Glomerular Structure and Mechanisms of Disease (Word Doc) Flashcards
What filters the liquid portion of the blood? The solid portion?
liq = glomerulus s = spleen
What do afferent arterioles branch into?
capillary loops
How does the glomerulus form, embryologically?
arteriole pushes into the blind end of a tubular structure, causing it to invaginate. This forms a double epithelial cell layer.
Podocytes are formed by layer closer to capillaries (visceral).
Bowman capsule formed by distal/parietal layer.
What is the space between the (continuous) parietal and visceral layer? What two areas does this span?
urinary space (Bowman space)
extends continuously from glomerulus into the tubule
What do podocytes and pediceles cover? What is between these two structures?
capillaries of the glomerular tuft, with basement membrane between them
Embryologically, from what does the glomerular basement membrane originate?
endothelial and epithelial basement membrane
What are mesangial cells? What do they support?
mesenchymal cells (equivalent to pericytes) that secrete a basement membrane-like matrix
supports the glomerular tuft
What would you find on each side of the (fused) basement membrane? Which layer is on the OUTER surface of the capillaries, facing the urinary space?
endothelial cells
podocytes/pediceles (on side facing urinary space)
What lies between and connects pediceles?
slit pore diaphragm
What are the 8 primary glomerular diseases?
- minimal change disease
- membranous nephropathy
- post-strep glomerulonephritis
- focal segmental glomerulosclerosis
- membranoproliferative glomerulonephritis
- IgA nephropathy (Berger’s)
- hereditary nephritis (Alport syndrome)
- congenital nephrotic syndrome
What are some secondary glomerular diseases? (5)
hypertensive nephropathy diabetic nephropathy lupus nephritis amyloidosis Goodpasture syndrome
Approx. ____% of glomerular diseases in kids are primary; only ____% of glomerular diseases in adults are primary.
95
60
Most common glomerular disease:
Second:
Third:
- vascular, hypertensive nephropathy
- diabetes
- immune-mediated
Infectious diseases often involve what parts of the kidney?
tubules and interstitium (more so than the glomeruli)
What clotting disorders may involve the glomeruli?
hemolytic uremic syndrome
TTP
DIC
Renal neoplasms arise from…
tubular epithelium
Why is hemodynamic glomerular injury common?
The glomerular capillaries have higher hydrostatic pressure than other capillaries .
What drives filtration?
higher pressure in glomerular capillaries than Bowman space
What does “supra-normal” pressure through the glomerular capillaries cause?
injury, which stimulates:
GBM thickening
mesangial cell hypertrophy/hyperplasia
mesangial matrix production
High BP causes hyaline sclerosis of:
AFFERENT arterioles
Diabetes causes hyaline sclerosis of:
BOTH afferent and efferent arterioles
In HTN and diabetes, what causes narrowing of the afferent arteriole lumen? Which does this ultimately cause?
- plasma leaks into the wall
2. arterionephrosclerosis, which is global sclerosis of glomeruli
End stage renal disease due to HTN is eight times more likely in what population, and why?
- African americans
- Mutations in the gene for apoliporotein L1, which confer resistance to Trypanosoma brucei rhodesiense (African sleeping sickness)
(variant apoL1 does not bind to the trypanosomal protein that blocks the action of an apoL1 complex; this lyses parasites)
What genetic abnormality is associated with focal segmental glomerulosclerosis?
mutations in the gene for apoliporotein L1
much more common in African Americans
What is malignant hypertensive nephropathy? What develops if it isn’t treated?
rapidly progressive condition that is part of a multi-organ syndrome called malignant hypertension
renal failure
What are some symptoms/characteristics of malignant hypertensive nephropathy?
- more common in African Americans, esp black males ~40 y/o
- increased intracranial pressure; causes HA, scotomas and vomiting
- BP usually >200/120
- proteinuria and microscopic hematuria
How does malignant hypertension affect arterioles (2)?
- produces fibrinoid necrosis, which leads to necrosis of glomeruli
- hyperplastic arteriosclerosis, which is an “onion-skin” proliferation of intimal cells in small arteries
What causes “flea bitten kidney”?
