19 Pathology of Glomerular Disease

Question 1

Glomerulus

• Site of…
• Capillary beds
• Surrounded by…
• Visceral epithelial cells
• PT epithelial cells

Answer 1

• Site of ultrafiltration of plasma resulting (following tubular modification) in the formation of urine
• First of two capillary beds in the kidney that connects the AffAs & EffAs
  
  • Second capillary bed is the peritubular capillary plexus in the cortex & the vasa recta in the medulla
• Surrounded by Bowman’s capsule
  
  • Covered by parietal epithelial cells
• Visceral epithelial cells (podocytes) cover the glomerular capillary surfaces
  
  • Formed as the parietal epithelial cells
• PT epithelial cells reflect over the vascular and tubular poles
• Podocytes
  
  • Important part of the filtration barrier of the glomerulus
  • Cover the entire glomerular BM

Question 2

Basement membrane overlying glomerular capillaries

• 3 layers (from outer to inner)
• Endothelial cell
• Overlying mesangial areas, the BM has 2 layers
• Deep to the BM is the…
• Mesangial matrix contains mesangial cells that have 3 functions

Answer 2

• 3 layers (from outer to inner)
  
  • Lamina rara externa
  • Lamina densa
  • Lamina rara interna
• Endothelial cell
  
  • Internal to the BM
  • Unique flat cell with numerous holes or fenestrations that retard cells but allow plasma to freely enter the BM
• Overlying mesangial areas, the BM has 2 layers
  
  • Lamina rara externa
  • Lamina densa)
• Deep to the BM is the…
  
  • Mesangial matrix
  • Contiguous with the lamina rara interna
• Mesangial matrix contains mesangial cells that have 3 functions
  
  • Tether BM to mesangium –> formation of glomerular segments with multiple peripheral capillaries & a central mesangial unit
  • Phagocytosis of cell debris & material that gets deposited in the mesangium & lamina rara interna
  • Production of cytokines that stimulate glomerular cellular proliferation in response to injury

Question 3

Assessing glomeruli in a renal biopsy

• Histologic sections
• Glomerular mesangial areas
• Glomerular capillaries
• Glomerular capillary walls
• Urinary space
• H&E stain
• Methenamine silver stains
• PAS stains
• Renal biopsy paraffin histologic sections

Answer 3

• Histologic sections
  
  • 2D representation of a 3D structure
• Glomerular mesangial areas
  
  • Relatively inapparent
  • Contain < 3 mesangial cells / mesangial area
    
    • Exception: hilum has a greater # of mesangial cells
• Glomerular capillaries
  
  • Patent
• Glomerular capillary walls
  
  • Glomerular BM + endotehlial cell + podocyte
  • Thin & expanded
• Urinary space
  
  • Empty
• H&E stain
  
  • Limited by its inability to distinguish cytoplasm of endothelial cells, podocytes, & mesangial cells from GBM & mesangial matrix
• Methenamine silver stains
  
  • Stain type IV collagen in glomerular & tubular BMs, bowman’s capsule, & extraglomerular blood vessels
• PAS stains
  
  • Stain polysaccharides in glomerular & tubular BMs, bowman’s capsule, & extraglomerular blood vessels
• Renal biopsy paraffin histologic sections
  
  • Cut at 2-3 microns in thickness
  • Thicker sections –> cell overlapping –> appearnace of hypercellularity

Question 4

Clinical classifications

• Primary
• Secondary
• Onset
• Single occurence
• Chronic

Answer 4

• Primary
  
  • Limited to the kidney
• Systemic
  
  • Secondary glomerulonephropathies
• Onset
  
  • Acute
  • Insidious (chronic)
  • Sublincial (detected as a lab abnormality only)
• Single occurence
  
  • Resolves w/ no clinical or pathologic sequelae
    or
  • Organizes w/ a persistent & stable deficit
• Chronic
  
  • Periods of alternating activity & inactivty (relapses & remissions)
  • Frequently –> progressive loss of glomeruli & progressive renal dysfunction

Question 5

Glomerular syndromes

• Acute nephritic syndrome
• Rapidly progressive glomerulonephritis
• Nephrotic syndrome
• Chronic renal failure
• Asymptomatic hematuria or proteinuria

Answer 5

• Acute nephritic syndrome
  
  • Hematuria, azotemia/ARF, variable proteinuria, oliguria, edema, & hypertension
  • Reversible lesion that doesn’t –> glomerular scarring
  • Renal biopsy: proliferative glomerular disorder w/o necrotizing lesions / crescents
• Rapidly progressive glomerulonephritis
  
  • Often presents like an acute nephritic syndrome w/ proteinuria & ARF
  • Progressive w/o therapy
  • –> glomerular scarring w/ loss of functional glomeruli
  • In some pts, the disease is more slowly progressive
  • Renal biopsy: glomerular necrotizing lesions / crescents
• Nephrotic syndrome
  
