Flashcards in Seventeen Deck (50):
1
What are the 4 components of the glomerus with subcomponents?
• Epithelial cells
– Visceral
– Parietal
• B tM b asement Membrane
• Endothelial cells
• Mesangium
– Cells
– M ti a r x
2
Describe visceral epithelial cells and their function.
• Podocyte
• F too processes
• Attach to BM via adhesion proteins (integrins)
• Produce, maintain GBM
• Filtration slits extend between foot processes
• Slits are major barrier to passage of plasma
proteins
3
Describe the filtration slit diaphragm including the proteins involved and the function.
• Modified adherens junction
• Critical role in glomerular filtration barrier
• SD proteins control glomerular permeability
• Podocin, nephrin, CD2AP interact with membrane
proteins actin cytoskeleton proteins, actin cytoskeleton
4
Describe the GBM
• Made by VEC
• 300 nm thick
• 3 layers
• Type IV collagen, laminin,
fibronectin, proteoglycans,
glycoproteins
• Anionic
5
What are the functions of the mesangium?
• Contract
• Phagocytosis
• Synthesize matrix,
cy g tokines, growth factors
• Can proliferate and lay down
new matrix
• Continuous with
extraglomerular cells of JGA
6
What are 4 possible etiologies of glomerular injury?
• Glomerulus
– Immune-mediated
– Hemodynamic
– GBM abnormality
– Podocyte abnormality
7
What are 3 possible visceral epithelial cell pathologies? What can happen with parietal epithelial cells?
• Visceral
– Foot process effacement (fusion)
– Detach from GBM
– Subepithelial (epimembranous) immune deposits
• Parietal
– Proliferate (crescent)
8
What are 6 GBM pathologies?
• Too thick
• Too thin
• Too permeable
• Infiltrated
• Anti-GBM
• Intramembranous immune deposits
9
Name 2 endothelial cell pathologies.
• Proliferate
• Subendothelial immune
deposits
10
Name 4 mesangial pathologies.
• Cells/matrix increase
– Expand mesangial area
– Interpose between endothelium and GBM endothelium and GBM“interposition”
• Inflamed
• Intramesangial immune deposits
11
What do focal, diffuse, segmental, and global mean? What do endocapillary and extracapillary refer to?
Focal-some glomeruli in the kidney
Diffuse-all glomeruli
Segmental-only some parts of the glomerulus
Global-The whole glomerulus
• Increased cells
– Endocapillary
– Extracap y( ) illary (crescent)
12
What are immune deposits? What do they do? What are 4 ways in which they get to the glomerulus? Where in the glomerulus do the immune complexes deposit?
• Deposit = Immune complex
• A ti n gen-A tib d Antibody
complexes
• Complement activation and Complement activation and
induction of cytotoxic or p y roinflammatory complement components
• Activate macrophages, mesangial cells
• Circulating Ag-Ab compl t di ex trapped in
glomerulus
– Exogenous Antigen Exogenous Antigen
– Endogenous Antigen
• Ab reacts Ab reacts in-situ
– Fixed intrinsic Antigen
–“Planted” Antigen
• Subepithelial (epimembranous)
• Subendothelial
• Intramembrano s Intramembranous
• Mesangial
13
Describe the two clinical presentations of glomerular disease. What is pathognomonic for glomerular disease? Which test is necessary?
Nephrotic Syndrome
• Proteinuria (PU)
– 3-3.5 g/24h
• Hypoalbuminemia
• Edema
• Hyperlipidemia
Nephritic Syndrome
• Hematuria
– RBC casts
• Oliguria, azotemia (BUN)
• Hypertension
• Proteinuria
Marked proteinuria or hematuria with RBC cast th i f ts pathognomonic glomerular disease.
Urinalysis
14
What are the causes of hypoalbuminemia in nephrotic syndrome? What is the cause of hyperlipidemia? Describe the pathophysiology of nephrotic syndrome. Describe the
• Hypoalbuminemia
– Urine loss
– ? Hepatic synthesis ↓, renal degradation ↑, extra renal
disposition change.
• H li id i Hyperlipidemia
– ↑ VLDL synthesis
Increased permeability to plasma proteins
• Lose size, charge selective protein barrier
• Structural, physicochemical change
– GBM proteoglycans
– Endothelium/epithelium sialoglycoprotein coat
– Slit diap g hra m
15
What are 6 causes of nephrotic syndrome? How does the likelihood of the causes differ between adults and children?
