Renal Glomerulonephritis Part 2

Front 1

Describe IgA nephropathy

Back 1

-Mesangial proliferation
-Little proteinuria/GFR preserved
->3 cells in mesangiym is considered hypercellular
-Lumen well preserved

Front 2

Describe the demographics of IgA nephropathy

Back 2

-Ages: 4-80 (mean 25) years, 65% of patients in 2nd/3rd decade
-M:F=2/1
-Rare in blacks
-Incidence 5-10% in N. America, UK, Scandinavia
-Incidence 20-30% in Europe, Australia
-Incidence 25-45% in Asia

Front 3

What is the most common primary glomerulonephritis worldwide?

Back 3

IgA Nephropathy

Front 4

Describe the two forms of IgA nephropathy

Back 4

-IgA nephropathy is a pure renal disease
-Henoch Schonlein Purpura is the systemic version

Front 5

Describe Henock Schonlein Purpura

Back 5

-Vasculitis with IgA-dominant immune deposits affecting small vessels, ie capillaries, venules, or arterioles
-Typicall involves skin, guy and glomeriuli and is associated with arthralgias or arthritis
-Presents with glomerulonephritis, arthralgias, deposition of immune complexes in the gut leading to abdominal pain leading to bleeding in stool
-These patients have purpura from skin involvent with IgA deposition in the dermal capillaries
-Nonblanching, sometimes palpable Purpuric rashes present on lower extremities

Front 6

Describe the different pathogenesis of IgA nephropathy

Back 6

1.Defective hepatic clearance of IgA. This can occur in alcoholics with cirrhosis. The serum IgA is picked up by the hepatocytes and excreted into the bile
2. Ingcreased IgA production. Most common. Associated with elevated serum IgA. Onset may follow upper respiratory infection or gastroenteritis. If with URI, nephropathy occurs at same time, no delay
3. Defect of antigen exclusion at the mucosal surface. Can be due to inflammation or erosion. Occurs with URI, gastoenteritis, celiac dlease. IgA is refluxed back into the circulation

Front 7

Describe the IgA abnormality in IgA nephropathy

Back 7

-Polymorphic form of IgA1 is culpable
-Some sugar changes are present in the hinge region and confer vulnerability
-Patients with defective galactose moieties at the hinge region are more vulnerable

Front 8

Describe the etiology of IgA Nephropathy

Back 8

-Most common idiopathic GN worldwide
-Defined by IgA deposition in mesangium
-Clinical Presentation
-Young - gross hematuria/tea pee
-Adults - Asymptomatic Proteinuria+hematuria
-Not "benign" hematuria (Berger's Disease)
-20-30% progresss to ESRD over 20 years

Front 9

Describe the tratment options for IgA Nephropathy

Back 9

-ACE inhibitors/AR blockers - block RAS decreaseing pressure in glomerular filters causing less proteinuria and glomerular scarring
-Steroids
-Fish oil
-Mycophenolate

Front 10

Describe active lupus

Back 10

-Has malar rash with a butterfly distribution
-Anti-DNA antibody positive
-Lupus nephritis is the renal form of systemic lupus
-Most severe form is diffuse proliferative lupus nephritis
-Wire loop lesions can be present
-There is proliferation of the indigenous cells of the glomerular tuft -mesangial and endothelial cells - narrowing down the capillary.

Front 11

Describe the deposits in active lupus

Back 11

-Deposits form subendothelially between the endothelium and glomerular basement membrane leading to exubuerant proliferation int he endocapillary zone
-Wire loops thickenings are due to the fact the immune load is huge
-The GBM defines the outer aspect of the deposit. More of the irregularity is on the inner aspect.
-Here we have an acute and chronic immune complex mediated disease.
-We have deposits that form in the mesangium and in some cases are so abundant that they overwhelm the mesangium and become deposited in the peripheral capillary walls subendothelially.
-This subendothelial location attracts the inflammatory cells and gives rise to the endothelial and mesangial proliferation causing the endocapillary proliferative pattern.

Front 12

What is the pathognomonic lesion form lupus?

