection)
(3) idiopathic

Question 11

What causes most of the damage seen in GN?

Answer 11

Activation of complement and recruitment of leukocytes by immune complexes leads to damaging inflammation.

Question 12

Where can immune complexes be deposited?

Answer 12

(1) Sub-endothelial
(2) Sub-epithelial
(3) mesangial matrix.

Question 13

What is the prototypical disease caused by in situ immune complex formation?

Answer 13

Anti-GBM glomerulonephritis. Often caused by Goodpastures syndrome.

Question 14

What pattern of immunoflourescent staining is seen in anti-GBM GN?

Answer 14

linear pattern of immunoflourescense

Question 15

What GBM antigen is often responsible for anti-GBM GN?

Answer 15

The alpha-3 non-collagenous domain of type IV collagen is often the antigen bound by anti-GBM antibodies. This is also present in the lung alveoli, thus goodpastures syndrome affects the lung and the kidney.

Question 16

Inflammatory reactions with glomerular infiltration of leukocytes is ellicited by immune complex deposition in what locations?

Answer 16

The endothelium and sub-endothelium

Question 17

Non-inflammatory lesions such as membranous nephropathy are usually caused by immune complex deposition in what locations?

Answer 17

The epithelium or sub-epithelium

Question 18

Can T cells be responsible for glomerulonephritis?

Answer 18

Possibly. It is suspected that T cells may be responsible for GN that is associated with low or absent immune complex formation. However, the evidence is inconclusive.

Question 19

What are the manifestations of glomerular injury and loss of glomerular barrier function?

Answer 19

(1) proteinuria

2) reduction in GFR (sometimes

Question 20

How does complement mediate glomerular injury?

Answer 20

Complement is activated by immune complexes and can

(1) recruit neutrophils and monocytes
(2) initiate MAC on epithelial cells

Question 21

How do neutrophils and monocytes mediate glomerular injury?

Answer 21

(1) they release proteases that degrade the GBM
(2) They release ROS which damage cells
(3) They release arachidonic acid metabolites which reduce GFR

Question 22

What causes ECM proliferation in some forms of GN?

Answer 22

The MAC upregulates TGF-beta receptors on podocytes. This results in increased synthesis of ECM.

Question 23

How can podocyte injury lead to GN?

Answer 23

If podocytes are damaged there may be damage or faulty formation of filtration slit diaphragms. Additionally if podocytes are killed neighboring podocyte may expand there processes to cover the open area. However, this leads to fewer filtration slits (effacement) and increased pressure on the effaced podocytes. If the pressure become great enough podocytes may be blown off the GBM causing GBM damage and inflammation.

Question 24

What kind of renal injury leads inexorably to end stage renal failure?

Answer 24

The loss of enough functioning nephrons to reduce the GFR to 30-50% of normal inevitably leads to end stage renal failure.

Question 25

What microscopic pathological finding is often associated with substantial loss of functioning nephrons?

Answer 25

Glomerulosclerosis.

Question 26

Why does loss of functioning nephrons lead to glomeruloslcerosis?

Answer 26

Because the remaining nephrons will hypertophy in an attempt to compensate for the lost nephrons. This leads to increased pressure in the remaining nephrons and sclerosis which eventually kills the nephrons further exacerbating the process.