Rupturing of small arteries and arterioles damaged by malignant hypertension
(occurs all over the kidney)
Note: only 50% have 5 year survival, and 90% of these patients die of renal disease
T/F: Hyperplastic arteriosclerosis and arterial fibrinoid necrosis are highly specific for malignant hypertension.
F: They are also seen in acute thrombotic microangiopathies and in scleroderma renal crisis
T/F: Malignant hypertension is a medical emergency.
T **LEARN THIS!!!
________ is probably the most common cause of glomerular disease, partly because glomerular disease causes ________.
Hypertension (both!)
“vicious positive feedback loop of glomerular disease of any cause”
A discontinuous cytoplasmic barrier that allows for the free filtration of fluid, plasma solutes and protein.
glomerular capillary endothelium (note: has fenestrations)
As much as ____% of the capillary endothelial surface may correspond to doughnut hole fenestrations.
50
In the absence of glomerular capillary endothelium, what sorts of unwanted molecules reach the basement membrane?
macromolecules (including antibodies)
Injury to glomerular capillary endothelium results in _______ formation, resulting in a group of diseases termed:
thrombus
thrombotic microangiopathies
What layers comprise the glomerular basement membrane? (Describe their location)
- lamina lucida (or rara) interna
closer to the endothelium - lamina densa
- lamina rara externa
closer to the epithelial cells
Why is the lamina densa so thick?
represents the embryologic fusion of 2 basement membranes (endothelial and epithelial)
Note: the lamina dense is twice as thick as the lamina rara int/ext are
The 5 major components of basement membranes:
- perlecan
- entactin
- fibronectin
- laminin
- type IV collagen
*1-4 are glycoproteins
What basement membrane component binds calcium?
Entactin
What basement membrane component provides a strong negative charge? Why is this significant?
Perlecan
Its negative charge is important in keeping albumin (also negatively charged) from entering and traversing the basement membrane
What basement membrane component is important in BM connection and adhesion? How?
Fibronectin; binds to collagen, heparan sulfate and integrins
What basement membrane component contains heparan sulfate?
Perlecan
________ is a basement membrane component formed by three different chains (which exist in various isoforms). It binds to (what 3 proteins) and to cells, which is mediated by ______.
- Laminin
- binds to type IV collagen, entactin, heparan sulfate
- mediated (in many cases) by integrins
What is the glomerular basement membrane is MAINLY composed of? What is the function of this?
type IV collagen, provides its major scaffolding
Why is there significant variability in the make-up of basement membranes?
the biggest component of BM, collagen, is formed by 3 out of 6 possible alpha chains
the individual molecules are thus very variable
What are the 2 possible heterotrimers comprising adult glomerular basement membranes?
alpha3, alpha4, alpha5(IV)
alpha5, alpha5, alpha6(IV)
What is a “non-collagenous” (NC) domain, and what pathologic condition is related to it?
- non-helical globular COLLAGENOUS domain
2. antibodies against an epitope in the NC1 domain of the alpha3 (IV) chain cause glomerulonephritis with hematuria
The glomerular basement membrane of men is significantly (thinner/thicker) than that of women, and anti-GBM disease is more common in (men/women).
thicker; men
What is anti-GBM associated with, and what function does plasmapheresis serve?
- smoking
- antibodies circulate before they are deposited, so removing them can help prevent damage
note: this represents <1% of glomerulonephritis
Visceral epithelial cells that are continuous with the parietal cells of Bowman capsule.
podocytes
*note: the cells of Bowman capsule are continuous with the cells lining the proximal tubule
What interdigitating structures cover the capillaries?
pediceles
What is/causes nephrotic syndrome?
severe loss of protein
- retraction of foot processes (or their effacement)
- loss of the slit pore diaphragms
- foot processes detach from basement membrane
- basement membrane degrades, which allows plasma proteins to leak into urinary space
What is/causes crescentic glomerulonephritis?
Crescent-shaped area of inflammation and proliferation of parietal epithelial cells
Loss of podocytes and slit pore diaphragm causes leakage of plasma proteins [plus antibodies, immune complexes, inflammatory cytokines, inflammatory cells and their ROS] into the urinary space
Crescentic glomerulonephritis progresses (slowly/quickly), and extends to the outermost part of the glomerulus.
quickly
“The crescentic pattern of glomerulonephritis is the histopathologic correlate of the clinical syndrome of rapidly progressive glomerulonephritis.”
