Normal Kidney Review; Pathogenesis & General Pathologic Features of Glomerular Injury Flashcards
What structures are found in the cortex of the kidney? Medulla?
Cortex - Primarily renal corpuscles and convoluted tubules (proximal and distal)
Medulla - inner layer containing mostly loops of Henle and collecting ducts
Describe the flow of urine from the collecting ducts to the ureter. What epithelium lines it?
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)
What is a lobe vs a lobula of the kidney?
Lobe - a grossly apparent medullary pyramid with its associated cortex, separated by cortical columns
Lobule - group of nephrons draining into a common collecting duct
What cells support the tuft of the glomerulus (4-8 lobules of capillaries)? What is their origin?
Mesangial cells + extracellular matrix
They are of mesenchymal origin, with contractile, phagocytic, and proliferative properties
What are the three layers of the glomerular filtration membrane?
- Fenestrated capillary endothelial cells
- Glomerular basement membrane - fused basal lamina of endothelium + epithelium
- Podocyte foot processes (visceral epithelial cells) - separated by filtration slits
What are the three layers of the glomerular basemement membrane by TEM?
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
What does the glomerular basement membrane consist of? What do the components do?
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
How is the GBM best visualized by staining?
PAS stain - will stain glycoproteins
Silver stain - best stain for the mesangial matrix composed of Type III collagen
What cells line the Bowman capsule?
Parietal epithelial cells
How do you tell proximal convoluted tubule from distal convoluted tubule?
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.
Where is a portion of the distal convoluted tubule often found and why?
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.
How is the collecting duct told apart from the distal convoluted tubule?
Collecting duct has fairly clear cytoplasm and more distinct cellular border than the DCT
Describe the blood flow of the kidneys from renal artery to efferent arterioles.
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.
What are the two possible fates of the efferent arterioles and what determines this?
- Efferent arterioles supply the peritubular capillaries of the renal cortex, before draining into the interlobular veins and ultimately renal veins
- Inner 1/3 of glomeruli give off efferent arterioles which form vasa recta, which ultimately drain into arcuate veins.
How does immune complex deposition look like by direct immunofluoresence? What are we looking for?
Has a granular, “lumpy-bumpy” appearance due to heterogenous deposition of immune complexes in the filtration membrane,
Look for immunoglobulin deposition and often complement
What are the two general processes which can dictate deposition of immune complexes? Give an example of a condition causing this in each.
- 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
- Circulating immune complexes deposit
What are some sources of planted antigen which can deposit around the GBM?
Endogenous origin - i.e. DNA and other nuclear components
Exogenous origin - products of microorganisms, medications
What are some causes of circulating immune complexes depositing in the GBM?
- Endogenous origin - DNA or tumor antigens from malignancy
2. Exogenous origin - infectious pathogens, i.e. Group A strep, HBV, HCV
What factors determine where planted antigens and circulating immune complexes deposit in the glomerulus?
Molecular charge and size, as well as glomerular hemodynamics (i.e. high RBF pushes it farther in).
What size and charge of particles are generally disincluded from being nephritogenic and why?
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
Where do slightly anionic molecules, neutral molecules, and cationic molecules end up in the glomerulus?
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
What are anti-GBM antibodies directed against? What is their DIF staining pattern? What type of glomerular disease do they cause?
noncollagenous domain of type IV collagen (NC1)
Staining pattern - fixed and regular, causing a diffuse, linear staining pattern
Usually cause rapidly progressive glomerulonephritis (RPGN)
What is Goodpasture syndrome?
Anti-GBM antibodies + antibodies are cross-reacting to GBM in pulmonary alveoli -> lung disease as well
Does cell mediated immunity play a role in glomerular disease? How?
T cells and macrophages do play a role, even if disease initiated by antibody-mediated mechanisms
What disease is characterized by alternative complement pathway activation? What is this pathway?
Alternative complement activation - deposition of C3b on cell surface, with no need for initial C3 convertase
Dense-deposit disease: Membranoproliferative glomerulonephritis, Type II
What part of the glomerulus is most susceptible to direct damage by toxins, antibodies, and cytokines?
Podocytes -> easiest to damage since the cells are so complicated
-> leads to effacement of podocytes and glomerular protein leakage
What cells are the primary mediators of glomerular injury and how are they recruited?
neutrophils and macrophages
Recruited and activated by complement (C5a anaphylotoxin)
Noxious substances from granules damage membrane
How do platelets and mesangial cells contribute to glomerular damage?
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
With significant loss in functioning of nephrons and reduction of GFR, what happens to the kidneys?
Regardless of cause, there is a fairly constant rate of progression to chronic kidney disease
What is responsible for the progression of focal segmental glomerulosclerosis (FSGS)?
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
What happens when resident glomerular cells are injured in FSGS?
- Endothelial injury -> activation of coagulation cascade
- Damage to podocytes -> effacement and proteinuria. Also decreases support for glomerular capillaries -> pressure imbalances and segmental capillary asymmetries
- 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
What does proteinuria and decreased blood flow through efferent arteriole lead to? How does this correlate to renal function?
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
What is diffuse vs focal glomerular injury?
Diffuse - affects most glomeruli (greater than 50%)
Focal - affects only some glomeruli (less than 50%)
What is it called when glomerular injury involves the entire glomerulus vs only a portion of each glomerulus?
Entire glomerulus -> global injury
Portion of each glomerulus -> segmental injury
What causes hypercellularity of the glomeruli?
- Intrinsic cell proliferation (mesangial and endothelial cells)
- Infiltration by WBCs (neutrophils and monocytes)
What causes crescent formation / hypercellularity?
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
What leads to thickening of the GBM?
- Abnormal deposits (i.e. immune complexes, fibrillary material such as amyloid)
- Increased protein synthesis (i.e. diabetes)
What is hyalinosis?
Accumulation of glassy, homogenous, eosinophilic extracellular material
-> destroys glomerular structure by deposition of plasma proteins
How is sclerosis different than hyalinosis and fibrosis?
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)