Back 12

-Hematoxylin/hematoxophil body
-This is the extruded nucleus of a leukocyte and circulating antinuclear antibodies have bound to it forming a swollen, large, rounded basophilic inclusion within the glomerular tuft

Front 13

Describe the classes of Lupus Nephritis

Back 13

I Minimal mesangial
II Mesangial Proliferative
III Focal proliferative (<50% glom)
IV Diffuse proliferative (>50% glom)
V Membranous
VI Chronic Sclerosing

Front 14

Describe the mesangial proliferative form of lupus nephritis

Back 14

-Deposits are limited to teh mesangial regions
-No loop pattern
-There is proliferation within the mesangiumin respose to the immune deposits.
-These patients have asymptomatic hematuria.
-They have low levels of proteinuria and preserved renal function

Front 15

Describe Focal proliferative lupus

Back 15

-There are some glomeruli spared
-Others show lesions that are typically segmental in distribution
-Some endocapillary proliferation
-In these areas the deposits extend out subendothelially inciting the complement activation and the ingress of inflammatory cells and the proliferation as a response

Front 16

Describe Membranous Lupus

Back 16

-Patients typicall present with full nephrotic sndrome or at least heavy proteinuria
-There is in situ immune complex formation
-Nucleosomes which are cationic have an affinity for the basement membranes
-They form in situ giving rise to the membranous pattern

Front 17

Describe the treatment approach to SLE nephritis

Back 17

-Class I: Treat extrarenal lupus
-Class II: Treat extrarenal lupus
-Class III: Steroids, Cytotoxics
-Class IV: Steroids, Cytotoxics
-Class V: Steroids, Cytotoxics (in high risk patients)
-Class IV: Prepare for renal replacement

Front 18

Describe the side effects of corticosteroids

Back 18

Severe weight gain

Front 19

Describe the side effects of cyclophosphamide

Back 19

-Hypertension
-Ischemic heart disease
-Hyperlipidemia
-Valvular heart disease
-Avascular necrosis
-Osteoporosis
-Premature menopause
-Major infections
-Herpes zoster infection

Front 20

Describe strategies for alternate therapies

Back 20

-Sequential cytotoxic therapy
-Cyclophosphamide followed by mycophenolate/Imuran
-Mycophenolate

Front 21

Describe Wegener's granulomatosis

Back 21

-Typically involves the glomerulus with crescentic or extracapillary proliferation
-The crecentic proliferation has caused compression of the glomerular tuft, narrowing down the capillaries in the areas of involvement
-Pauci-Immune glomerulonephritis
-Lots of fibrin but no immune deposits
-Sometimes see a vasculitis in the kidney
-Lungs can have a hemorrhagic process

Front 22

Describe the lung in Wegener's granulomatosis

Back 22

-Lungs can have a hemorrhagic process
-Pulmonary capillaritis
-There are neutrophils and massive hemorrage in the alveolar spaces
-Can involve upper airways as well (sinuses, nasal cavities)
-Can rupture the bridge of the nose

Front 23

Describe ANCA

Back 23

-Anti-neutrophil cytoplasmic antibody
-cANCA (cytoplasic) due to specificity for proteinase 3 (PR3) which is present in azurophilic granules of the primary lysosomes of neutrophils and monocytes
-pANCA (perinuclear) due to antibody for myeloperoxidase

Front 24

Describe how pauci-immune diseases lead to disease

Back 24

-Antigen is sequestered inside the cell
-Neutrophils have to be primed by viral infection
-Viral infection causes release of cytokines that cause neutrophiles to undergo change
-ANCA present in primary lysosomes which more to surface
-ANCA displayed on plasma membrane
-Antibody causes neutrophil activation with respiratory burst and release of ROS
-Caused vasculitis and glomerulonephritis in the absence of immune complex deposits

Front 25

Describe the three types of pulmonary-renal vasculitic syndrome

Back 25

-Pauci Immune (usually ANCA associated)
-Wegener's granulomatosis
-Microscopic polyangiitis (pANCA)
-Immune Complex Deposits (granular)
-SLE
-Cryoglobulinemic vasculitis
-Anti-Glomerular Basement Membrane Antibody Deposits (linear)
-Goodpasture's Syndrome

Front 26

Describe the types of antibody mediated glomerulonephritis

Back 26

-Circulating anti-GBM antibodies with linear glomerular IF staining
-Glomerular immune complex localization with granular IF staining
-Circulating ANCA with paucity of glomerular IF immunoglombulin staining