The minimal space between two pediceles is called:
The thin structure bridging that space is the:
- filtration slit
2. slit pore diaphragm
Slit pore diaphragm proteins that bind adjacent pediceles:
cadherin and FAT
Slit pore diaphragm proteins that play a role in filtration:
nephrin and podocin
Major component of the slit pore diaphragm:
Nephrin (transmembrane glycoprotein)
The selective permeability of the glomerular barrier discriminates against:
What maintains the selective permeability?
- large molecules
- negatively charged molecules
- molecules of certain configurations
nephrin
What will you find at the center of the slit pore diaphragm?
Nephrin molecules from adjacent podocyte foot processes bound via disulfide bridges
What causes rare congenital nephrotic syndromes characterized by defective slit pore diaphragm filtration?
Mutations in the nephrin and podocin genes
loss of large amounts of protein in urine
tuft of capillaries surrounded by first portion of a renal tubule containing blood filtrate normally destined to become urine
Glomerulus
long microscopic tube that carries glomerular filtrate to renal collecting system and converts it to urine along the way
Renal tubule
involving all or most of the glomeruli
Diffuse (glomerular disease)
involving some, but not most of the glomeruli
focal (glomerular disease)
involving all of a glomerulus
global (glomerular disease)
involving only part of a glomerulus
segmental (glomerular disease)
glomerular inflammation with increased cellularity due to proliferating glomerular cells and infiltrating inflammatory cells
Proliferative glomerulonephritis
glomerular disease due to increased basement membrane without increased cellularity
Membranous nephropathy
glomerular inflammation with both increased basement membrane and increased cellularity
Membranoproliferative glomerulonephritis
rapidly progressive necrotizing inflammation with inflammatory exudate and proliferating cells in a crescent in Bowman space
crescentic glomerulonephritis
rapidly progressive crescentic glomerular inflammation with a paucity of antibodies or immune complexes
pauci-immune glomerulonephritis
9 places in a glomerulus that disease can be located (this is an objective)
(1) arterioles
(2) capillaries [lumen + endothelial cells]
(3) between capillary endothelial cells and glomerular basement membrane [subendothelial]
(4) glomerular basement membrane
(5) between the glomerular basement membrane and epithelial cells [subepithelial]
(6) slit pore diaphragm
(7) podocytes
(8) Bowman space and capsule
(9) mesangium
What renal syndrome is associated with slit pore diaphragm disease?
nephrotic
Functionally, why do mesangial cells need to have contractile capabilities?
allows them to exert some regulation of glomerular blood flow
Functionally, why so mesangial cells need to have phagocytic capabilities? What do they phagocytose?
–Allows them to scavenge substances that leak into the mesangial matrix
–Substances (e.g. antibodies + ag-ab complexes) that have been trapped in the glomerular basement membrane, which “flow” along GBM until they reach mesangial matrix
What is a type of glomerulonephritis with localization of immune complexes in the mesangium? What causes this?
- IgA nephropathy
- Production of abn IgA with decreased glycosylation of hinge region GalNAc residues (with galactose and/or sialic acid)
What do underglycosylated IgA bind to (in the basement membrane and mesangial matrix)?
- other IgA (self-aggregate)
- IgG (which think they’re antigens)
- fibronectin in the basement membrane, which can incorporate into the immune complex
- soluble form of the IgA receptor (CD89)
- transferrin receptor (CD71) on mesangial cells
How are mesangial cells activated, and what do they do once activated?
activation = binding and phagocytosing these immune complexes
once activated = proliferate and increase production of extracellular matrix proteins and cytokines
What generates the damaging inflammation in IgA nephropathy?
complement activation:
alternative pathway = 75% of patients
lectin pathway = 25% of patients
Immune complexes that can be deposited in the glomerulus are either from:
circulation or in situ development
*in situ may be against intrinsic (fixed) antigens or “planted” antigens from the circulation
How do antibodies damage the glomerulus? (3)
- directly cytotoxic
- elicit and activate leukocytes, which secrete lysozyme and ROS
- activate complement
What types of cells secrete arachidonic acid metabolites, which reduce glomerular filtration?
