The Kidney In Systemic Diseases Part I

Front 1

What are the four vascular injury syndromes?

Back 1

ANCA-associated glomerulonephritis
Thrombotic microangiopathy
Lupus nephritis
Scleroderma

Front 2

What are the two major components in the pathogenesis of vascular disorders?

Back 2

1. Inflammation of blood vessels (seen in vasculitides)
2. Loss of thromboresistance (seen in thrombotic microangiopathies)

Front 3

Two types of renal disease in the setting of vasculitis?

Back 3

Medium vessel disease
Small vessel disease

Front 4

Example of medium vessel disease and disease process.

Back 4

Example = classical polyarteritis nodosa

--> renal infarcts and distal glomerular ischemia --> decline in GFR NOT ASSOCIATED With glomerular inflammation in RBC casts

--> ANCA NEGATIVE!

Front 5

Small vessel disease examples and disease process.

Back 5

Microscopic polyangiitis, Wegener's, Churg-Strauss

--> focal necrotizing lesions with crescent formation, active urinary sediment (ANCA+), and rapid progression of kidney failure

Front 6

What is shown here?

Back 6

Polyarteritis nodosa (segmental transmural necrotizing vasculitis)

Front 7

What is shown here?

Back 7

Polyarteritis nodosa in the kidney.

Front 8

What is shown here?

Back 8

White arrows = renal infarcts
Black arrows = arterial aneurysms

Both due to polyarteritis nodosa

Front 9

What is pauci-immune glomerulonephritis?

What is it often associated with? Do ANCA titers always parallel disease activity?

Back 9

Negative immunofluorescence studies in the setting of crescentic glomerulonephritis.

ANCAs with extrarenal findings (arthritis, anthralgias, myalgias, fatigue) = NO!

Front 10

Can pauci-immune glomerulonephritis be ANCA negative and without extrarenal findings?

Back 10

Yes!

Front 11

What are the two distinct patterns of ANCAs?

Back 11

C-ANCA (PR3-ANCA) and P-ANCA (MPO-ANCA)

Front 12

What type of reactivity does C-ANCA have?
What is it due to? What does positivity strongly suggest?

Back 12

Diffuse cytoplasmic reactivity
Antibodies --> cytoplasmic serine protease (proteinase 3)

WEGENER'S GRANULOMATOSIS

Front 13

What type of reactivity does P-ANCA have?
What is this due to?
In what diseases will it be +?
Non-myeloperoxidase P-ANCA has been detected in what diseases?

Back 13

Perinuclear only
Antibodies directed at lysosomal myeloperoxidase
30% of patients with anti-GBM, low titers in SLE

Sclerosing cholangitis, ulcerative colitis, Crohn's disease

Front 14

Summary slide

Back 14

Summary slide

Front 15

What is shown in each image?

Back 15

Left = cANCA
Right = pANCA

Front 16

What does binding of ANCAs to neutrophils result in?
What are the adhesion proteins?

What cells are the primary target in small vessel vasculitis?

Back 16

PMN activation
Increased contact and adhesion with endothelial cells and vascular structures

Adhesion = B-2 integrin, mac-1, Fcy

Endothelial cells

Front 17

What is the three step pathogenesis of endothelial cell injury by anti-neutrophil cytoplasmic auto-antibodies specifically agianst proteinase 3 (PR3)?

Back 17

1. PMN activation by ANCA
2. Inhibition of PR3-inactivation by ANCA
3. EC activation/lysis by ANCA

Front 18

What does Wegener's granulomatosis lead to?
Symptoms?

Back 18

Sinopulmonary renal syndrome

Rhinorrhea, sinusitis, nasopharyngeal mucosal ulcerations
Cough, dyspnea, hemoptysis, transient pulmonary infiltrates on chest X-ray
10% azotemia
Non specific (fever, weight loss, arthalgias, arthritis, mononeuritis, multiplex, skins lesions may be seen)

Front 19

What is a sensitive and specific test for Wegeners?

Back 19

C-ANCA (PR3-ANCA)

Front 20

What is shown at each number?
What is the blue haze?

Back 20

1-4 = multinucleated giant cells
Blue haze = necrosis

Necrotizing granulomatous inflammation of granulomatosis with polyangiits.

Front 21

What is shown here?

Back 21

Front 22

What is shown here?

Back 22

Front 23

What is shown here?

Back 23

Front 24

How do you treat Wegener's?
What is the mortality if untreated?
Does relapse occur?

Back 24

Cyclophosphamide-based regimens, steroids, plasmapheresis.

80-90% if left untreated

25-50% relapse with 3-5 years follow-up.

Front 25

What are the two broad categories of thrombotic microangiopathies? TMA

Back 25

Hemolytic uremic syndrome
Thrombotic thrombocytopenic purpura

Front 26

What are three symptoms of hemolytic uremic syndrome?

Back 26

1. Hemolytic anemia (schistocytes)
2. Renal dysfunction
3. Thrombocytopenia (due to platelet consumption)

Front 27

What are five symptoms of thrombotic thrombocytopenic purpura?