  • >3.5 gm proteinuria / day, hypoalbuminemia, hyperlipidemia, hyperlipiduria, & edema
  • Renal biopsy: non-proliferative glomerular disorder w/ consistent podocyte injury manifested by foot process fusion, in addition to other disease specific pathology
• Chronic renal failure
  
  • Renal impairment (azotemia) progressing gradually to renal failure over a period of years
  • May be associated with…
    
    • All forms of progressive glomerular disease
    • Glomerular diseases which occur as a single episode –> significant loss of glomeruli w/ subsequent progressive hyperfiltration injury & glomerular loss occurring in the remaining glomeruli
• Asymptomatic hematuria or proteinuria
  
  • Non-progressive subclinical hematuria or proteinuria
  • Detected on urine evaluation during a routine physical exam
  • Glomerular hematuria: sub-nephrotic proteinuria

Question 6

Glomerulopathy:
Approach to morphologic classification

• Establish…
• Define…
• Define…
• Assess…

Answer 6

• Establish glomerulus as primary target of injury
• Define distribution of glomerular injury
  
  • Subcapsular vs. juxtamedullary vs. random
  • Diffuse vs. focal
  • Global vs. segmental
  • Peripheral (capillayr loop) vs. central (mesangial) vs. extraglomerular
• Define light microscopic pattern of glomerular injury
• Assess for involvement of other renal compartments

Question 7

Morphologic (pathologic) classification:
Light microscopy

• Normal subcapsular glomerulus including Bowman’s space/capsule measures…
• Juxtamedullary glomeruli may measure…
• Compare the structure of the glomerulus to that of a tree
  
  • Trunk & branches –>
  • Leaves –>
• More peripheral mesangium (in a 2-3 micron section)…
• More centrally towards to the hilum…
• Capillary loops
• Capillary walls
• Light microscopic (H&E) classification of glomerular disorders
• Specific etiologic diagnosis
• Renal biopsy
• For those disorders which characteristically diffusely involve glomeruli…
• For early stage focal glomerular disorders…
• For non-random focal processes…

Answer 7

• Normal subcapsular glomerulus including Bowman’s space/capsule measures…
  
  • 250 microns in max diameter
• Juxtamedullary glomeruli may measure…
  
  • Up to 300 microns
• Compare the structure of the glomerulus to that of a tree
  
  • Trunk & branches –> mesangium
  • Leaves –> capillary loops
• More peripheral mesangium (in a 2-3 micron section)…
  
  • Inapparent matrix
  • < 3 mesangial cells
• More centrally towards to the hilum…
  
  • Both mesangial matrix & cellularity are increased
• Capillary loops
  
  • Peripheral structures
  • Widely patent
• Capillary walls
  
  • Combination of endothelial & epithelial cells & BM
  • Thin and uniform
• Light microscopic (H&E) classification of glomerular disorders
  
  • Descriptive: based on the qualitative & quantitative morphologic alterations from the normal glomerulus
  • Iintended to define the distribution & pattern of glomerular injury
• Specific etiologic diagnosis
  
  • Based on the integration of the clinical & serologic data + light (H&E & special histochemical stains), IF, & EM
• Renal biopsy
  
  • Represents a sampling of a pathologic process occurring in the kidney
  • May or may not be representative of this process
• For those disorders which characteristically diffusely involve glomeruli…
  
  • Sampling which includes a single glomerulus may be sufficient to define the disease process
• For early stage focal glomerular disorders…
  
  • Adequate sampling is critical for establishing the diagnosis
  • > 10 non-sclerotic glomeruli are arbitrarily required for an adequate biopsy only if the focality of the glomerular process is random
• For non-random focal processes…
  
  • E.g. glomerular disorders which preferentially affect subcapsular or juxtamedullary glomeruli
  • Full thickness cortical (with medullary) sampling is optimal to evaluate glomeruli at all levels within the cortex
  • Best accomplished by examination of > 2 1.5 cm needle biopsy cores

Question 8

Morphologic (pathologic) classification:
Light microscopy:
Distribution of injury

• Diffuse vs. focal
• Global vs. segmental
• Mesangial vs. peripheral vs. extraglomerular

Answer 8

• Diffuse vs. focal
  
  • Diffuse: > 50% of glomeruli affected
  • Focal: < 50% of glomeruli are affected
• Global vs. segmental
  
  • Global: entire glomerulus
  • Segmental: subtotal of glomerular involvement by a lesoin affecting > 1 anatomic segments
• Mesangial vs. peripheral vs. extraglomerular
  
  • Mesangial: mesangium
  • Peripheral: GBM + podocytes
  • Extraglomerular: bowman’s space

Question 9

Morphologic (pathologic) classification:
Light microscopy:
Patterns of injury:
Increased ECM

• Sclerosis
• Types
• On silver stain, 2 patterns of obsolescence are seen

Answer 9

• Sclerosis (ex.)
  
