Nichols: Glomerular Structure and Mech of Disease Flashcards
What part of the glomerulus is significantly thicker in men than women?
GBM (glomerular basement membrane)
Anti-GBM disease is significantly more common in what population?
Young, white males
What happens to the glomeruli in nephrotic syndrome?
Podocytes retract foot processes, leading to loss of slit pore diaphragms, so that long segments of capillary are invested by cytoplasm of a single podocyte. Foot processes detach from the basement membrane, which degrades and allows proteins to leak into urinary space.
Name the laminae of the GBM
1) lamina lucida/rara interna (closer to endothelium) 2) lamina densa 3) lamina rara externa (closer to epithelial cells)
What is the space between to pediceles called?
filtration slit
What is the thin structure bridging the space between two pediceles
slit pore diaphragm
What proteins are found in the slit pore diaphragm, and what are their functions?
1) cadherin and FAT bind adjacent pediceles 2) nephrin and podocin play a role in filtration
Mutations in which slit pore diaphragm proteins result in congenital nephrotic syndrome?
nephrin and podocin
What are the main components of basement membrane? Which one is the major component of GBM?
1) perlecan 2) entactin 3) laminin 4) fibronectin 5) type IV collagen - major component of GBM
Which component of basement membranes imparts the strongest negative charge, and why is this important?
Perlecan (highly charged PG containing heparan sulfate) - important for keeping albumin from entering and traversing the basement membrane
How many alpha chains form one collagen molecule?
3 alpha chains form a collagen molecule.
What is the non-helical, globular domain of a collagen molecule called? Why is this domain important?
Non-collagenous (NC) domain. Some diseases, such as Goodpasture syndrome, are caused by antibodies directed against an epitope in the NC1 domain of the alpha3 chain
What are mesangial cells?
Mesenchymal cells with phagocytic and contractile properties, equivalent to pericytes around other capillaries. Substances trapped in GBM flow along GBM until they get to mesangial matrix, where they are phagocytosed
What are the three common mechanisms of glomerular disease? Which is the most common?
1) Immune-mediated 2) Metabolic (diabetic) 3) Hemodynamic (hypertensive) - most common
What are the mechanisms in which immune-mediated glomerular disease can occur?
1) Immune complexes can be deposited from circulation OR formed in situ 2) In situ antibodies can be against intrinsic (fixed) antigens OR planted antigens, originally from bloodstream
What is the mechanism of glomerular damage in lupus nephritis?
Large circulating immune complexes cannot pass through GBM and get stuck in subendothelial location, causing the formation of “wire loops”
What is the mechanism of glomerular damage in Goodpasture syndrome?
Circulating antibodies against GBM deposit in a subendothelial location, in a linear pattern along GBM
What is the mechanism of disease in membranous glomerulonephritis?
Circulating antibodies against antigens in the cell membrane of podocytes deposit outside of basement membrane and form in situ immune complexes, injuring podocytes.
What kind of pattern do immune complexes have on immunofluorescence?
granular
What kind of pattern does anti-GBM antibody have on immunofluorescence?
linear
What kind of pattern do antibodies/immune complexes found in “pauci-immune” crescentic glomerulonephritis have on immunofluorescence?
none (ANCA not visible on immunofluorescence)
Why can anti-GBM antibodies be treated with plasmapheresis?
They circulate before they are deposited, can treat by removing the antibodies.
In which disease do subepithelial “humps” form, corresponding to granular deposits on immunofluorescence?
Post-streptococcal glomerulonephritis
What is the mechanism of metabolic (diabetic) glomerular injury?
1) Non-enzymatic glycosylation of proteins in blood and GBM, causes some to get trapped in GBM, stimulating production of new GBM protein. This eventually causes thickened GBM, distorted by glycosylated proteins. 2) AOPP, renal angiotensin system, TGF-beta, and AGE induce/activate NADPH oxidases, producing ROS, which cause mesangial matrix production, podocyte injury and apoptosis, and proteinuria
What mediates some of the accelerated aging that characterizes the effects of diabetes on organs?
advanced glycation-end products (AGE)
What are the effects of elevated glomerular capillary blood pressure on glomerular structure?
Causes injury which stimulates GBM thickening, mesangial cell hypertrophy and hyperplasia, and mesangial matrix production. High blood pressure also causes hyaline sclerosis of the afferent arterioles of glomeruli, followed by gradual ischemic atrophy of glomerulus. Eventually results in globally sclerotic glomeruli
What is the term for end-stage hypertensive nephropathy?
Arterionephrosclerosis
Why is arterionephrosclerosis 8 times more common in African Americans?
Mutations in apoL1 gene that confers resistance to trypanosoma (parasite that causes African sleeping sickness)
How could you win a Nobel prize?!
figure out how apoL1 mutation causes aterionephrosclerosis
In which population is malignant hypertension more common?
African Americans, especially males around 40yo
What are the presenting symptoms of malignant hypertension?
bp >200/120, headache, vomiting, proteinuria, hematuria, scotomas, and renal failure
How does malignant hypertension damage glomeruli?
1) Produces fibrinoid necrosis of arterioles, leading to necrosis of glomeruli. 2) Hyperplastic arteriosclerosis (proliferation of intimal cells in small arteries), giving arterioles an onion-skin appearance. *These are not specific for malignant HTN*
What is this?
Flea-bitten kidney. Small arteries and arterioles damaged by malignant HTN have burst all over the kidney
Is malignant hypertension a medical emergency
YES. 5-year survival is ~50%, and renal disease causes death in 90%
Describe this glomerular disease.
Diffuse - involving all or most of glomeruli
Describe this glomerular disease.
Focal - involving some but not most of the glomeruli
Describe this glomerular disease.
Global - involving the whole glomerulus
Describe this glomerular disease.
Segmental - involving only part of the glomerulus
What is proliferative glomerular disease?
Increased cells (proliferating native cells) and/OR infiltrating inflammatory cells
What is membranous glomerular disease?
Increased GBM without increased cells
Describe this glomerular disease.
Crescentic (glomerulonephritis) disease involving Bowman space with proliferating parietal epithelial cells, infiltrating macrophages, and inflammatory exudate and leaked plasma, BAD NEWS.
Describe this glomerular disease.
Necrotizing (glomerulonephritis)
Describe this glomerular disease.
Necrotizing and organizing
Describe this glomerular disease.
Glomerulosclerosis - fibrous scar replacing glomerulus
Describe this glomerular disease.
Segmental glomerulosclerosis - scar replacing part of glomerulus
What are numbers 1-3?
1) Endothelial fenestration
2) Endothelial half of basement membrane
3) Epithelial half of basement membrane
What component of the glomerulus is stained black?
Basement membrane
What has happened to the podocytes in this picture? What condition is this?
Effacement of podocytes, caused by nephrotic syndrome
