The Kidney In Systemic Diseases Part Ii

Front 1

What are the five systemic diseases in this lecture?

Back 1

Sickle cell nephropathy
Amyloidosis
Light chain disease
HIV-associated nephropathy
Cryoglobulinemia

Front 2

What do many 60% of patients with hgb SS disease (sickle cell) have over 45 years?
What will a small minority (4-12%) develop?

Back 2

Microalbuminuria

ESRD

Front 3

What results in polymerization of deoxygenated hemoglobin S and subsequent sickling of erythrocytes?

Back 3

Relative hypoxia (partial pressure of oxygen 10-35 mmHg), acidosis, and hyperosmolarity of inner medulla

Front 4

What is shown in each?

Back 4

Injection micrographs:

A = no hemoglobinopathy (visible vasa recta)
B = sickle cell trait (cortical vasculature decrease, vasa recta attenuated and distorted)
C = sickle cell disease (decrease in cortical vasculature, vasa recta absent)

Front 5

What will you see clinically in sickle cell nephropathy?

Back 5

Microalbuminuria --> proteinuria
Hyperphosphatemia and increased creatinine secretion
Increased GFR early childhood --> adult, decreasing GFR from fourth decade onward
Impairment of distal H+ ion and K+ secretion
Diminished concentrating ability (hyposthenuria)

Front 6

What is seen in the earlier stages of sickle cell nephropathy?

Later stages?

Back 6

Glomerular hypertrophy, hemosiderin deposits, focal areas of hemorrhage or necrosis

Interstitial inflammation, edema, fibrosis, tubular atrophy, papillary infarcts

Front 7

What is seen in end stage sickle cell nephropathy?

Back 7

Glomerular enlargement and focal segmental glomerulosclerosis

Front 8

What is shown here? What does sickle cell crisis result from?

Back 8

Sickle cell nephropathy

Glomeruli occluded by sickled red cells
Extensive congestion and sickling in peritubular capillaries

Sickle cell crisis = sickling in kidney, particularly vasa recta

Front 9

What is shown here?

What will the patient have clinically?

Back 9

Sickle cell nephropathy

Glomerulomegaly and mesangial expansion
Tubular epithelial hemosiderin accumulation
Interstitial fibrosis and vascular stenosis

Chronic renal disease and proteinuria

Front 10

What is shown here?

Back 10

Renal artery thrombosis in sickle cell disease

Front 11

What is the definition of amyloidosis?

Back 11

Group of chronic diseases characterized by the deposition of abnormal protein in blood vessels and interstitium, eventually leading to organ malfunction.

Front 12

What is the epidemiology of amyloidosis?

What is the range of severity?

Back 12

Uncommon, primarily in late middle-aged and elderly persons, may be primary (most common) or secondary (reactive systemic).

Incidental to fatal

Front 13

Pathogenesis of amyloidosis?

Where is it first deposited? Then where? What does it do there? Result?

Back 13

Misfolded proteins (chemically diverse but similar) all folded into beta-pleated sheets

Blood vessel walls --> interstitial --> squeezes cells to death --> organ failure

Front 14

What are the old and new schemes for the classification of amyloidosis?

Back 14

Front 15

Draw the pathways of amyloid deposition.

Back 15

Lymphocyte and plasma cell derived immunoglobin light chains are amyloidogenic in fibrillogenic environment.

Chronic inflammatory disease --> synthesis of acute phase reactants by liver (SAA) --> SAA in presence of AEF released by macrophages and in fibrillogenic environment forms amyloid.
Macrophages degrade amyloid --> involved in amyloid deposition and turnover.

Front 16

What does advanced renal disease result in?
What will happen to size of kidney?
What may predominate?
What can tubular and interstitial deposits lead to?

Back 16

Nonproliferative, noninflammatory glomerulopathy
Increase
Vascular involvement
Tubular atrophy and interstitial fibrosis

Front 17

What is shown here? Describe.

Back 17

Amyloid kidney
Amorphous hyaline and eosinophilic

Front 18

What is shown here? Stain type?