  • Fibrillar collagen (scar)
  • Mucopolysaccharides
  • Non-collagen proteins
  • Immune complex deposits
• Types
  
  • Mesangial
  • Peripheral (capillary loop) BM
  • Bowman’s space/capsule
  • Obsolescence (entire glomerulus is eosinophilic and hypocellular on H&E stain)
• On silver stain, 2 patterns of obsolescence are seen
  
  • Tuft is collapsed and fibrosis is present only in Bowman’s space
    
    • Ischemic pattern
  • Fibrosis replaces part of or entire glomerulus and fills Bowman’s space
    
    • Organization of a necrotizing inflammatory GN or crescent

Question 10

Morphologic (pathologic) classification:
Light microscopy:
Patterns of injury:
Increased cellularity

• Intraglomerular
  
  • Mesangioproliferative
  • Endocapillary proliferative = mesangiocapillary proliferative
  • Membranoproliferative
  • Exudative
• Extraglomerular
  
  • Pure epithelial
  • Crescent

Answer 10

• Intraglomerular
  
  • Mesangioproliferative
    
    • Iincreased cellularity & matrix confined to mesangial areas
    • > 3 mesangial cells / mesangial area
  • Endocapillary proliferative = mesangiocapillary proliferative
    
    • Increased mesangial & capillary loop cellularity
    • Increased mesangial matrix
    • Capillary wall thickening
    • Capillary luminal occlusion secondary to endothelial swelling &/or BM thickening
  • Membranoproliferative
    
    • Special forms of mesangiocapillary proliferative GN
    • Distinctive features on silver stains
      
      • Double GBM contours
      • Mesangial cell ingrowth into contiguous subendothelial GBM (mesangial interposition)
  • Exudative
    
    • Mesangiocapillary proliferative GN
    • Increased numbers of glomerular intracapillary neutrophils
• Extraglomerular (glomerulus peripheral to the BM)
  
  • Pure epithelial
    
    • Visceral &/or parietal)
    • Correlates with podocyte injury
  • Crescent
    
    • Results from glomerular necrotizing lesion (glomerular capillary vasculitis)
    • Ttransmural glomerular capillary wall breaks
    • Bleeding into Bowman’s space
    • Earliest crescents have blood and fibrin in Bowman’s space (fibrinous crescent)
    • Cytokines produced by incoming monocytes cause proliferation of parietal epithelial cells (cellular crescent)
    • Recruitment of fibroblasts –> fibrosis in the affected area of the glomerular tuft & adjacent Bowman’s space (fibrocellular –> fibrous crescent)

Question 11

Morphologic (pathologic) classification:
Light microscopy:
Patterns of injury:
Other

Answer 11

• Hyalinosis
  
  • Plasma protein insudation in mesangium, capillary BM, arterioles &/or Bowman’s capsule
  • Due to endothelial or epithelial injury w/ serum protein leakage & entrapment
  • In diabetes, hyalinosis lesions are designated as
    
    • Fibrin caps (glomerular tuft)
    • Capsular drops (Bowman’s capsule).
• Necrosis or necrotizing lesion
  
  • Necrotizing glomerular capillaritis associated w/ inflammatory cells, karyorrhectic nuclear debris & fibrin
  • Organization –> segmental or global sclerosis / scar
• Glomerular foam cells
  
  • Frequently seen in glomerular – associated proteinuric disorders
  • Correspond to resorption of protein & lipoprotein in macrophages within the glomerular tuft
• Mesangiolysis
  
  • Disruption of mesangium
  • Because several capillary loops are tethered to one mesangial area, mesangiolysis may –> single large capillary loop (microaneurysm)

Question 12

Morphologic (pathologic) classification:
Light microscopic description

• LM classification/description (ex.s)
• Etiological specificity
• Specific diagnosis requiresintegration of…

Answer 12

• LM classification/description = distribution pattern(s) + morphologic pattern(s) of injury (ex.s)
  
  • Focal segmental glomerulosclerosis with hyalinosis.
  • Focal segmental endocapillary proliferative and necrotizing glomerulonephritis with focal cellular crescents.
  • Diffuse global endocapillary proliferative and exudative glomerulonephritis.
  • Diffuse mesangioproliferative glomerulonephritis.
  • Etc.
• Etiological specificity
  
  • A particular LM description may be shared by a variety of etiologically distinctive glomerular disorders
  • Conversely, a specific disorder (e.g. lupus) may display >1 glomerular morphologic pattern of injury
    
    • Depends upon factors such as the time course in the illness, physical properties of deposited materials (e.g. immune complex deposits), host-specific immune response to injury, etc.
• Specific diagnosis requires integration of…
  
  • Clinical & serologic data
  • LM
  • IF
  • EM

Question 13

Morphologic (pathologic) classification:
​Immunofluorescence microscopy

• Used to assess…
• Uses…
• Panel of stains usually includes…
• Procedure
• A positive signal with a particular antibody indicates…