leukocytes platelets endothelial cells glomerular epithelial cells mesangial cells
What types of cells aggregate in the glomerulus during immune-mediated injury (contributing to glomerular disease)?
platelets
Endothelial cells, glomerular epithelial cells and mesangial cells contribute to glomerular damage by secreting:
- cytokines (particularly IL-1)
- arachidonic acid metabolites
- growth factors
endothelial cells also secrete:
- nitric oxide
- endothelin
Glomerular diseases that include a component of thrombus formation in the capillaries yield _________; by triggering protease-activated receptors, this causes (2):
thrombin
- leukocyte infiltration
- glomerular cell proliferation
(weird Nichols sentence = weird question, sorry)
What does “important concept #5” consider to be a major mechanism of glomerular injury?
Antibody deposition
The three sites of immune complex deposition within glomeruli:
subepithelial
subendothelial
mesangial
Where do large circulating immune complexes become deposited, and why?
(What condition do you see this in?)
- -endothelial side of GBM (“under the endothelial cells in a subendothelial location”)
- -they cannot “traverse” GBM
- -lupus nephritis
Subendothelial deposits of immune complexes thicken the capillary walls, resembling:
wire loops
How does poststreptococcal glomerulonephritis
streptococcal antigens from the circulation are “planted” in subendothelium of glomerulus
How do antibodies damage podocytes?
antibodies against phospholipase A2 receptor and antigens in cell membrane of podocytes are formed in situ and deposit outside basement membrane and injure podocytes
*this causes the great majority of membranous glomerulonephritis
T/F: Antigens and antibodies can arrive in the glomerulus separately and form complexes in situ.
T
What is used to detect antibody or complement deposition in glomeruli?In what pattern are they deposited?
Immunofluorescence
clumped, granular pattern
What is used to detect antibody or complement deposition in glomeruli?In what pattern are they deposited?
Immunofluorescence
clumped, granular pattern
Post-streptococcal glomerulonephritis presents with antibodies apparently against what proteins? In what pattern are these antibodies deposited?
streptococcal exotoxin B
streptococcal GAPDH
endostroptosin
granular, subepithelial “humps” seen in electron microscopy
Post-streptococcal glomerulonephritis presents with antibodies apparently against what proteins? In what pattern are these antibodies deposited?
streptococcal exotoxin B
streptococcal GAPDH
endostroptosin
granular, subepithelial “humps” seen in electron microscopy
What is used to determine the location of immune complexes?
Electron microscopy
What is used to determine the location of immune complexes?
Electron microscopy
In what pattern does anti-GMB antibody deposit on immunofluorescence and electron microscopy?
linear pattern on immunofluorescence invisible in electron microscopy
In what pattern does anti-GMB antibody deposit on immunofluorescence and electron microscopy?
linear pattern on immunofluorescence invisible in electron microscopy
What is used to determine the type of immune complexes and other protein components of deposits in the glomeruli? What complement factors does this especially detect?
immunofluorescence
C1q, C3 and C4
What three forms of microscopy are needed to diagnose diseases in glomeruli, and why are all three necessary? (NOTE: this is unique to kidneys!)
light microscopy, immunofluorescence and electron microscopy
because “so much of glomerular disease is immune-mediated”
Why is Jones methenamine silver stain used in light microscopy?
it highlights the basement membrane so you can fully visualize glomerular disease
Why is periodic acid Schiff (PAS) stain used in light microscopy?
it highlights cellular cytoplasmic inclusions so you can fully visualize glomerular disease
Why is trichrome stain used in light microscopy?
it highlights collagen so you can fully visualize glomerular disease
The optimal diagnosis of medical renal disease requires clinicopathologic correlation with numerous clinical datapoints such as: (5)
- antibody tests for lupus, scleroderma and Goodpasture syndrome
- serum albumin
- serum creatinine
- urinalysis
- age, sex and race of the patient
IMPORTANT CONCEPT 6: The location and pattern of __________ are helpful in distinguishing among various types of glomerular disease.
immune complexes
What is the pattern of immunofluorescence of antibodies or immune complexes in crescentic glomerulonephritis?