Front 27

Describe anti-GBM nephritis

Back 27

-Much less common than ANCA associated glomerulonephritis
-Crescentic GM
-Patient presents with rapidly progressive glomerulonephritis
-Crescent contain fibrin
-Rupture of GBM allows fibrin to enter urinary space, inciting a cresentic reaction

Front 28

Describe the the immunofluorescence is linear with Goodpasteur's syndrome/Anti-GBM GN

Back 28

-The antigen and the antibody is directed to a normal structural component of the glomerular capillary wall, collagen IV
-It is regularly distributed in the GBM so antibody forms linear patterns
-Mechanism is the same: complement comes in, leukocytes are activated releasing their lysosomal enzymes and produce big holes in the basement membrane. Platelets come in and fibrin is activated promoting parietal epithelial cell proliferation

Front 29

What is the pathogenic antigen in Goodpasteur's?

Back 29

-The alpha3 chain of Collagen IV
-Antigen is located in the noncollagenous domain
-It is normally hidden int he tertiary structure of the collagen molecule so an insult is required to expose it
-Goodpasteur is a pulmonary-renal disease because the antigen is present in both basement membranes

Front 30

Describe rapidly progressive glomerulonephritis

Back 30

-A clinical term
-Rapidly progressive renal failure
-Histopathologic termis crescentic GN
-Pathogenesis:
-AntiGBM disease
-Immune complex GN
-Pauci-Immune GN
-Treatment and course depend on etiology

Front 31

Describe the treatment for antiGBM disease

Back 31

Steroids, Cytotoxincs, PTE. Plasma phoresis to remove antiGBM antibodies and then steroids/cytotoxics to prevent new antibody formation

Front 32

Describe the treatment for immune complex CN

Back 32

Treat underlying disease

Front 33

Describe the treatment for pauci-immune RPGN

Back 33

Cytotoxics and plasma phoresis to remove ANCA

Front 34

How do you assess treatment of lupus?

Back 34

In lupus if you have antiDNA antibodies and they are high titer you have lupus. If the titer is high you have active lupus. If you treat them the titer of antiDNA antibody goes from positive to negative.

Front 35

How do you assess treatment of Wegener's and polyarteritis nodosa?

Back 35

If you have positive p or c ANCA and it is high titer you likely have polyarteritis or Wegener's. If the disease is active the titer is high. As you treat them the titer falls.

Front 36

Back 36

-Henoch-Schonlein Purpura
-Patients can present with purpuric rashes on the lower extremities
-Each one is a vasculitis involving the dermal capillaries

Front 37

Back 37

-IgA nepropathy
-Mesangial proliferation
-Little proteinuria because GFR is preserved
-Disease localized to mesangium

Front 38

Back 38

-IgA Nepropathy
-IgA fluoresces
-There is IgA and C3 localized to the mesangium
-Deposits are located where the proliferation is located

Front 39

Back 39

-EM of IgA nephropathy
-Capillary lumen is patent
-Electron dense deposits located in the mesangium
-There is some breakdown of the basement membrane
-RBCs have made it into the urinary space

Front 40

Back 40

Malar rash of Lupus

Front 41

Back 41

-Lupus
-This is the most severe form of renal involvment in lupus: diffuse proliferative lupus nephritis
-Glomeruli have undergone diffuse proliferation
-They have all undergone varying degrees of endocapillary proliferation

Front 42

Back 42

-Diffuse proliferative lupus nephritis
-Lots of infiltrating leukocytes
-Some monocytes
-Proliferation of indigenous cells of the glomerular tuft (mesangial and endothelial cells) narrowing down the capillary
-Some pinkish material which is immune deposits thickening the capillary walls

Front 43

Back 43

-Wire loops lesions of lupus nephritis
-There are deposits that are so large we can see them with LM
-They are subendothelial and wrap around the capillaries and can protrude into the lumen
-High immune complex load associated with this GN

Front 44

Back 44

-Lupus nephritis
-"Full house" pattern - (IgG, IgM, IgA, C3, C1)
-There is a failure of tolerance to autoantigens and the patient produces a vast array of autoantibodies
-Some are tissue specific but others are not
-Anti-dsDNA antibody most specific to lupus
-Deposits in mesangium, peripheral capillary wall
-Not granular