Answer 13

• Used to assess…
  
  • Evidence of antibody-mediated immunologic injury
• Uses…
  
  • A panel of commercially prepared fluorescein labeled antibodies which recognize specific antigens
• Panel of stains usually includes…
  
  • Ig heavy chain classes (IgG, IgM, IgA) & light chains (kappa, lambda)
  • Complement components of the shared (C3), classical (C1q, C4) and alternative (properdin) pathways
  • Fibrinogen
  • Albumin
• Procedure
  
  • One frozen section slide is prepared for each specific antibody used
  • The fluorescein labeled antibody is incubated with the frozen section tissue
• A positive signal with a particular antibody indicates…
  
  • Presence & location of that antigen within the tissue

Question 14

Morphologic (pathologic) classification:
​Immunofluorescence microscopy:
Distribution

• Glomerular
• Extragomerular

Answer 14

• Glomerular (including glomerular tuft and Bowman’s space/capsule)
  
  • Diffuse vs. focal
  • Global vs. segmental
  • Mesangial vs. peripheral (GBM + podocytes)
  • Bowman’s space
• Extraglomerular components
  
  • Tubules (cytoplasm and tubular basement membrane)
  • Interstitium
  • Blood vessels

Question 15

Morphologic (pathologic) classification:
​Immunofluorescence microscopy:
Patterns

• Granular
• Linear
• Homogeneous, smudgy, or irregular
• Intracellular droplet staining
• Absence

Answer 15

• Granular
  
  • Discrete immune complex deposits
• Linear
  
  • Uniform distribution of targeted antigen
  • Weak BM linear staining for albumin and IgG is always present
    
    • Corresponds to small amounts of these proteins that get into the BM (background staining)
  • Specific pathologic staining only if albumin stain is less intense than another more intense stain
    
    • E.g. IgG in anti-GBM / Goodpasture disease
• Homogeneous, smudgy, or irregular
  
  • Protein trapping / insudation within an area of sclerosis (usually IgM & C3).
  • Deposition of a non-immune complex protein (e.g. amyloid)
• Intracellular droplet staining
  
  • Protein resorption droplets within glomerular epithelial cells or tubular cells
• Absence of staining

Question 16

Morphologic (pathologic) classification:
​Immunofluorescence microscopy:
Staining profile

• Used to assess…
• Uses…
• Panel of stains usually includes…
• Procedure
• A positive signal with a particular antibody indicates…

Answer 16

• Focal segmental glomerulosclerosis
  
  • Homogeneous
  • Segmental IgM and C3
• IgA nephropathy
  
  • Granular mesangial IgA, C3
• Membranous nephropathy
  
  • Granular peripheral staining for IgG and C3
• Amyloid
  
  • Smudgy mesangial + GBM staining for deposited amyloid protein
• Lupus
  
  • Granular mesangial and/or peripheral loop IgG, IgM, IgA, C3, C1q, C4
  • “Full house”

Question 17

Morphologic (pathologic) classification:
Electron microscopy

• Transmission EM
• Features assessed
  
  • Cellular alterations
  • ECM changes
  • Electron dense deposits

Answer 17

• Transmission EM
  
  • Permits resolution of ultrastructural anatomy & morphologic alterations, which are below the resolution of LM or IF
  • Provides the highest sensitivity for diffuse glomerular disorders
  • However, b/c only 1-2 glomeruli are usually examined, focal processes may be missed.
• Features assessed
  
  • Cellular alterations
    
    • Podocyte foot process effacement (fusion)
    • Intracellular inclusions (e.g. viruses)
  • ECM changes
    
    • BM (increase, remodeling (e.g. duplication, splitting, breaks, etc.), thinning, interruption)
    • Mesangium.
  • Electron dense deposits
    
    • Immune complexes, protein insudates, protein deposits w/ organized substructure (e.g. amyloid)
    • Location
      
      • Mesangial, subendothelial, subepithelial, intramembranous, Bowman’s space/capsule
    • Substructural detail
      
      • Some immune complexes, e.g. those occurring in lupus or cryoglobulinemia, have distinctive substructures
    • Reaction of the glomerulus to the protein deposits
      
      • E.g. mesangial interposition with new subendothelial basement membrane formation in type 1 membranoproliferative GN
      • Subepithelial basement membrane encasement of deposits in membranous GN

Question 18

Pathogenesis of glomerular disorders

• Determinants of the clinical expression of glomerular disease
• Glomerulopathies
• Glomerular proteinuria
• Glomerular hematuria
• Glomerulopathies presenting with acutely impaired renal function
• Unrecognized slowly progressive chronic renal disorders

Answer 18

• Determinants of the clinical expression of glomerular disease
  
  • Relative quantity (proportion) of injured glomeruli
  • Type of injury
• Glomerulopathies
  
  • Either focal or diffuse without impairment of overall glomerular filtration
  • May produce proteinuria or hematuria
  • Typically don’t present with loss of renal function
• Glomerular proteinuria
  