Back 27

1. Fever
2. Hemolytic anemia
3. Thrombocytopenia
4. Renal dysfunction
5. Neurologic dysfunction (seizures).

Front 28

What is the pathogenesis of thrombotic microangiopathy?

Back 28

Loss of thromboresistance by endothelial cell --> platelet activation --> deposition of platelet and fibrin thrombi in the lumen of affected vessels

Fibrin deposition in subintima and media of vessels --> Onion skin appearance

Front 29

What is shown here?

Back 29

Thrombotic microangiopathy in a glomerulus (thombosed capillary)

Front 30

What is this?

Back 30

Thrombotic microangiopathy (thrombosed arteriole)

Front 31

What are some things that cause endothelial damage?

Back 31

E. coli H7:O157 --> verotoxing --> cytotoxic antiendothelial antibodies

Chemotherapeautic agents (cyclosporine, gemcitabine, bleomycin/cisplatinum)

Radiation

Front 32

What could the platelet activation be due to?

Back 32

1. Increased vWF multimers
2. Familial TTP = genetic deficiency of vWF cleaving protease
3. Autoimmune TTP = antibody to vWF cleaving protease develops
4. TTP = occurs in setting of other autoimmune diseases

Front 33

Comment on prothrombin time and partial thromboplastin times in TMA and DIC.

What are TMAs associated with as opposed to DIC?

Back 33

TMA = normal times
DIC = prolonged times

TMAs = thrombotic diathesis as opposed to bleeding diathesis

Front 34

What is important here? Diagnosis?

Back 34

??

Front 35

What is a systemic disease sparing no organ system and caused by an aberrant immune response?

Where is the highest prevalence?
10 year survival rate?

Back 35

SLE

Brazil
70%

Front 36

Know the lupus criteria again.

Back 36

Malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorders, neurologic disorder, hematologic disorder, immunologic disorder, antinuclear antibody

Front 37

What are the six classes of lupus? Most common? Least common?

Back 37

Front 38

What is shown here? Is this severe or mild?

Back 38

Lupus nephritis class II
Mesangial proliferative

(MILD)

Front 39

What is shown here? (severity?)

Back 39

Lupus nephritis class III
Focal proliferative
Moderate

Front 40

What is shown here?
Severity?

Back 40

Lupus nephritis class IV
Diffuse proliferative

Notice inflammatory cells, mesangial cells, capillary endothelial cells)

SEVERE

Front 41

What is shown here? SPECIFICALLY!

Back 41

Lupus nephritis class IV
Diffuse proliferative

Wireloop lesions, hyaline thrombus in capillary
SEVERE!

Front 42

What is shown here?

Back 42

Lupus nephritis class IV
Diffuse proliferative

Damaged glomerulus, crescent formation, excess cells of carious types

SEVERE!

Front 43

What is shown here? Quality?

Back 43

Lupus nephritis class V
Membranous

NEPHROTIC

Front 44

What is shown here?

Back 44

Lupus nephritis EM:

Subendothelial and mesangial deposits

Front 45

What is shown here?

Back 45

Subendothelial deposits?

Front 46

What is shown here?

What is this referred to?

Back 46

Immunofluourescence of lupus nephritis

Staining of deposits with antisera to IgG, IgM, IgA, C3, and C4 typically --> FULL HOUSE IMMUNOFLUORESCENCE

Front 47

Notice the renal survival rates of the difference classes of SLE?

Back 47

Front 48

What is the treatment for SLE?

Back 48

1. Aspirin
2. GLUCOCORTICOIDS
3. Immunosuppressants (cyclophosphamide and mycophenolate mofetil)
4. Inhibit toll-like receptor (hydroxychloroquine)
5. Hormone manipulation (dehyroepiandrosterone)
6. Modulation of cell signaling (tacrolimus, sirolimus)

Front 49

What are the only drugs approved by FDA for lupus treatment?

Back 49

Aspirin, glucocorticoids, hydroxychloroquine

Front 50

Another term for scleroderma?
Definition?
Who is affected?
Two types based upon pattern of skin involvement?

Back 50

Front 51

Clinical features of both limited and systemic scleroderma?

Back 51

Simplify this somehow?

Front 52

Involvement of what organ is frequent in scleroderma? What is scleroderma renal crisis?
How is it treated?

Back 52

Mild renal involvement (mild dysfunction, protetinuria, hypertension)

Scl renal crisis --> new onset of accelerated arterial hypertension and/or rapidly progressive oliguric renal failure

ACE INHIBITORS --> unusual!

Front 53

What are risk factors for scleroderma?

Back 53

1. early diffuse systemic sclerosis
2. rapidly progressive skin disease
3. anti-RNA polymerase antibodies
4. corticosteroid therapy

Front 54

What occurs in arcuate arteries in scleroderma?
What else is common?
What vascular changes do you see associated with a poorer outcome?

Back 54

Intimal and medial proliferation with luminal narrowing
Fibrinoid necrosis and thrombosis

Mucoid intimal thickening and thrombosis

Front 55

What is shown here?

Back 55

Concentric sclerosing intimal thickening of interlobar arteries 150-500 microns in diameter resembling onion skin.

Systemic Sclerosis (scleroderma)