• Diagnosis varies with age
• Children: Primary renal disease, minimal change
disease FSGS
• Adults: Primary or syst i em c disease, membranous
glomerulopathy
• Minimal Change Disease
• Focal Segmental Glomerulosclerosis (FSGS)
• Membranous
• MPGN
• Diabetes
• Amyloidosis
16
What are some other names for minimal change disease? What are some its clinical characteristics? What does MCD look like with LM/EM?
• Lipoid nephrosis
• Nil disease
• MCD
• Nephrotic syndrome
• Children>>Adults
• Selective proteinuria
• Normal renal function
• Steroid responsive
• Not immune complex- mediated
• T-cell mediated VEC damage with cytokine release, GBM or slit diaphragm damage
• Loss of glomerular polyanion
• Mutation in nephrin
Light microscopy
Normal glomeruli
Lipoid Nephrosis (sloughing off of the epithelium (which contains lipid) into the PT lumen, which results in oval fat bodies in urine)
EM
Complete foot process effacement
17
What is FSGS? What are some of its clinical characteristics?
What are some of its epidemiological characteristics? What is the most common cause of FSGS? What are some other causes?
Focal segmental glomerulosclerosis
• Nephrotic syndrome
• Nonselective proteinuria
• Less steroid responsive than MCD, >50% ESRD in 5 yrs.
• Adults - 35% of NS, Children 10% of NS
• More prevalent in African-
American, Hispanic
• Primary (idiopathic) most common
• Renal ablation nephropathy, obesity
• “Healed” glomerulonephritis
• HIV, heroin, SS disease
• Mutations in slit diaphragm proteins
18
What causes primary FSGS? What causes secondary FSGS?
Primary
• VEC injury
• Circulating factor,
cytokine?
Secondary
• Hemodynamic injury-Reduced nephron number relative to body mass (unilateral agenesis, advanced renal disease, obesity)
• Mutation in gene for slit diaphragm protein
– Nephrin, podocin, alpha-actinin-4 TRPC6 4, TRPC6
19
What does FSGS look like histologically? In LM? EM?
LM
• Sclerosis of some, but not all glomeruli (FOCAL
• Sclerosis affects a segment but not all of a glomerulus
(SEGMENTAL)
EM
– Fusion of foot processes (effacement)
– Epithelial detachment
20
What are some synonyms for membranous nephropathy? What are some clinical characteristics of membranous nephropathy? What is the most common cause? What are some other causes? What are some other association?
Epimembranous glomerulonephritis
Membranous glomerulonephritis
Membranous glomerulopathy
MGN
MN
PU or Nephrotic Syndrome
Adults>Children
25% progress to failure
Usually primary
• Autoimmune disease
• Carcinoma
– Lung, colon, melanoma
• Drugs
– Gold, penicillamine, NSAIDs
• Infections
– Hep B, C, syphilis, malaria
• Other associations
– DM, Renal vein thrombosis
• ATIII, Protein C and S lost in urine
21
Describe the pathogenesis of membranous nephropathy.
Chronic immune complex deposition
• In-situ formation: antibody to endogenous VEC autoantigen (autoimmune disease) or planted ag
• Circulating immune complexes:
Endogenous or exogenous ag
22
What is the most common antigen responsible in membranous nephropathy? In which type is it most common? What other antigens can be responsible?
• Endogenous in VEC
– In 70% of adults VEC phospholipase A (PLA2R) 2 receptor
– Neutral endopeptidase (NEP)
• Planted antigen Planted antigen
– Hep B, C proteins
– dsDNA histone RNA
23
Describe the LM pathology in membranous nephropathy. EM pathology? Immunoflourescence?
LM
No glomerular inflammation, no intracapillary proliferation
• Spikes on subepithelial GBM
EM
• Subepithelial (epimembranous) immune deposits
• Spikes are projections of lamina densa around deposits
Immunoflourescence
• Diffuse granular immune deposits along GBM
(antibody + complement)
24
What are some synonyms for membranoproliferative glomerulonephritis? What are some clinical characteristics? What are the types?
MPGN
Mesangiocapillary GN
Hypocomplementemic GN
Lobular GN
• Children, young adults
Nephritic OR nephrotic
• Hypocomplementemic
• Can progress to ESRD
Two types
Type I
Type II (Dense Deposit Disease)
25
What is the pathology of membranoproliferative GN? Which type is more common?
• Proliferation of mesangial
cell l l l lls along glomerular
basement membrane in
subendothelial location subendothelial location
• Type I and II similar by LM
– I more common than II I more common than II
26
What is the pathogenesis in type I MPGN? What are some causes? waht does it look like with LM? EM? IF?