  • Results from injury to the podocyte or GBM
• Glomerular hematuria
  
  • Results from GBM breaks with bleeding into Bowman’s space
• Glomerulopathies presenting with acutely impaired renal function
  
  • Typically diffuse and proliferative
  • Associated with glomerular capillary narrowing & reduced glomerular perfusion / filtration
• Unrecognized slowly progressive chronic renal disorders
  
  • May ultimately present with symptomatic renal failure simulating acute renal failure
  • Typically show diffuse chronic changes in all four renal compartments, with glomeruli showing diffuse (non-proliferative) segmental and global glomerulosclerosis

Question 19

Pathogenesis of glomerular disorders:
Proteinuria

• Proteinuria
• Hematuria
• Renal function
  
  • Normal
  • Azotemia

Answer 19

• Proteinuria
  
  • Injury to GBM &/or podocytes w/o capillary wall break
• Hematuria
  
  • Break in glomerular capillary wall
• Renal function
  
  • Normal
    
    • Focal glomerulopathy +/- proliferation
    • Diffuse glomerulopathy w/o proliferation
  • Azotemia
    
    • Diffuse glomerulopathy w/ proliferation +/- necrosis/crescents (acute)
    • Diffuse glomerulosclerosis (chronic)

Question 20

Pathogenesis of glomerular disorders:
Proteinuria

• Glomeruli filter…
• Blood cells, large molecules (proteins) and intermediate-sized negatively charged molecules (proteins)
• Small molecules (water, electrolytes, glucose, small proteins, etc.) & positively charged intermediate sized molecules (proteins)
• Damage to the podocyte filtration slit diaphragms (most important size barrier) or reduction in the negative charge in the GBM &/or podocyte & endothelial cell surfaces
• If the tubules are unable to reabsorb the filtered proteins…
• Albumin
• Selective proteinuria
• If the glomerular permeability defect is greater…
• Low MW proteins irrespective of charge
• Tubular proteinuria
• Overflow proteinuria
• The three types of proteinuria can be distinguished by…

Answer 20

• Glomeruli filter…
  
  • A large volume of blood (blood cells and plasma) each day
• Blood cells, large molecules (proteins) and intermediate-sized negatively charged molecules (proteins)
  
  • Prevented from being filtered b/c of size & charge barriers in the glomerular capillary wall
• Small molecules (water, electrolytes, glucose, small proteins, etc.) & positively charged intermediate sized molecules (proteins)
  
  • Forced through the glomerular capillary walls by hydrostatic & oncotic pressure in the circulating blood within glomerular capillaries
• Damage to the podocyte filtration slit diaphragms (most important size barrier) or reduction in the negative charge in the GBM &/or podocyte & endothelial cell surfaces
  
  • Allows progressively larger & less negatively charged molecules to be filtered
• If the tubules are unable to reabsorb the filtered proteins…
  
  • Proteinuria develops
• Albumin
  
  • Intermediate sized protein in high concentration in the blood
• Selective proteinuria
  
  • Less severe glomerular capillary wall injury leads to selective proteinuria (albuminuria)
• If the glomerular permeability defect is greater…
  
  • Larger proteins in high concentration in the blood (i.e. Igs) are also filtered
  • –> non-selective glomerular proteinuria (albumin + immunoglobulin)
• Low MW proteins irrespective of charge
  
  • Normally filtered by the glomerulus
  • Don’t appear in the urine because they’re in small conc in the blood & filtrate, & are easily reabsorbed by proximal tubules
• Tubular proteinuria
  
  • When there is tubular injury (w/o glomerular injury), filtered low MW proteins aren’t reabsorbed & appear alone in the urine
• Overflow proteinuria
  
  • Occurs when small proteins not normally present in the blood (e.g. monoclonal free light chain immunoglobulin or Bence-Jones protein occurring in patients with multiple myeloma) are overproduced
  • Proteins are freely filtered by a normal glomerulus
  • If the concentration of this protein in the filtrate exceeds the tubules’ capacity for reabsorption, the overflow protein appears in the urine (overflow proteinuria)
• The three types of proteinuria can be distinguished by…
  
  • Urine protein electrophoresis

Question 21

Pathogenesis of glomerular disorders:
Immune mediated glomerular injury

• Clinical glomerular disease is the result of…
• For immunologic diseases, the inciting process involves either…
• Immunoglobulins produce glomerular injury through either…
• Immune complex deposits form when…
• In a naïve host…
• Approximately 1-2 weeks after the introduction of the antigen…
• As the antigen is cleared…
• In immune complex associated glomerular disorders, this process may either…

Answer 21

• Clinical glomerular disease is the result of…
  
  • An initiating pathologic process that may directly injure the glomerulus, or alternatively mediate injury indirectly via the host response
• For immunologic diseases, the inciting process involves either…
  
  • Humoral (type II or III hypersensitivity) immune responses
  • Cell mediated (type IV hypersensitivity) immune responses
• Immunoglobulins produce glomerular injury through either…
  
