Normal Kidney Review; Pathogenesis & General Pathologic Features of Glomerular Injury

Question 1

What structures are found in the cortex of the kidney? Medulla?

Answer 1

Cortex - Primarily renal corpuscles and convoluted tubules (proximal and distal)

Medulla - inner layer containing mostly loops of Henle and collecting ducts

Question 2

Describe the flow of urine from the collecting ducts to the ureter. What epithelium lines it?

Answer 2

All of the collecting ducts in a pyramid converge to form a papilla. The papilla projects into a minor calyx.

Several minor calyces drain into a major calyx. The last unit which drains all the major is the renal pelvis -> drains into the ureter thru the hilum

Epithelium is transitional epithelium by the level of the calyces (urothelium)

Question 3

What is a lobe vs a lobula of the kidney?

Answer 3

Lobe - a grossly apparent medullary pyramid with its associated cortex, separated by cortical columns

Lobule - group of nephrons draining into a common collecting duct

Question 4

What cells support the tuft of the glomerulus (4-8 lobules of capillaries)? What is their origin?

Answer 4

Mesangial cells + extracellular matrix

They are of mesenchymal origin, with contractile, phagocytic, and proliferative properties

Question 5

What are the three layers of the glomerular filtration membrane?

Answer 5

1. Fenestrated capillary endothelial cells
2. Glomerular basement membrane - fused basal lamina of endothelium + epithelium
3. Podocyte foot processes (visceral epithelial cells) - separated by filtration slits

Question 6

What are the three layers of the glomerular basemement membrane by TEM?

Answer 6

Lamina rara interna - electron-lucent peripheral layer near capillary endothelial side

Lamina densa - Thick, electron-dense central layer

Lamina rara externa - electron-lucent peripheral layer near podocyte foot processes

Question 7

What does the glomerular basement membrane consist of? What do the components do?

Answer 7

Collagen - mostly Type IV - triple helix of alpha chains

NC1 - non-collagenous domain which is anti-GBM target -> organizing function Type IV collagen

Glycoproteins - irrelevant

Question 8

How is the GBM best visualized by staining?

Answer 8

PAS stain - will stain glycoproteins

Silver stain - best stain for the mesangial matrix composed of Type III collagen

Question 9

What cells line the Bowman capsule?

Answer 9

Parietal epithelial cells

Question 10

How do you tell proximal convoluted tubule from distal convoluted tubule?

Answer 10

Proximal - columnar epithelial cells granular, intensely eosinophilic cytoplasm (many mitochondria), and an apical brush border of microvilli which make it look hazy

Distal - low cuboidal epithelial cells with a more pale eosinophil cytoplasm and “clear” luminal appearance.

Question 11

Where is a portion of the distal convoluted tubule often found and why?

Answer 11

Vascular pole of the glomerulus -> where afferent and efferent arteriole enter and exit

• > distal convoluted tubule gives rise to the macula densa of the JGA.
• > Macula densa senses NaCl and signals to the juxtaglomerular cells and secrete renin. MD cells also signal for efferent arteriole vasoconstriction to increase GFR or afferent arteriole vasoconstriction to decrease GFR.

Question 12

How is the collecting duct told apart from the distal convoluted tubule?

Answer 12

Collecting duct has fairly clear cytoplasm and more distinct cellular border than the DCT

Question 13

Describe the blood flow of the kidneys from renal artery to efferent arterioles.

Answer 13

Renal artery branches into interlobar arteries which travels between pyramids.

Interlobar arteries branch perpendicularly at the corticomedullary junction into arcuate arteries

Arcuate arteries branch perpendicularly again (parallel with interlobar arteries) into the cortex as interlobular arteries, where afferent arterioles come off.

Afferent arterioles supply the glomeruli and leave as efferent arterioles.

Question 14

What are the two possible fates of the efferent arterioles and what determines this?

Answer 14

1. Efferent arterioles supply the peritubular capillaries of the renal cortex, before draining into the interlobular veins and ultimately renal veins
2. Inner 1/3 of glomeruli give off efferent arterioles which form vasa recta, which ultimately drain into arcuate veins.

Question 15

How does immune complex deposition look like by direct immunofluoresence? What are we looking for?

Answer 15

Has a granular, “lumpy-bumpy” appearance due to heterogenous deposition of immune complexes in the filtration membrane,

Look for immunoglobulin deposition and often complement

Question 16

What are the two general processes which can dictate deposition of immune complexes? Give an example of a condition causing this in each.

Answer 16

1. In situ immune complex formation -> primary membranous glomerulonephropathy, with autoantibodies to phospholipase A2 receptor in podocytes.

Also, can be due to planted antigens with immune complexes forming there

2. Circulating immune complexes deposit

Question 17

What are some sources of planted antigen which can deposit around the GBM?

Answer 17

Endogenous origin - i.e. DNA and other nuclear components

Exogenous origin - products of microorganisms, medications

Question 18

What are some causes of circulating immune complexes depositing in the GBM?

Answer 18

1. Endogenous origin - DNA or tumor antigens from malignancy

2. Exogenous origin - infectious pathogens, i.e. Group A strep, HBV, HCV

Question 19

What factors determine where planted antigens and circulating immune complexes deposit in the glomerulus?

Answer 19

Molecular charge and size, as well as glomerular hemodynamics (i.e. high RBF pushes it farther in).

Question 20

What size and charge of particles are generally disincluded from being nephritogenic and why?

