Pathogenesis of Glomerular Disease

Question 1

1. Define the basic terminology employed in glomerular disease. (mesangium, parietal epithelium, capillary tuft)

Answer 1

mesangium: mesangial cells and mesangial matrix; functions as the scaffold for the capillaries, may have some smooth muscle and draining functions

parietal epithelium= bowman’s capsule

capillary tuft- capillaries that make up the glomerulus

BONUS: crescent- accumulation of cells in the Bowman’s space (monocytes or Boowman’s space

Question 2

1. Review glomerular structure and function. Note the layers between blood supply and Bowman’s capsule.

Answer 2

fenestrated endothelium (charge exclusion)
GBM: charge barrier (collagen IV and heparin sulfates) (charge exclusion)
visceral epithelial cells: podocytes with slit diaphragm of nephrin(size and charge barrier)

Question 3

2. Summarize clinical findings associated with glomerular diseases.

Answer 3

hematuria- specifically dimorphic RBC or RBC casts
proteinuria- sulfosalicylic acid turbidity test (all proteins) or antibodies
edema
hypertension
renal failure

Question 4

2. Describe the causes and ways of measuring hematuria and proteinuria in more detail.

Answer 4

hematuria: urologic (tumor or infection) or glomerulopathic (dysmorphic RBC, RBC casts); microscopic hematuria is detected with urinary sediment while macroscopic is visible to naked eye
proteinuria: glomerular permeability causes protein to leak into urine; detected by 24h urine collection (nephrotic range >3.5 g/24h)

Question 5

3. Identify laboratory studies used in the diagnosis of glomerulopathies. (both nephritic and nephritic)

Answer 5

nephritic: UA (hematuria and proteinuria; oliguria), BP- **HTN, blood BUN and creatinine (azotemia)
nephrotic: UA (proteinuria >3.5g/d; lipiduria), lipid panel (hyperlipidemia) serum albumin (hypoalbuminemia)

Question 6

4. Describe indications for the kidney biopsy.

Answer 6

best diagnostic tool for a glomerular disease (important in following tx. too)

suspected disease that call for renal biopsy: proteinuria, SLE, acute renal failure, hematuria, chronic renal failure, vasculitits

Question 7

4. Describe interpretation of the kidney biopsy. (hint, what is evaluated?, what are examples of pathological findings?)

Answer 7

glomeruli, tubules and interstitial and vessels are evaluated looking for proliferation/infiltration of cells , capillary wall abnormalities and matrix/protein accumulation

Question 8

5. List major pathological changes seen in glomerular diseases.

Answer 8

proliferation or infiltration of cells in the mesangium, in the capillary or both

capillary wall abnormalities: thickening of BM or deposition of proteins; intrinsic, structural GBM abnormalities like basket weave formation of Alport syndrome, amyloid deposition

Question 9

6. Describe non-immunologic mechanisms of glomerular injury.

Answer 9

ischemia (i.e. atheromatous plaque): glomeruli become scarred with collagen
endothelial injury (i.e. cyclosporin or bacterial toxins): can cause clotting and ischemia
deposition of proteins (hyaline deposition, light chain or amyloidosis): mohawk of capillary loops, stippled pattern of the BM

Question 10

6. Describe immunologic mechanisms of glomerular injury.

Answer 10

antibody-mediated (intrinsic, planted or circulating immune complexes)
cell-mediated
alternative pathway of complement activation

Question 11

Describe the clinical signs of a mixed nephritic and nephrotic syndrome. What diseases might cause this?

Answer 11

proteinuria >3.5 in the context of hematuria, renal failure and hypertension

diseases: Lupus nephritis, Membranoproliferative glomerulonephritis

Question 12

What is the triple approach to examining a biopsy?

Answer 12

light microscopy
immunofluorescence
electron microscopy

Question 13

What do H&E, PAS, Trichrome and HMS stains highlight about the glomerulus?

Answer 13

H&E shows overall structure
PAS: highlights membranes
Trichrome: highlights collagen
HMS: basement membrane is as a dark band

Question 14

Additional study…

Answer 14

may be helpful to go over pathology slides in this lecture

Question 15

Compare the mechanism that causes damage and the pattern of damage in nephrotic v. nephritic.

Answer 15

in nephritic syndrome there is widespread alteration of the capillary walls

in nephritic syndrome the ‘holes’ that lead to hematuria are due to inflammation

Question 16

Describe the following terms used to denote the degree of involvement and distribution of lesions in glomerularnephritis.

Answer 16

distribution

focal: involving <50% of the glomuli
diffuse: involving 50%+ of the glomeruli

segmental: involving a portion of the glomerular tuft
global: involving the entire glomerular tuft

Question 17

Describe the pathology that is characteristic of Membranoproliferative GN.

Answer 17

proliferation and GBM abnormalities

Question 18

Give examples of antibody mediated immunologic injury in native antigen of glomerulus

Answer 18

Non-collagenous domain I (NCI) of the a3 chain of the collagen type IV is a major component of GBM to which autoantibodies and induce crescentic (extra capillary proliferation) glomerulonephritis (and lung): linear deposition

Question 19

Give examples of antibody mediated immunologic injury in native antibody of glomerulus.

Answer 19

M-type phospholipase A2 receptor (PLA2R) is a protein on the surface of podocytes, binding of antibodies leads to idiopathic membranous glomerulopathy (sub epithelial deposition is less inflammatory leading to widespread loss of proteins)

Question 20

Give examples of antibody mediated immunologic injury in circulating complex.

Answer 20

drug or virus protein can act as a planted antige (binds to GBM) leading to secondary membranous glomerulopathy

antigens (ie. bacterial proteins) can cause circulation immune complexes and complexes get trapped in glomerular capillary wall; leading to diffuse proliferative, post infectious GN (course granular deposits)

antibodies can block inhibitory binding in complement convertase and complement can accumulate in the glomerulus

Question 21

Describe the sequelae of glomerular disease.

Answer 21

1. glomerulosclerosis: resulting irreversible scarring and hyalin deposition
2. interstitial fibrosis and tubular atrophy

causes of chronic GN include: post streptococcal GN, crescentic GN, membranous nephropathy, focal segmental glomerulosclorsis, membranoproliferative GN and IgAN

Question 22

Describe the relationship between location of immune complexes and antigen location. (comparison of nephrotic and nephritic)

Answer 22

complexes in the podocytes are not exposed to circulation and do not show increased cellularity but do lead to proteinuria (nephrotic)

complexes deposited in sub endothelial layer elicit an inflammatory repines with increased cellularity and disruption of the capillary wall (nephritic)