“pauci-immune”
*there are no/little antibodies and immune complexes
What antibodies are present in patients with crescentic glomerulonephritis?
Either:
- P-ANCA (microscopic polyangiitis or Churg-Strauss syndrome)
- C-ANCA (granulomatous with polyangiitis, aka Wegener’s)
*NOTE: these antibodies are not visible on immunofluorescence or electron microscopy of glomeruli
How does hyperglycemia affect proteins in the blood and GBM?
It causes non-enzymatic glycosylation, which results in these proteins becoming trapped in GBM and stimulating production of GBM proteins
(proteins in GBM include type IV collagen, laminin, entactin)
What is the eventual result of hyperglycemia, in terms of the GBM?
thickened GBM distorted by glycosylated proteins
What are advanced glycation end-products (AGE)?
further metabolized glycosylated proteins
AGE mediate some of the accelerated aging that characterizes the effect of diabetes mellitus on organs throughout the body
What are 4 ways to induce and/or activate NADPH oxidases, producing ROS?
- Advanced oxidation protein products (AOPP)
- Activation of the renal angiotensin system
- TGF-beta
- AGEs
What does activating/inducing NADPH oxidases (producing ROS) result in?
(What conditions are these characteristic of?)
- mesangial cell hypertrophy and hyperplasia
- diffuse mesangial matrix production
- podocyte injury + apoptosis
diabetes and hemodynamic glomerular injury (HTN)
The renal damage due to diabetes results in:
proteinuria
The hyperglycemia of diabetes mellitus causes thickening of __________.
glomerular and tubular basement membranes
*also causes several varieties of deposits within the glomerulus, at least partly due to plasma leakage
T/F: Patients with diabetes often have metabolic syndrome–a disorder characterized by high blood pressure, yet normal cholesterol.
F: metabolic syndrome = hypertension, obesity and dyslipidemia
The end result of many glomerular diseases is:
nephron loss
What occurs after a nephron becomes necrotic (how does the body correct for the loss)?
- *no new nephrons are generated
1. surviving nephrons undergo hypertrophy
2. glomerular and tubular cells undergo hyperplasia and tubules lengthen
3. increased filtration per glomerulus
4. increased glomerular transcapillary pressure
T/F: The body compensates well short term and long term for nephron loss, and quickly replaces any damaged structures.
F: NO NEW nephrons are generated, and:
“compensation eventually hits a wall of limits, becomes maladaptive and starts causing injury, setting up a positive feedback loop of destruction”
T/F: Many patients have multiple types of glomerular disease at the same time and many types of glomerular disease have multiple, sometimes shared mechanisms of disease.
T (IMPORTANT CONCEPT 7)
What could be easier than remembering that global glomerular disease refers to the distribution of disease within a single glomerulus?
Apparently, nothing. . They even start with the same three letters.
Proliferative glomerulonephritis features increased cellularity including proliferating cells, which include:
cells native to the glomerulus
infiltrating inflammatory cells
What glomerular condition is characterized by increased glomerular basement membrane without an increase in cells?
Membranous glomerulopathy
Glomerular condition which is a combination of increased GBM and increased cellularity:
Membranoproliferative glomerulonephritis
What are 4 causes of the visible crescent of inflammation around the glomerular tuft of capillaries present in crescentic glomerulonephritis?
infiltrating macrophages
inflammatory exudate
leaked plasma
proliferating partietal epithelial cells
Glomerulonephritis is described as “necrotizing” when:
the inflammation causes necrosis of glomerular tissue.
List 2 glomerular conditions that are “bad news”:
crescentic
necrotizing
The most common type of crescentic glomerulonephritis:
Pauci-immune , aka ANCA-associated
no antibodies or immune complexes detectable by immunofluorescence or electron microscopy
The end result of many glomerular diseases is:
It can be (global/segmental) and (diffuse, focal)?
glomerulosclerosis (fibrous replacement of the glomerulus)
It can be global or segmental and diffuse or focal!!