  • Direct antibody dependent cytotoxicity targeted against glomerular cells (type II hypersensitivity)
  • Formation of immune complexes forming or secondarily depositing in the mesangium and/or GBM (type III hypersensitivity reaction) (more common)
• Immune complex deposits form when…
  
  • An antigen stimulates the immune system to produce an antigen-specific antibody, initially forming soluble single antigen - antibody complexes that are easily cleared by the reticuloendothelial system (RES; liver, spleen, lymph nodes, bone marrow, etc.)
• In a naïve host…
  
  • There is a latency of several days before antigen-specific antibodies are produced, with the antigen initially present in higher concentration (antigen excess)
• Approximately 1-2 weeks after the introduction of the antigen…
  
  • The antibody conc increases & becomes proportionate to the antigen concentration
  • Allows cross-linking of single antigen - antibody complexes
  • Allows the formation of insoluble larger immune complex deposits that deposit in vascular walls
  • When this occurs, the host develops an immune response and clinical features of an immune complex disorder (small vessel vasculitis and / or glomerulonephritis)
• As the antigen is cleared…
  
  • The relative antibody conc increases (antibody excess)
  • The immune complex disorder resolves
• In immune complex associated glomerular disorders, this process may either…
  
  • Occur s a single episode
  • May be recurrent

Question 22

Pathogenesis of glomerular disorders:
Mechs of glomerular immune deposition

• Most immunologic glomerular injury has been shown to occur…
• Two distinctive forms of antibody-associated injury

Answer 22

• Most immunologic glomerular injury has been shown to occur…
  
  • On a humoral basis
• Two distinctive forms of antibody-associated injury
  
  • Injury mediated by circulating antibodies binding in-situ to intrinsic or planted glomerular antigens
  • Injury resulting from deposition of preformed soluble circulating antibody-antigen (Ab-Ag) immune complex deposits

Question 23

Pathogenesis of glomerular disorders:
Glomerular immune complex localization

• Immune complex deposits can form in either…
• The location of intraglomerular immune complex deposits is determined by multiple physical factors of the immune complex deposit, including…
• The intraglomerular location of immune complex deposits determines…

Answer 23

• Immune complex deposits can form in either…
  
  • Glomerular locations
    
    • GBM (subepithelial, subendothelial)
    • Mesangial
  • Extraglomerular locations
    
    • Tubular BM
    • Interstitium
    • Extraglomerular blood vessels
• The location of intraglomerular immune complex deposits is determined by multiple physical factors of the immune complex deposit, including…
  
  • Stability of the immune complex deposit in the circulation
    
    • Determined in part by antigen – antibody affinity
    • Preformed circulating immune complex deposit vs. dissociated antigen & antibody
  • Size and shape of the immune complex deposit
  • Charge of the immune complex deposit
• The intraglomerular location of immune complex deposits determines…
  
  • The clinical presentation & pathologic appearance of the affected glomeruli

Question 24

Pathogenesis of glomerular disorders:
In-situ immune deposition

• In-situ immune deposition indicates that…
• Two well-characterized models of GN arising on the basis of in-situ immune deposition
  
  • Anti-glomerular basement membrane (anti-GBM) disease
  • Heymann’s nephritis
• Subepithelial deposits are formed in-situ, either…

Answer 24

• In-situ immune deposition indicates that…
  
  • The antigen & antibody arrive independently & initially form an immune complex at the site of deposition
  • As opposed to a preformed circulating antigen – antibody immune complex that deposits as an intact structure
• Two well-characterized models of GN arising on the basis of in-situ immune deposition
  
  • Anti-glomerular basement membrane (anti-GBM) disease
    
    • Circulating antibodies which recognize an epitope of type IV collagen molecule within the lamina densa bind diffusely & uniformly to this portion of the GBM
      
      • Produce a linear fluorescence pattern w/o discrete electron dense deposits by EM
    • Inflammatory host response –> necrotizing / crescentic glomerulonephritis
  • Heymann’s nephritis
    
    • An experimental model of membranous glomerulopathy characterized by a non-proliferative GN w/ diffuse GBM thickening due to numerous subepithelial deposits
    • Animals are immunized w/ a preparation of PT brush border
      
      • This preparation contains a 330 kD glycoprotein (GP330) which is also present on the basal surface of the podocyte foot processes
    • The resulting circulating GP330 antibody may traverse the GBM & bind to the podocyte foot process cell membrane, either…
      
      • Inducing a complement rxn at the cell surface –> podocyte foot process injury/lysis
      • Surface immune complex deposits that form may be shed into the lamina rara externa, altering GBM protein permeability by reducing negative charge in the GBM & inciting the formation of new GBM around the deposits
    • Lastly, antibodies may react with previously planted nonglomerular (circulating) antigens
      
      • Typically cationic molecules trapped in the anionic GBM (e.g. endostreptosin or hepatitis B surface antigen)
• Subepithelial deposits are formed in-situ, either…
  