Answer 20

Very large immune complexes - efficiently removed by phagocytes (Kupffer cells in liver)

Very small immune complexes - generally cleared by binding to RBC C4b receptors (fix early complement cascade so they’re efficiently cleared)

Highly anionic molecules - GBM has a negative charge which will repel it

Question 21

Where do slightly anionic molecules, neutral molecules, and cationic molecules end up in the glomerulus?

Answer 21

Slightly anionic - subendothelial, between inner GBM and endothelial cells -> repelled by GBM so they can’t get through.

Neutral molecules - in mesangial network (i.e. immunoglobulins in IgA nephropathy)

Cationic molecules - subepithelial -> between outer GBM and podocytes

Question 22

What are anti-GBM antibodies directed against? What is their DIF staining pattern? What type of glomerular disease do they cause?

Answer 22

noncollagenous domain of type IV collagen (NC1)

Staining pattern - fixed and regular, causing a diffuse, linear staining pattern

Usually cause rapidly progressive glomerulonephritis (RPGN)

Question 23

What is Goodpasture syndrome?

Answer 23

Anti-GBM antibodies + antibodies are cross-reacting to GBM in pulmonary alveoli -> lung disease as well

Question 24

Does cell mediated immunity play a role in glomerular disease? How?

Answer 24

T cells and macrophages do play a role, even if disease initiated by antibody-mediated mechanisms

Question 25

What disease is characterized by alternative complement pathway activation? What is this pathway?

Answer 25

Alternative complement activation - deposition of C3b on cell surface, with no need for initial C3 convertase

Dense-deposit disease: Membranoproliferative glomerulonephritis, Type II

Question 26

What part of the glomerulus is most susceptible to direct damage by toxins, antibodies, and cytokines?

Answer 26

Podocytes -> easiest to damage since the cells are so complicated

-> leads to effacement of podocytes and glomerular protein leakage

Question 27

What cells are the primary mediators of glomerular injury and how are they recruited?

Answer 27

neutrophils and macrophages

Recruited and activated by complement (C5a anaphylotoxin)

Noxious substances from granules damage membrane

Question 28

How do platelets and mesangial cells contribute to glomerular damage?

Answer 28

Platelets - activated by immune-mediated cell damage, release eicosanoids and growth factors which are prothrombotic

Mesangial cells - activated by local injury, release growth factors to cause proliferation, as well as a number of inflammatory cytokines, proteases, and oxidants

Question 29

With significant loss in functioning of nephrons and reduction of GFR, what happens to the kidneys?

Answer 29

Regardless of cause, there is a fairly constant rate of progression to chronic kidney disease

Question 30

What is responsible for the progression of focal segmental glomerulosclerosis (FSGS)?

Answer 30

Significantly decreased functioning of some nephrons results in compensatory changes in remaining nephrons -> increased GFR, blood pressure, and filtration

-> injury to resident glomerular cells due to high pressures

Question 31

What happens when resident glomerular cells are injured in FSGS?

Answer 31

1. Endothelial injury -> activation of coagulation cascade
2. Damage to podocytes -> effacement and proteinuria. Also decreases support for glomerular capillaries -> pressure imbalances and segmental capillary asymmetries
3. Proliferation of mesangial cells and infiltration by monocytes and macrophages leads to increased production of growth factors and synthesis of ECM -> “sclerosis”

Result: vicious cycle of progression to worsening

Question 32

What does proteinuria and decreased blood flow through efferent arteriole lead to? How does this correlate to renal function?

Answer 32

Leads to tubular eischemia and injury / activation of tubular cells
-> production of proinflammatory cytokines / growth factors and interstitial inflammation / fibrosis

End result: Tubulointerstitial fibrosis, correlates better decreased renal function than the extent of glomerular damage

Question 33

What is diffuse vs focal glomerular injury?

Answer 33

Diffuse - affects most glomeruli (greater than 50%)

Focal - affects only some glomeruli (less than 50%)

Question 34

What is it called when glomerular injury involves the entire glomerulus vs only a portion of each glomerulus?

Answer 34

Entire glomerulus -> global injury

Portion of each glomerulus -> segmental injury

Question 35

What causes hypercellularity of the glomeruli?

Answer 35

1. Intrinsic cell proliferation (mesangial and endothelial cells)
2. Infiltration by WBCs (neutrophils and monocytes)

Question 36

What causes crescent formation / hypercellularity?

Answer 36

Severe glomerular damage -> leakage of cytokines and procoagulants into urinary space, leading to fibrin deposition
-> glomerular epithelial cell prolofieration (mostly parietal cells) + infiltration of leukocytes and hypercellularity

Leads to rapidly progressive glomerulonephritis, with fibrotic crescent formation

Question 37

What leads to thickening of the GBM?

Answer 37

1. Abnormal deposits (i.e. immune complexes, fibrillary material such as amyloid)
2. Increased protein synthesis (i.e. diabetes)

Question 38

What is hyalinosis?

Answer 38

Accumulation of glassy, homogenous, eosinophilic extracellular material
-> destroys glomerular structure by deposition of plasma proteins

Question 39

How is sclerosis different than hyalinosis and fibrosis?

Answer 39

Sclerosis - Deposition of extracellular matrix, primarily collagen (vs hyalinosis, which is deposition of plasma proteins)

Fibrosis - deposition of extracellular matrix by fibroblasts (vs sclerosis, where the ECM is made by mesangial cells)