• Circulating immune complexes lead to complement activation
• Idiopathic
• Secondary
– Infectious: Hepatitis B, C, endocarditis, shunt infection
– SLE
– Chronic liver disease Chronic liver disease
– Hereditary complement deficiency
– Chronic Liver disease
– Cryogloblinemia
– IV drug use
LM
• Enlarged lobular cellular glomeruli mesangial
proliferation, inflamed
• Interposition of mesangial cells between
endothelium and GBM “double contour”
EM
• Subendothelial, mesangial deposits
• Interposition of mesangial cells between
GBM and endothelium
IF
IgG, complement granular deposits over glomerular
capillary loops
27
Describe the pathogenesis of Dense deposit disease. What does it look likes in LM? EM? IF?
• Circulating IgG autoantibody C3 Nephritic Factor (C3NeF) binds to and stabilizes C3bBb (C3 convertase), which causes enhanced C3 breakdown, low C3, increased biologically active C3b
LM
Like type I
EM
Dense homogenous ribbon of deposits in GBM
IF
C3 in GBM adjacent to dense deposits, in mesangium
No IgG
28
Describe the pathogenesis and pathophys of diabetic nephropathy.
Part of microangiopathy
– Retinopathy, coronary artery disease, peripheral nerves
• Hyperfiltration “theory”
– glomerular hypertension, hyperfiltration, hyperperfusion
• Metabolic “theory”
– Insulin deficiency, hyperglycemia, hyperlipidemia lead to AGEs (nonenzymatic glycated proteins, lipids)
– AGEs react with RAGE, generate growth factors, cytokines with glomerular injury
• Common in diabetics (30%)
• Nonenzymatic glycosylation of GBM proteins increases permeability
• Proteinuria, glucosuria
• Progress to ESRD
• Function of severity, duration of hyperglycemia, hypertension, smoking, ?genetic factors
• Hemodynamic injury (increased GFR, capillary pressure)
29
How does diabetic nephropathy look with LM? EM?
LM
• Enlarged glomeruli, increased mesangial matrix
• Nodular glomerulosclerosis
– Kimmelstiel-Wilson lesion
• Hyaline arteriolosclerosis of afferent and efferent
arteriole
EM
• GBM thickened
• Mesangium expanded
– Cells + matrix increase
30
What is amyloidosis? What are some symptoms? What occurs in renal amyloidosis?
• Systemic disease
• Accumulation of misfolded proteins in many organs
• Hepatosplenomegaly, heart failure, neuropathy, macroglossia, carpal tunnel syndrome
RENAL AMYLOIDOSIS
• Amyloid accumulates in glomerulus
• AL (g ) y light chain) amyloid (80%) or AA (Serum
amy ) loid A)
• Massive proteinuria
• Can progress to ESRD
31
What does renal amyloidosis look like on LM? Special stains?
• Early - amyloid in mesangium
• Late – obliteration of capillary loop
• Interstitium, vessels infiltrated by amyloid
• With Congo red stain, polarized light, amyloid polarized light, amyloid has apple green birefringence
EM
Amyloid fibrils (pick up sticks)
32
What are the nephritic syndromes usually associated with ? What are some clinical characteristics? List 6 disorders that results in nephritic syndrome.
Acute glomerulonephritis, proliferative inflammatory process
Usually acute
Hematuria, RBC casts (RBCs from glomerulus join up in tubule)
Azotemia, proteinuria, hypertension, oliguria
Acute glomerulonephritis
SLE
IgA nephropathy
Anti-GBM Nephritis
Hereditary Nephritis
Rapidly progressive GN
33
What are some clinical aspects of acute glomerulonephritis? What is the etiology? What are some lab findings?
Common
Sudden onset nephritic syndrome
Good prognosis in children
1-4 wk after infection with nephritogenic strain of Gp A beta hemolytic strep (impetigo or strep throat)
Other infections (Staph, pneumococcus, HIV, IM, malaria
Elevated ASO titer, circulating immune complexes, hypocomplementemia
RBC casts, smoky colored urine
34
Describe the pathogenesis of acute GN.
Trapped circulating or in situ immune complex formation
Antigen part of infectious organism planted in glomerulus
Cationic antigens NAPlr from nephritogenic strep and SPE B in glomeruli
35
What does acute GN look like with LM? EM? IF?
