Flashcards in Seventeen Deck (50):
What are the 4 components of the glomerus with subcomponents?
• Epithelial cells
• B tM b asement Membrane
• Endothelial cells
– M ti a r x
Describe visceral epithelial cells and their function.
• 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
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
Describe the GBM
• Made by VEC
• 300 nm thick
• 3 layers
• Type IV collagen, laminin,
What are the functions of the mesangium?
• Synthesize matrix,
cy g tokines, growth factors
• Can proliferate and lay down
• Continuous with
extraglomerular cells of JGA
What are 4 possible etiologies of glomerular injury?
– GBM abnormality
– Podocyte abnormality
What are 3 possible visceral epithelial cell pathologies? What can happen with parietal epithelial cells?
– Foot process effacement (fusion)
– Detach from GBM
– Subepithelial (epimembranous) immune deposits
– Proliferate (crescent)
What are 6 GBM pathologies?
• Too thick
• Too thin
• Too permeable
• Intramembranous immune deposits
Name 2 endothelial cell pathologies.
• Subendothelial immune
Name 4 mesangial pathologies.
• Cells/matrix increase
– Expand mesangial area
– Interpose between endothelium and GBM endothelium and GBM“interposition”
• Intramesangial immune deposits
What do focal, diffuse, segmental, and global mean? What do endocapillary and extracapillary refer to?
Focal-some glomeruli in the kidney
Segmental-only some parts of the glomerulus
Global-The whole glomerulus
• Increased cells
– Extracap y( ) illary (crescent)
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
• 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
– Exogenous Antigen Exogenous Antigen
– Endogenous Antigen
• Ab reacts Ab reacts in-situ
– Fixed intrinsic Antigen
• Subepithelial (epimembranous)
• Intramembrano s Intramembranous
Describe the two clinical presentations of glomerular disease. What is pathognomonic for glomerular disease? Which test is necessary?
• Proteinuria (PU)
– 3-3.5 g/24h
– RBC casts
• Oliguria, azotemia (BUN)
Marked proteinuria or hematuria with RBC cast th i f ts pathognomonic glomerular disease.
What are the causes of hypoalbuminemia in nephrotic syndrome? What is the cause of hyperlipidemia? Describe the pathophysiology of nephrotic syndrome. Describe the
– Urine loss
– ? Hepatic synthesis ↓, renal degradation ↑, extra renal
• 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
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
• Adults: Primary or syst i em c disease, membranous
• Minimal Change Disease
• Focal Segmental Glomerulosclerosis (FSGS)
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
• Nephrotic syndrome
• 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
Lipoid Nephrosis (sloughing off of the epithelium (which contains lipid) into the PT lumen, which results in oval fat bodies in urine)
Complete foot process effacement
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-
• Primary (idiopathic) most common
• Renal ablation nephropathy, obesity
• “Healed” glomerulonephritis
• HIV, heroin, SS disease
• Mutations in slit diaphragm proteins
What causes primary FSGS? What causes secondary FSGS?
• VEC injury
• Circulating factor,
• 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
What does FSGS look like histologically? In LM? EM?
• Sclerosis of some, but not all glomeruli (FOCAL
• Sclerosis affects a segment but not all of a glomerulus
– Fusion of foot processes (effacement)
– Epithelial detachment
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?
PU or Nephrotic Syndrome
25% progress to failure
• Autoimmune disease
– Lung, colon, melanoma
– Gold, penicillamine, NSAIDs
– Hep B, C, syphilis, malaria
• Other associations
– DM, Renal vein thrombosis
• ATIII, Protein C and S lost in urine
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
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
Describe the LM pathology in membranous nephropathy. EM pathology? Immunoflourescence?
No glomerular inflammation, no intracapillary proliferation
• Spikes on subepithelial GBM
• Subepithelial (epimembranous) immune deposits
• Spikes are projections of lamina densa around deposits
• Diffuse granular immune deposits along GBM
(antibody + complement)
What are some synonyms for membranoproliferative glomerulonephritis? What are some clinical characteristics? What are the types?
