The Kidney in Systemic Disease 1/2

Question 1

What are 4 vascular injury syndromes?

Answer 1

ANCA-assc glomerulonephritis
Thrombotic Microangiopathy
Lupus Nephritis
Scleroderma

Question 2

What are the 2 pathogenesises of vascular disorder?

Answer 2

1. inflammation of blood vessels

2. Loss of thromboresistance (= loss of normal resistance to clot formation)

Question 3

What are the differences between medium vessel disease and small vessel disease?

Answer 3

medium vessel disease:

• renal infarcts and distal glomerular ischemia
• decline in GFR not assc with glomerular inflammation
• NO RBC casts
• usually ANCA negative
• aka polyarteritis nodosa

small vessel disease:

• focal necrotizing lesions with crescent formation
• active urinary sediment
• rapid progression of kidney failure (decline in GFR)
• aka microscopic polyangiitis

Question 4

What is pauci-immune glomerulonephritits? When is it usually seen?

Answer 4

negative immunefluoresence studies usually in the setting of crescentic glomerulonephritis

*often assc with ANCAs + extra renal findings (arthritis, athralgias, myalgias, fatigue) but not always and CRESCENTIC glomerulonephritis

Question 5

What are ANCAs?

Answer 5

anti-neutrophil cytoplasmic Abs with 2 distinct patterns:

1. C-ANCA: anti-proteinase 3
2. P-ANCA: anti-lysosomal myeloperoxidase

Question 6

What disease(s) are assc with positive C-ANCA Abs?

Answer 6

granulomatosis with polyangitis (Wegner’s)

Question 7

What disease(s) are assc with positive P-ANCA Abs?

Answer 7

• anti-GBM disease (~30% of pts)
• low titers seen in SLE
• sclerosing cholangitis, ulcerative colitis, and chron’s disease

Question 8

Describe the difference between C and P ANCAs with immunofluorescence?

Answer 8

C-ANCA: cytosplamic staining

P-ANCA: peri-nuclear staining

Question 9

How are ANCAs pathogenic?

Answer 9

binding of ANCAs to neutrophils activates them –>
-inc contact and adhesions with endothelial cells/vascular structures by: B-2 integrin, Mac-1, Fc-gamma

• -> endothelial cell injury (to glomeruli and blood vessels)
• inhibition of PR-3 inactivity
• EC activation
• ADCC
• complement activation via alt pathway
• monocyte activation/release of ROS and chemotactic molecules

Question 10

_______ cells are the primary target in small vessel vasculitis.

Answer 10

endothelial cells

Question 11

What is a specific and sensitive test for Wegner’s Granulomatosis?

Answer 11

C-ANCA

Question 12

What are signs and symptoms assc with granulomatosis with polyangitis (Wegner’s)?

Answer 12

• Upper respiratory tract involvement with: rhinorrhea, sinusitism nasopharyngeal mucosal ulcerations
• Lower Respiratory Tract involvement with: cough, dyspnea, hemoptysis, transient pulmonary infiltrates on X-ray
• !0% have azotemia at presentation
• fever, weight loss, arthralgias/arthritis, mononeuritis multiplex, skin lesions

Question 13

T or F: In most autoimmune mediated vascular necrosis, arteries and veins are involved

Answer 13

F: usually only arteries

**granulomatosis with polyangiitis/Weger’s has BOTH a and v!!

Question 14

Describe the shape/type of glomerulonephritis of granulomatosis with polyangiitis/Wegners.

Answer 14

crescentric

Question 15

What is the treatment of granulomatosis with polyangiitis?

Answer 15

cyclophosphamide based with steroids, plasmapheresis

*80-90% mortality if left untreated

Question 16

What are the 2 types of TMAs (thrombotic microangiopathies)?

Answer 16

TTP

HUS

Question 17

How are TTP and HUS differentiated?

Answer 17

HUS:

• hemolytic anemia
• renal dysfunction
• thrombocytopenia

TTP:

• hemolytic anemia
• renal dysfunction
• thrombocytopenia
• fever
• neurologic dysfunction

Question 18

Describe the appearence of vessels on biopsy that are assc with TMAs?

Answer 18

onion skin

Question 19

What is the pathogenesis of TMAs?

Answer 19

• endothelial cell loses thromboresistance
• platelet activation
• fibrin clot formation in lumen of affected vessels
• endothelial cell injury

Question 20

What are 3 causes of endothelial damage in HUS?

Answer 20

1. verotoxin producing E. coli that cause production of cytotoxic antiendothelial Abs
2. chemotherapeutic agents (cyclosporine, gemcitabine, bleomycin/cisplastinum)
3. radiation (BM transplant)

Question 21

Familial TTP is seen with a genetic deficiency of …

Answer 21

ADAMTS13 (vWF cleaving protease)

Question 22

T or F: inc levels of vWF multimers may directly enhance platelet aggregation.

Answer 22

T

Question 23

What are the differences between TMA and DIC?

Answer 23

PT and PTT are normal in TMA and prolonged in DIC

TMAs are assc with a thrombotic diathesis
DIC are assc with a bleeding diathesis

Question 24

T or F: SLE is a systemic disease that spares no organ system

Answer 24

T

Question 25

What is the ten year survival rate of SLE?

Answer 25

70%

Question 26

What are the 11 criteria for SLE?

Answer 26

mala rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurologic disorder, immunologic disorder, antinuclear Abs

Question 27

What are the stages of lupus nephritis?