Back 18

Amyloid kidney:
Congo red stain

Front 19

What is shown here? Test?

Back 19

Congo red stain under polarized light = apple green birefringence.

Front 20

Can you tell what type of amyloid it is with congo red stain?

What is an immunoperoxidase stain used for (above)?
Problems?

Back 20

Never
Amyloid A

Plagued with false positives and false negatives so becoming uncommon to send off for molecular testing.

Front 21

What is the most common amyloid type?
What does it consist of?
What is it called in urine?
15% of patients with what disease have this?
Most patients will just have what?

Back 21

Amyloid L (primary)

Immunoglobin light chains
Bence-Jones proteins
Multiple myeloma
Monoclonal gammopathy

Front 22

Median age of diagnosis of amyloid L?
Symptoms?
Kidney changes?

Back 22

64 years
Weakness, weight loss, nephrotic syndrome, peripheral neuropathy, autonomic neuropathy

Renal insufficiency w/ enlarged kidneys.

Front 23

Are AL patients usually hypertensive?
What other illnesses will you see associated?

Back 23

No
Restrictive cardiomyopathy, sick sinus syndrome, myocardial infarction, gastrointestinal dysmotility, malabsorption, hemorrhage or obstruction, bleeding diathesis.

Front 24

What will most patients with AL eventually develop?

What patients with multiple myeloma are more likely to develop AL?

What factors modify the chances of a patient developing amyloidosis?

Back 24

Plasma cell dyscrasias, B-cell lymphomas, or multiple myeloma

Those with I chains

Amino acid sequence, macrophage activity, and extracellular environment

Front 25

What is shown here? Where do they precipitate and what do they form?

Back 25

Bence Jones proteins

Precipitate in urine or in tubules
Tubular epithelial cells can coalesce into a syncytium around them

Front 26

What is the treatment for amyloidosis--AL?

What about for patients less than 50 years old?

What is the median survival time?

Back 26

Low dose oral melphalan and dexamethasone
High dose melphalan with autologous cell transplant in patients < 50 years i age

10 months

Front 27

What is reactive systemic (amyloid A) secondary to?
What diseases?

What does it consist of? What is acute phase reactant produced by? In response to what?

Back 27

Secondary to chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, or anklyosing spondylitis

Serum A amyloid protein
(acute phase reactant produced by liver in response to Il-1 and Il-6)

Front 28

What is main target in AA?
Another common target?
How diagnosed?
Follows what?

Back 28

Kidney
GI tract
Renal biopsy
Serum AA levels

Front 29

Treatment for AA?
Mechanism?

Back 29

Eprodisate

Limits deposition of AA fibrils by interfering with their interaction with tissue glycosaminoglycans
Slows renal decline (but not risk of death)

Front 30

What is death from AA usually from?

Back 30

Infection or dialysis related complication

Front 31

What does amlyoid beta2m occur with?
What does it consist of?

Where does it deposit?

Back 31

Long term hemodialysis

Beta-2-microglobulin (small molecule, component of MHC class I, normally some in serum) which is not efficiently filtered trough dialysis membrane

Synovium, joints, and tendon sheaths

Front 32

What is shown here? What does it result in?

Back 32

A b2m

Deposition in bone --> destructive arthropathy

Front 33

What is shown here?
How do the deposits appear?

Back 33

Ab2m deposits in a joint
Homogenous pink or yellow
Destroying and replacing bone and cartilage

Front 34

What are the two types of amyloid ATTR?

What does it consist of?
Where does it form?
4% of what population have a mutated transthyretin?
Clinical presentation?

Back 34

Senile or familial

Transthyretin
Seniele = heart (and pulmonary blood vessels)
African Americans
Heart failure or arrhythmia

Front 35

What is transthyretin?

Back 35

Serum protein that binds and transports thyroxine and retinol

Front 36

What is light chain deposition disease?
Will congo red be positive?
Does it have fibrillar organization?
What does it involve precipitation of and without what?
What is it usually associated with?