• Children, young adults
Nephritic OR nephrotic
• Can progress to ESRD
Type II (Dense Deposit Disease)
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
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
– Infectious: Hepatitis B, C, endocarditis, shunt infection
– Chronic liver disease Chronic liver disease
– Hereditary complement deficiency
– Chronic Liver disease
– IV drug use
• Enlarged lobular cellular glomeruli mesangial
• Interposition of mesangial cells between
endothelium and GBM “double contour”
• Subendothelial, mesangial deposits
• Interposition of mesangial cells between
GBM and endothelium
IgG, complement granular deposits over glomerular
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
Like type I
Dense homogenous ribbon of deposits in GBM
C3 in GBM adjacent to dense deposits, in mesangium
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)
How does diabetic nephropathy look with LM? EM?
• Enlarged glomeruli, increased mesangial matrix
• Nodular glomerulosclerosis
– Kimmelstiel-Wilson lesion
• Hyaline arteriolosclerosis of afferent and efferent
• GBM thickened
• Mesangium expanded
– Cells + matrix increase
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
• Amyloid accumulates in glomerulus
• AL (g ) y light chain) amyloid (80%) or AA (Serum
amy ) loid A)
• Massive proteinuria
• Can progress to ESRD
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
Amyloid fibrils (pick up sticks)
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
Hematuria, RBC casts (RBCs from glomerulus join up in tubule)
Azotemia, proteinuria, hypertension, oliguria
Rapidly progressive GN
What are some clinical aspects of acute glomerulonephritis? What is the etiology? What are some lab findings?
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
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
What does acute GN look like with LM? EM? IF?
Endocapillary hypercellularity (neutrophils, monocytes
Extracapillary hypercellularity possible
Humpshaped or dome shaped subepithelial deposits
Occasional subendothelial deposits
granular IgG, C3 over capillary walls
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
-Anti dsDNA, Anti Sm (core proteins of ribonucleoproteins), very specific for lupus
What is kidney look like under LM in lupus ? EM? IF
Can look like anything:
Glomeruli enlarged, endocapillary proliferation, inflamed
Segmental necrosis, karyorrehexis
Capillary loop thrombi
May have extracapillary proliferation
Wire loop lesions
Deposits can be anywhere:
Deposits can be anywhere:
IgG, IgM, IgA, C3, C1q over BM, in mesangium="Full house" pattern
What are some epidemiological characterists of IgA nephropathy? Clinical? Describe the two forms.
Children, young adults
Boys > girls
Most common glomerular disease worldwide
Can progress to ESRD
Henoch Schoenlein Purpura
-palpable purpura (dermal hemorrhage, leukocytoclastic vasculitis, IgA in dermal vessel walls), buttocks
colicky abdominal pain
-limited to kidney
What are some ways to get secondary IgA nephropathy?
Intestinal autoimmune diseases with gluten intolerance
IBD, sarcoidosis, HIV, neoplasis
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
What does LM look like in IgA nephropathy? IF? EM?
Mesangial proliferation (cells and matrix)
Mesangial IgA containing immune complexes and C3
Mesangial electron dense deposits
Describe rapidly progressing GM. What are the causes?
Rapidly loss in renal function
May become anephric
-90% of untreated have ESRD
Associated with other renal or systemic disease
Immune mediated in most cases
Describe the 3 types of RPGN.
Type I-Anti GBM disease
type II-Due to immune complex nephritis
-SLE, IgA, post-streptococcal
-no renal deposits
-ANCA associated vascultis
Wegeners, microscopic polyangiitis
Describe RPGN under LM.
Focal segmental necrosis
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
Plasmapheresis can help.
Autoantibody to intrinsic GBM antigen (Col4A3 usually)
-Antigen usually cryptic
Anti-GBM may cross react with alveolar BM in goodpasture syndrome
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.
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
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%)
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.