  • As described above
  • Less commonly by dissociation of preformed subendothelial deposits with reassociation in the subepithelial space

Question 25

Pathogenesis of glomerular disorders:
Mesangial & subendothelial deposits

• Circulating immune complex deposits are physiologically generated…
• Some of these immune complexes…
• While most…
• Most free & adsorbed immune complexes are removed by the…
• Mesangial/subendothelial immune complex deposits usually form by…
• The mesangium…
• When the capacity of the mesangium is overwhelmed…
• Immune complex deposit localization is determined by…
• Preformed immune complex deposits must be…
• Positively-charged, small-intermediate size immune complexes are preferentially deposited in the…
• Later, these immune complex deposits may…
• Deposits localizing to the mesangium are typically…
• Negatively charged immune complex deposits do not deposit in the…

Answer 25

• Circulating immune complex deposits are physiologically generated…
  
  • In small numbers, e.g. during transient bacteremias, etc
• Some of these immune complexes…
  
  • Remain solubilized within the plasma
• While most…
  
  • Become adsorbed to the surfaces of RBCs via the CR1 complement receptor
• Most free & adsorbed immune complexes are removed by the…
  
  • Reticuloendothelial system (RES)
• Mesangial/subendothelial immune complex deposits usually form by…
  
  • Deposition of preformed circulating immune complex deposits which have escaped the RES
• The mesangium…
  
  • Serves as the RES of the kidney
  • Normally removes small numbers of circulating physiologically generated immune complex deposits
• When the capacity of the mesangium is overwhelmed…
  
  • Immune complex deposit expand the mesangium and may diffuse into the continuous paramesangial / subendothelial space
• Immune complex deposit localization is determined by…
  
  • The size & charge of the immune complex deposit
• Preformed immune complex deposits must be…
  
  • Initially small enough to traverse the endothelial cell fenestrations
• Positively-charged, small-intermediate size immune complexes are preferentially deposited in the…
  
  • GBM lamina rara interna (subendothelial space) which is rich in negatively charged heparan sulfate proteoglycans
• Later, these immune complex deposits may…
  
  • Enlarge by coalescence
• Deposits localizing to the mesangium are typically…
  
  • Less positively charged (more often IgM or IgA containing)
• Negatively charged immune complex deposits do not deposit in the…
  
  • Mesangium or GBM

Question 26

Pathogenesis of glomerular disorders:
Mesangial & subendothelial deposits

• Complement activation occurs most intensely with…
• Complement activation may directly injure…via…
• Neutrophil degranuation at endothelial surfaces results in…
• A primary T-cell response may result in…
• Both humoral & cell mediated responses ultimately lead to the generation of…
• Damage to the podocyte filtration slit diaphragms, detachment of the epithelial cells from the GBM, and/or alteration of the size and charge barriers in the GBM results in…
• Transmural breaks in the capillary wall results in…
• Mesangial cells and inflammatory cells may secrete additional cytokines resulting in…

Answer 26

• Complement activation occurs most intensely with…
  
  • IgG-containing immune complex deposits
• Complement activation may directly injure glomerular cells & the GBM via…
  
  • Neutrophil chemotaxis (C5a) & activation
    
    • Immune complexes have antibody Fc components & C3b which bind to receptors on neutrophils & stimulate neutrophil degranulation in glomerular capillaries
  • The lytic portion of the complement cascade (C5-9)
• Neutrophil degranuation at endothelial surfaces results in…
  
  • Vascular wall injury (necrotizing capillaritis)
• A primary T-cell response may result in…
  
  • Cytokine generation w/ stimulation of macrophages & mesangial cells
• Both humoral & cell mediated responses ultimately lead to the generation of…
  
  • Oxidants, cytokines, proteases, growth factors, complement activation, etc., mediating glomerular cell and/or GBM injury
• Damage to the podocyte filtration slit diaphragms, detachment of the epithelial cells from the GBM, and/or alteration of the size and charge barriers in the GBM results in…
  
  • Proteinuria
  • The quantity and selectivity of the proteinuria are related to the magnitude of the permeability barrier alteration
• Transmural breaks in the capillary wall results in…
  
  • Leakage of a small amt of blood (blood cells and plasma) manifested as hematuria w/ RBC casts
  • B/c the blood loss through these lesions is small, patients don’t become anemic and don’t have significant proteinuria
• Mesangial cells and inflammatory cells may secrete additional cytokines resulting in…
  
  • Glomerular cellular proliferation, & later fibroblast proliferation

Question 27

Pathogenesis of glomerular disorders:
Glomerular proliferation, immune complex removal, & inflammatory response

