Glomerular Structure & Mech of Disease (Nichols) Flashcards
What is the glomerulus?
Renal filter for liquid portion of blood
What glomerular component stains black?
Basement membrane
What glomerular component stains white?
Bowmans space
What glomerular component stains pink?
Endothelial cells and Epithelial cells
Is the GBM significantly thicker in men or women? Who is anti- GBM disease more common in?
Men, especially young, especially white
What completely covers the outer surface of the capillary (facing the urinary space)
Interdigitating podocytes pedicles
What is the outer surface ofthe capillary(thats facing the urinary space) completely covered by ?
This picture of glomerularcapillary loop reveales what just below the red arrow?
Interdigitating podocyte pedicles
Fenestrations
What’s green?
What’s yellow?
What’s purple?
What’s blue?
Green:
Podocytes &
foot processes
Yellow:
Basement
membrane
Purple:
Endothelium
Stippled black
& blue:
Mesangium
How much of the capillary surface may correspond to fenestrations?
Up to 50%
What facilitates filtration and
accessibility of macromolecules (including antibodies*)
to glomerular basement membrane
The lack of a continuous cytoplasmic barrier
Podocytes cover the capillaries with an extensive network of ?
Cell processes-Pediceles
What are the visceral epithelial cells called?
Podocytes
Podocytes are in a layer that is continuous with what?
Parietal cells
The parietal cells are continuous with the podoctyes and what?
With the cells lining the proxmial tubule
What structure is found between the pediceles and connects them?
Slit pore diaphragm
What are conditions called that cause severe loss of protein through the glomeruli?
Nephrotic syndrome
What is effacement?
A retraction of foot processes and loss of slit pore diaphragm. On EM, it looks like fusion of foot processes
What also occurs in nephrotic syndrome in addition to effacement?
Detachment of
foot processes from the basement membrane and
degradation of glomerular basement membrane
allowing plasma proteins to leak into the urinary
space.
How many lamina does the glomerular basement membrane have?
Three. It’s a trilaminar structure
At the level of the lamina densa, of two basement membranes:
This structure of the basement
membrane represents the embryologic fusion,
Endothelial and epithelial
The minimal space between two pediceles is called?
Filtration slit
The thin structure bridging that space b/w two pediceles is?
Slit pore diaphragm
The slit pore diaphragm contains what?
Mutliple types of protein all secreted by podocytes
Some slit pore diaphragm proteins such as cadherin and FAT serve what purpose?
Bind adjacent pediceles
Some slit pore diaphragm proteins, such as nephrin and podocin, play a role in what?
Filtration
Mutations in the nephrin and podocin genes result in?
Congenital nephrotic syndromes due to the loss of large amounts of protein in the urine from the defective slit pore
diaphragm filtration.
What is the major component of the glomerular basement membrane?
Type IV collagen
What are the other 3 major components of the basement membrane?
Perlecan, entactin, and laminin
What is perlecan?
A highly charged proteoglycan containing heparan sulfate; it imparts most of the charge properties of basement membranes
What is entactin?
A glycoprotein with calcium binding properties
What is laminin?
A family of complex glycoproteins formed by three different chains.
Most of the alpha chains are in what characteristic conformation?
Helical. But there is a non-helical globular domain, which is called a “non-collagenous” (NC) domain
There are diseases caused by antibodies against an epitope in the NC1 domain of the alpha3 (IV) chain which cause?
Glomerulonephritis with hematuria (and pulmonary hemorrhage with hemoptysis, in about half of the patients
Goodpasture syndrome
What provides structural support to the glomerulus?
Glomerular mesangial cells and their matrix provide structural support to the glomerulus
Mesangial cells are mesenchymal cells with what properties?
With phagocytic and contractile properties; they’re equivalent to pericytes around other capillaries
What happens to substances like antibodies that reach mesangial cells?
Phagocytosed by mesangial cells
What are the three most common mechanisms of glomerular disease?
Immune-mediated
Metabolic
Hemodynamic
Many glomerular diseases are caused by what?
Antibodies and immune complex deposition
Immune complexes can be deposited from what two places?
From the circulation or in situ
In situ antibodies can be directed against what types of antigens?
Intrinsic (fixed) antigens or planted (antigens in the bloodstream)
What occurs in lupus nephritis?
Large circulating immune complexes
typically cannot pass through the GBM
and get stuck in a subendothelial
location
What occurs in Goodpasture syndrome?