Back 36

Nonamyloid monoclonal Ig deposition disease (MIDD)
Congo red negative
No
Precipitation of immunoglobulin chain w/o elongation seen in amyloid
Multiple myeloma and other lymphoproliferative disease

Front 37

What clinical stuff will you see in light chain deposition disease?
Severity of proteinuria? What syndrome? Renal function? Enlargements? Heart problems? Other random stuff?

Back 37

Proteinuria and renal failure
Non-nephrotic range proteinuria w/ tubulointerstitial syndrome
Rapidly declining renal function
Cardiomegaly, hepatomegaly, conduction disturbances
Peripheral neuropathy, GI distrubances, pulmonary nodules, arthropathy, sicca syndrome

Front 38

What is shown here?

What does it strongly resemble?

Back 38

Nodular glomerulosclerosis = characteristic appearance of light chain deposition disease

Diabetic nephropathy

Front 39

What is shown here?
What is characteristic of this disease?
What are the two possibilities?

Back 39

Light chain disease -- IF

Glomerular capillary loop, mesangial staining, and LINEAR tubular staining

Either kappa or lambda light chain paraprotein (KAPPA MOST COMMONLY)

Front 40

What is shown here?

Back 40

Light chain disease:
Endothelial cell side deposition of material likened to silt...like Mud Island (Nichols)

Front 41

When you have an increased suspicion of light chain disease?

What is the key to diagnosis?
When is renal and patient survival better?

Back 41

Nephrotic syndrome or rapidly progressive tubulointerstitial nephritis, cardiac diastolic dysfunction, and presence of monoclonal immunoglobin in the urine or serum

Renal biopsy
Pure MIDD without cast nephropathy

Front 42

What are the two viral-associate kidney diseases?

Back 42

HIV-associated nephropathy
Cyroglobulinemia

Front 43

What patient population is much more susceptible to HIV-associated nephropathy?

Clinical findings?

Back 43

African Americans

Progressive azotemia, significant proteinuria, and minimal peripheral edema in patients with advanced HIV disease

Front 44

What is HIV associated nephropathy classically a form of?
What will you see?
What does it result from?

Back 44

Focal segmental glomerulosclerosis
Prominent microcystic tubular dilation and interstitial inflammation and fibrosis
Podocyte dedifferentiation and proliferation

Direct infection by HIV-1 and expression of viral genes Nef and Vpr in renal epithelial cells in genetically susceptible host

Front 45

What may causes susceptibility of African Americans to HIV associated nephropathy?
Why?

Back 45

APOL1

G1 and G2 APOL1 mutations = resistance to Tryopanosoma brucei rhodesience (African sleeping sickness) infection as the inhibitor cannot bind to the variant protein.

Front 46

What is shown here? What is this due to?

Back 46

Front 47

What is shown here?
What is the most common lesion in HIV infection-related renal disease?

Back 47

Prominent microcytic tubular dilation.
Interstitial inflammation and fibrosis.
Tubules filled with proteinacious material

HIVAN (HIV associated nephropathy)

Front 48

What is cyroglobulinema? Clinical findings?

Back 48

Palpable purpura, anthralgia, asthenia accompanied by organ involvement (nephropathy and neuropathy) and elevated serum RF, Ig capable of binding to IgG

Front 49

What is mixed cryogrobulinemia associated with?
What type of disorder is it?

Back 49

Hepatitis C (90% cases)
B-cell lymphoproliferative disorder -- > deposition of immune complexes containing rheumatoid factor (RF), IgG, HCV RNA, and complement on endothelial surfaces, eliciting vascular inflammation

Front 50

True or false.
Patients with mixed cryoglobulinemia syndrome may be referred to different specialties according to prevalent symptoms.

Back 50

True

Front 51

Which is positive, which is negative? Temperature?

Back 51

Left = positive
Right = negative

Temp = 4 degrees Celsius

Front 52

What is shown here?
What can it have in capillary lumens?

Back 52

Cryoglobulinemic glomerulonephritis: membranoproliferative pattern

Can have pseudo-thrombi in capillary lumens

Front 53

What is the pathogenesis of cyroglobulin glomerulonephritis?

Back 53

Front 54

Summary of lecture?

Back 54

Summary of lecture?

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