Answer 27

``` I: minimak mesangial II: mesangial proliferative III: focal proliferative IV: diffuse proliferative V: Membranous VI: Advanced sclerosing ```

Question 28

What is the most common stage of lupus nephritis?

Answer 28

IV: diffuse proliferative

Question 29

Class __ is mild, class ___ is moderate, and class ___ is severe.

Answer 29

II, III, IV

Question 30

What pathologies can be seen in a biopsy of a class IV (diffuse proliferative) lupus nephritis?

Answer 30

wireloop lesions hyaline thrombus (immune complex) crescent formation excess cells

Question 31

What can be seen in EM with a pt with lupus nephritis?

Answer 31

subendothelial and mesengial depositis

Question 32

Describe immunofluroesence pattern that is consistant with a diagnosis of lupus nephritis.

Answer 32

"full house immunofluoresence" = all 3 Ig present (IgG, IgM, and IgA) as well as C3 and C4

Question 33

What is the treatment for SLE?

Answer 33

Glucocorticoids, aspirin, and hydroxychloroquine (TLR inhibitor) are FDA approved for the treatment of lupus *immunosuppresants can also be used (class 4 = cyclophosphamide and class 5 = mycophenolate mofetil)

Question 34

What class of lupus nephritis is assc with poor renal survival?

Answer 34

IV

Question 35

What is scleroderma?

Answer 35

disease that involves connective tissue and the microvasculature with fibrosis and vascualr occlusion

Question 36

What are the 2 subsets of scleroderma? What are they based on?

Answer 36

limited and diffuse cutaneous based on pattern of skin involvement

Question 37

What is the epidemiology of scleroderma?

Answer 37

femal predominance more frequent in AA 1 in 4000 US adults affected

Question 38

How is renal involvement of scleroderma characterized? Renal crisis?

Answer 38

proteinuria HYP (mild renal dysfuction) Renal crisis: new onset of accelerated arterial HYP and/or rapidly progressive oliguric renal failure

Question 39

How is scleroderma renal crisis treated?

Answer 39

ACE inhibitors

Question 40

What are the risk factors for scleroderma renal crisis?

Answer 40

- early diffuse systemic sclerosis (subtype) - rapidly progressive skin disease - anti-RNA pol Abs - corticosteriod therapy

Question 41

What happens to the arcuate arteries with scleroderma?

Answer 41

intimal and medial proliferation with luminal narrowing | *fibrinoid necrosis and thrombus is common

Question 42

Describe the histology of interlobar arteries with scleroderma.

Answer 42

concentric sclerosing intimal thickening --> resembles onion skin

Question 43

What disease from this lecture is sinopulmonay?

Answer 43

Wegner's

Question 44

What disease from this lecture is assc with puci-immune glomerulonephritis?

Answer 44

Wegner's

Question 45

What is scleroderma renal crisis?

Answer 45

new onset of accelerated arterial HYP and/or rapidly progressive oliguric renal failure

Question 46

What is the difference between microscopic polyangiitis and polyarteritis nodosa?

Answer 46

microscopic polyangiitis: small vessel disease (focal necrotizing lesions with crecentric formation) that causes glomerulonephritis (usually pauci-immune crescentric) polyarteritis nodosa: medium vessel disease that causes macroscopic areas of ischemia and infarction --> kidney damage/dec GFR

Question 47

What is the pathogenesis of HUS?

Answer 47

Shiga toxin in circulation causes widespread endothelial injury: - shiga toxin binds receptor on endothelial cell - inc endothelin production - dec NO production - TNF released - toxin internalized (10% of time) --> apoptosis - pro-coag state--> thrombus formation

Question 48

What is the classical presentation of HUS?

Answer 48

sudden onset of irritability, lethargy, weakness, pallor, and oliguira in a SMALL CHILD, 5 - 10 days following gastroenteritis

Question 49

TTP treatment

Answer 49

plasmaphoresis

Question 50

What is the characteristic feature of lupus nephritis? (occurs in 100% of pts)

Answer 50

proteinuria * nephrotic syndrome in 65% * microscopic hematuria in 80%

Question 51

Glossary of terms to know: inflammation of blood vessels, usually autoimmune

Answer 51

vasculitis

Question 52

autoimmune ANCA-negative medium vessel arteritis

Answer 52

Polyarteritis nodosa

Question 53

antibodies against proteinase 3 or myeloperoxidase associated with specific autoimmune diseases

Answer 53

ANCA

Question 54

autoimmune small vessel vasculitis cause of pauci-immune crescentic glomerulonephritis associated with P-ANCA

Answer 54

Microscopic polyangiitis

Question 55

autoimmune necrotizing granulomatous vasculitis of respiratory tract and cause of crescentic glomerulonephritis associated with C-ANCA

Answer 55

5. Granulomatosis with polyangiitis (Wegener’s

Question 56

thrombotic microangiopathy of glomeruli in small children due to Shiga toxin from diarrheal E. coli H7:O157 infection

Answer 56

HUS

Question 57

thrombotic microangiopathy due to von Willebrand factor multimers from ADAMTS13 deficiency

Answer 57

TTP

Question 58

immune complex-mediated glomerulonephritis of systemic lupus erythematosus (the prototype multi-system autoimmune disease)

Answer 58

Lupus nephritis

Question 59

rapidly progressive renal failure of systemic sclerosis

Answer 59

scleroderma renal crisis