Circulating antibodies against the GBM deposit in a subendothelial location and in a linear pattern all along the GBM.
What is used to detect antibody or complement deposition in glomeruli?
Immunofluorescence
Immune complexes tend to be deposited in clumps and have what kind of pattern?
Granular
Because the anti-GBM antibodies circulate before they are deposited, they can be treated how?
Plasma exchange
What occurs in membranous nephropathy?
Circulating antibodies against antigens in the cell membrane of podocytes deposit outside the GBM and injure podocytes
What is post-streptococcal glomerulonephritis?
An immune complex disease with antibodies apparently against streptococcal exotxin B, streptococcal GAPDH and endostroptosin
In post streptococcal glomerulonephritis, the immune complexes form what in EM?
Subepithelial “humps” which correspond to granular deposits on immunofluorescence.
What can rarely cause membranous nephropathy?
Antigens and antibodies that arrive separately and form complexes in a subepithelial location
What is Metabolic (diabetic) glomerular injury?
Hyperglycemia causes non-enzymatic glycosylation of proteins in blood and in GBM
In metabolic (diabetic) glomerular injury, what happens with some of the glycosylated plasma proteins?
They get trapped in the GBM along with the glycosylated native proteins, stimulating production of new GBM protein
What’s the eventual result of metabolic (diabetic) glomerular injury?
A thickened GBM distorted by glycosylated proteins (some further metabolized to advanced glycation end-products [AGE] that mediate some of the accelerated aging that characterizes the effect of diabetes on organs throughout the body.)
What activates NADPH oxidase?
Advanced oxidation protein products [AOPP], the renal angiotensin system, TGF-beta and AGEs
Activated NADPH produces ROS, which causes what?
Mesagial matrix production, podocyte injury, apoptosis, and proteinuria
What is Hemodynamic Glomerular Injury?
The difference in pressure in hemodynamic glomerular injury drives what?
Drives filtration, but supra-normal glomerular capillary pressures injure them, stimulating GBM thickening (green) and
mesangial cell hypertrophy and hyperplasia and mesangial matrix production
High blood pressure causes hyaline sclerosis to which arterioles of the glomeruli?
The afferent arterioles only.
What changes occur as a result of hyaline sclerosis?
Plasma leaks into the wall and gradually narrows the lumen. This is followed by gradual ischemic atrophy of the glomerulus.
HTN eventually results in what?
Globally sclerotic glomeruli
What is the term for end stage HTN neuropathy?
ARTERIONEPHROSCLEROSIS
Why is Arterionephrosclerosis 8 times more common in African Americans?
There are mutations in the gene for apoliporotein L1
unique to Africans conferring resistance to african sleeping sickness because the variant apoL1 does not bind a trypanosomal protein that blocks the action of a complex including apoL1, which lyses the parasites, as a function of innate immunity
How does malignant HTN usually present?
Usually presents with blood pressure >200/120 mm Hg, headache, vomiting, proteinuria, hematuria, scotomas (“spots before the eyes”) and renal failure, especially in youngish black males around age 40?
What does malignant HTN do?
Produces fibrinoid necrosis of arterioles (far end of spectrum with hyaline sclerosis) leading to necrosis of glomeruli.
Malignant hypertension also produces what?
Proliferation of intimal cells in small arteries, hyperplastic arteriosclerosis, giving them an onion-skin appearance.
Are hyperplastic arteriosclerosis and arterial fibrinoid necrosis specific for malignant hypertension?
No
What is flea bitten kidney?
Small arteries and arterioles damaged by malignant hypertension
Can malignant hypertension be fatal?
Yes.
Kidney biopsies are unique because they require what three types of microscopy?
Light microscopy, immunofluorescence, and electron microscopy
What does diffuse mean?
Involving all or most of the glomeruli
What does focal mean?
Involving some but not most of the glomeruli
What does global mean?
Involving the whole glomerulus
What does segmental mean?
Involving only part of a glomerulus
In glomerular disease, what does proliferative mean?
Increased cells: both native cell proliferation and or increases infltrating inflammatory cells
What does membranous mean?
Increased GBM, without increases cells
What is MPGN?
Membrano-proliferative
What is Crescentic (glomerulonephritis)?
Disease involving Bowman space with proliferating parietal epithelial cells and infiltrating macrophages