• Cellular proliferation correlates w/…
• The site of proliferation is dependent on…
• While the magnitude of the cellular response is in part determined by…
• Cellular proliferation is mediated through…
• The quantity of immune complex deposits is determined by…
• Immune complex deposits form a latticework structure when there is…
• Immune complexes are spontaneously reabsorbed when…
• Empirically, older immune complex tend to contain proportionately greater amounts of…
• Within the mesangium, immune complexes are further removed via…
• Within the subendothelial space, immune complex deposits may be…
• Subepithelial deposits are removed principally via…& are isolated by…

Answer 27

• Cellular proliferation correlates w/…
  
  • The presence of immune complex deposits in the mesangial-subendothelial space, but not in the subepithelial space
• The site of proliferation is dependent on…
  
  • The distribution of the immune complex deposits
• While the magnitude of the cellular response is in part determined by…
  
  • The quantity of immune complex deposits
• Cellular proliferation is mediated through…
  
  • The production of various cytokines
• The quantity of immune complex deposits is determined by…
  
  • The relative rates of their formation vs. removal
• Immune complex deposits form a latticework structure when there is…
  
  • An optimal ratio of Ab:Ag (zone of equivalence), permitting Ab-Ag crosslinking
• Immune complexes are spontaneously reabsorbed when…
  
  • Ab or Ag production ceases or when the relative concentrations of Ab and Ag change
  • –> either Ag or Ab excess & dissolution of the immune complex
• Empirically, older immune complex tend to contain proportionately greater amounts of…
  
  • Complement relative to Ig
  • Suggests that immune complexes may be removed in part by complement-mediated solubilization (steric disruption of immune complex lattice)
• Within the mesangium, immune complexes are further removed via…
  
  • Mesangial cell phagocytosis & transmigration of immune complexes back into the glomerular capillaries
• Within the subendothelial space, immune complex deposits may be…
  
  • Isolated & eliminated by the ingrowth of mesangium into the continuous lamina rara interna w/ the production of a new subendothelial layer of GBM
  • –> capillary wall mesangial interposition
    
    • Seen as tram tracking by silver stain
    • Occurs in type I membranoproliferative GNs
• Subepithelial deposits are removed principally via…& are isolated by…
  
  • Removed principally via solubilization
  • Isolated by the glomerulus by forming new GBM around each individual deposit
    
    • Spikes –> domes –> train tracks

Question 28

Pathogenesis of glomerular disorders:
Glomerular proliferation, immune complex removal, & inflammatory response

• The extent to which complement is activated in part determines the…
• Some immune complexes, e.g. IgG-strep Ag occurring in post-streptococcal GN…
• Whereas other deposits, e.g. IgA-Ag deposits occurring in IgA nephropathy…
• As a consequence, glomerular lesions in IgA nephropathy characteristically show…
• Significant complement activation may be reflected by…
• Pts with hypocomplementemia almost always have…
• Subendothelial complement-activating immune complex deposits produce some (but not all)…
• Like complement-activating subepithelial deposits, these immune complex deposits are capable of…
• However, b/c subendothelial ICs are physically accessible to circulating intracapillary neutrophils which contain Fc and C3 receptors on their surfaces, these immune complex deposits can…

Answer 28

• The extent to which complement is activated in part determines the…
  
  • Magnitude of the inflammatory response
• Some immune complexes, e.g. IgG-strep Ag occurring in post-streptococcal GN…
  
  • Readily activate complement with avid chemotaxis
• Whereas other deposits, e.g. IgA-Ag deposits occurring in IgA nephropathy…
  
  • Typically don’t intensely activate complement
• As a consequence, glomerular lesions in IgA nephropathy characteristically show…
  
  • Increased mesangial cellularity w/o an inflammatory response
• Significant complement activation may be reflected by…
  
  • Serum hypocomplementemia
  • In particular if the hepatic synthetic capacity is overwhelmed by the rate of complement consumption
• Pts with hypocomplementemia almost always have…
  
  • Proliferative glomerulonephritis
  • However, not all proliferative GNs are hypocomplementemic
• Subendothelial complement-activating immune complex deposits produce some (but not all)…
  
  • Necrotizing lesions
• Like complement-activating subepithelial deposits, these immune complex deposits are capable of…
  
  • Inflammatory cell chemotaxis
• However, b/c subendothelial ICs are physically accessible to circulating intracapillary neutrophils which contain Fc and C3 receptors on their surfaces, these immune complex deposits can…
  
  • Directly activate the neutrophils within the circulation
  • –> degranulation & the production of a necrotizing capillaritis (glomerulonephritis)

Question 29

Immune complexes:
Removal

• Spoontaneous solubilization
• Actie elimination
  
  • Mesangium
  • Subendothelial
  • Subepithelial

Answer 29

• Spoontaneous solubilization
  
  • Ab or A excess
  • Complement mediated solubilization
• Actie elimination
  
  • Mesangium
    
    • mesangial cell phagocytosis
    • Transmigration of ICs into vasculature
  • Subendothelial
    
    • Capillary loop mesangialization / mesangial interposition
  • Subepithelial
    
    • GBM surrounds individual ICs w/ incorporation of ICs into GBM