LM
Enlarged glomeruli
Endocapillary hypercellularity (neutrophils, monocytes
Extracapillary hypercellularity possible
EM
Humpshaped or dome shaped subepithelial deposits
Occasional subendothelial deposits
IF
granular IgG, C3 over capillary walls
Lumpy Bumpy
36
What are some clinical characteristics of lupus?
Multiple immune system abnormalities
Many SLE patients have renal disease
-90% will have abnormal renal biopsy
Nephritic or Nephrotic
Positive ANA
-Anti dsDNA, Anti Sm (core proteins of ribonucleoproteins), very specific for lupus
37
What is kidney look like under LM in lupus ? EM? IF
LM
Can look like anything:
Glomeruli enlarged, endocapillary proliferation, inflamed
Segmental necrosis, karyorrehexis
Capillary loop thrombi
May have extracapillary proliferation
Wire loop lesions
EM
Deposits can be anywhere:
Subendothelial
Subepithelial
Mesangial
Intramembranous
IF
Deposits can be anywhere:
IgG, IgM, IgA, C3, C1q over BM, in mesangium="Full house" pattern
38
What are some epidemiological characterists of IgA nephropathy? Clinical? Describe the two forms.
Children, young adults
Boys > girls
flank pain
Recurrent hematuria
Most common glomerular disease worldwide
-Japan, europe
Can progress to ESRD
Henoch Schoenlein Purpura
-palpable purpura (dermal hemorrhage, leukocytoclastic vasculitis, IgA in dermal vessel walls), buttocks
arthralgias
colicky abdominal pain
renal disease
Berger Disease
-limited to kidney
39
What are some ways to get secondary IgA nephropathy?
Liver disease
-Cirrhosis
Intestinal autoimmune diseases with gluten intolerance
-celiac disease
-dermatitis herpetiformis
IBD, sarcoidosis, HIV, neoplasis
40
Describe the pathogenesis of IgA nephropathy
IgA1 molecule is normally galactosylated with GalNac and Gal.
This is reduced
This incites antibody response
IgA nephropathy may have increased IgA concentration
41
What does LM look like in IgA nephropathy? IF? EM?
LM
Mesangial proliferation (cells and matrix)
IF
Mesangial IgA containing immune complexes and C3
EM
Mesangial electron dense deposits
42
Describe rapidly progressing GM. What are the causes?
Rapidly loss in renal function
Oliguria
Renal failure
>60% crescents
May become anephric
-90% of untreated have ESRD
Idiopathic
Associated with other renal or systemic disease
Immune mediated in most cases
43
Describe the 3 types of RPGN.
Type I-Anti GBM disease
type II-Due to immune complex nephritis
-SLE, IgA, post-streptococcal
Type III-Pauci-immune
-no renal deposits
-ANCA associated vascultis
Wegeners, microscopic polyangiitis
44
Describe RPGN under LM.
LM
Focal segmental necrosis
endocapillary proliferation
extracapillary proliferation
45
What is the epidemiology of Type I RPGN? Describe clinical aspects. Describe pathogenesis
Rare, young men
<5% of glomerulonephritites,
Can have pulmonary hemorrhage, necrotizing alveolitis (Goodpastures)
Anti GBM antibody
Rapidly progressive
Plasmapheresis can help.
Autoimmune disease
Autoantibody to intrinsic GBM antigen (Col4A3 usually)
-Antigen usually cryptic
Anti-GBM may cross react with alveolar BM in goodpasture syndrome
46
What does Anti-GBM disease look like with IF? Type II RPGN? Type III?
Anti-GBM binds with a diffuse linear pattern.
Type II-Granular immune complex label (underlying disease)
Type III-Pauci-immune-no glomerular label.
47
Decribe the two pathogeneses for type III RPGN.
Underlying small vessel vasculitis, ANCA +
Wegeners Disease-necrotizing GN, granulomatous sinusitis, pulmonary hemorrhage
Microscopic polyangiitis-Necrotizing GN w/o sinus disease or granulomas
48
Describe the clinical presentation in hereditary nephritis (alport syndrome). Clinical characteristics?
Episodic hematuria (early)
Proteinuria, hypertension, ESRD late
Can be isolated renal disease, or part of multisystem disease
Sensorineural deafness, lens defect, cataracts
Xlinked (80%)-Men usually have it worse, women variable
AD, AR (20%)
49
Describe the pathogenesis for the different inheritances of alport syndrome
X-linked = mutation with COL4A5 which is on the x chromosome. Leads to abnormal GBM assembly and structure. Not immune injury. Some develop Anti-GBM allograft.
AD/AR-COL4A (3/4) which is on chromosome 2.
50