Front 45

Back 45

-Hematoxylin/hemotoxophil body
-Pathognomonic lesion of lupus
-Bluish staining material in these areas is the extruded nucleus of a leukocyte
-Antinuclear antibody has bound and there is clumping and enlargement resulting in a swollen, large, rounded, basophilic inclusion in the glomerular tuft

Front 46

Back 46

-Lupus Nephritis Class II
-Mesangial electron dense deposits
-Do not involve peripheral capillary loop

Front 47

Back 47

-Class III Lupus Nephritis
-Focal Segmental Lupus Nephritis
-Some glomeruli are spared and others show lesions that are typically segmental in distribution
-There is some endocapillary proliferation
-In these areas deposits extend out subendothelially inciting complement activation and the ingress of inflammatory cells and proliferative response

Front 48

Back 48

-Class IV Lupus Nephritis
-Membranous Lupus Nephritis with spikes
-Patients typically present with full nephrotic syndrome or at least heavy proteinuria
-In situ immune complex formation
-Cationic nucleosomes have an affinity for the basement membrane
-They form in situ, giving rise to this membranous pattern

Front 49

Back 49

-Wegener's Granulomatosis
-Crescentic form of glomerulonephritis
-Proliferation is outside the glomerular basement membrane
-Crescentic proliferation has caused compression of glomerular tuft, narrowing down the capillaries in the areas of involvment

Front 50

Back 50

-Wegener's Granulomatosis
-There is rupture of the glomerular basement membrane
-There is blind ending glomerular basement membrane which should never happen
-Through this fibrin has come out and this red material and extracapillary proliferation/crescent formation ensued

Front 51

Back 51

-Wegener's Granulomatosis
-Immune staining panel is negative
-No immune complex deposits
-Lots of fibrin on fibrin stain in the distribution of the crescent
-Called Pauci-Immune glomerulonephritis

Front 52

Back 52

-EM of Wegener's Granulomatosis
-No Immune deposits
-Ruptured glomerular capillary wall
-Crescent is closing off urinary space

Front 53

Back 53

-EM of Wegener's Granulomatosis
-There are huge holes in the glomerular basement membrane
-Damage to capillary wall allows red and white cells to get out
-Lots of inflammatory mediators reach urinary space
-Fibrin causes parietal epithelial cell proliferation and crescent formation

Front 54

Back 54

-Wegener's granulomatosis
-Vasculitis in kidney
-Occurs with transmural inflammation/arteritis
-There is some fibrinoid necrosis
-Only 10-15% of biopsies have actual vasculitis

Front 55

Back 55

-Lung in Wegener's Granulomatosis
-Hemorrhagic process can occur
-Neutrophils and massive hemorrhage in the alveolar spaces
-Wegener's manifests as a pulmonary-renal disease
-Can cause cavitary lesions where you have granulomatous inflammation of the pulmonary parenchyma

Front 56

Back 56

-Wegener's granulomatosis in Upper Airways
-From the sinus
-Shows sequestration of bone and the severe inflammation that has giant cells as well as many lymphocytes and infiltrating macrophages
-This is a granulomatous, necrotizing, inflammatory process that can happen in the ears, nose, eyes, sinuses, lung and kidney

Front 57

Back 57

cANCA

Front 58

Back 58

pANCA

Front 59

Back 59

Circulating antiGBM antibodies with linear glomerular IF staining

Front 60

Back 60

Glomerular immune complex localization with granular IF staining

Front 61

Back 61

Circulating ANCA with paucity of glomerular IF immunoglobulin staining

Front 62

Back 62

-AntiGBM nephritis
-Crescentic glomerulonephritis
-Patient presented with rapidly progressive glomerulonephritis

Front 63

Back 63

-AntiGBM nephritis
-Crescents contain fibrin
-Rupture of GBM and fibrin entering the urinary space led to crescentic reaction

Front 64

Back 64

-AntiGBM immunofluorescence
-Linear staining of IgG
-GBM are outlined

Front 65

Back 65

-Goodpasteurs/AntiGBM in the lung
-Linear staining along the basement membrane that lines the pulmonary capillaries
-Fibrin and hemorrhage into the alveolar spaces has resulted

Front 66

Back 66

-Flea bitten kidney in Goodpasteurs/AntiGBM syndrome
-Appearance due to presence of RBC casts

Front 67

Back 67

-RBC casts in Goodpasteur's Syndrome