Nephrotic Syndrome Ii

Front 1

What are the two podocytopathies?

Back 1

Minimal change disease
Focal segmental glomerulosclerosis

Front 2

What are important findings in minimal change disease?

Back 2

Facial and lower extremity edema
Pitting edema
Low albumin
4+ proteinuria
Urine protein creatinine ration = 18

Front 3

Describe the following in minimal change disease:
Age
Most common cause of ...
Onset of edema
BP
Renal function
What type of proteinuria?

Back 3

Front 4

Pathogenesis of minimal change disease?
Two major types? Causes of each type?

Back 4

Front 5

What is shown here? Pathology?

Back 5

Glomerulus
Minimal!

Front 6

What is shown here? Pathology?

Back 6

Tubules
Minimal!

Front 7

What is shown with each arrow? Red and blue.

Back 7

Red = detachment of foot processes
Blue = effacement of foot processes

Front 8

What is shown here?

Back 8

Answer from class.

Front 9

What is the cornerstone of treatment for minimal change disease? Children have the best response to what? Is this the same for adults? Is recurrence common? What should you do if there is a poor response to a steroid?

Back 9

Front 10

What are some common clinical findings in focal glomerulosclerosis?

Back 10

Lower extremity edema
Hypertension
Pitting edema
High creatinine
Low albumin
4+ proteinuria
Urine protein/creatinine ratio elevated

Front 11

Is FSGS increasing in incidence?
Is proteinuria selective in FSGS?
Is hypertension present in FSGS?
50% of patients with FSGS develop what within 10 years of diagnosis?

Back 11

Front 12

What is the "novel discovery" that is in the circulation in patients with primary FSGS?

Back 12

suPAR

Front 13

What does the suPAR do?

Back 13

Produced by neutrophils, monocytes, and T cells -> enters glomerulus --> binds and activates B3 integrin, anchoring protein of GBM

Front 14

What are the two major types of FSGS?

Back 14

Primary and secondary

Front 15

What is the cause of primary FSGS?

Back 15

Idiopathic

Front 16

What are causes of secondary FSGS?

Back 16

Familial
Infection
Drugs
Adaptive structural-functional response (loss of nephron mass -> partial removal of kidney tissue)

Front 17

What are some familial secondary causes of FSGS?

Back 17

Mutations in genes for alpha-actinin-4, podocin, and TRCP6
APOL1

Front 18

What are infectious causes of FSGS?

Back 18

HIV, parvo virus

Front 19

What are some drugs that cause FSGS?

Back 19

Pamidronate, heroin, lithium

Front 20

How are these proteins of the podocyte slit diaphragm involved in proteinuria?

Back 20

Answer from class

Front 21

What is the significance of APOL1 in the secondary cause of FSGS?

Back 21

A sequence variant in the apolipoprotein L1 gene (APOL1) on chromosome 22 appears to be strongly associated with an increased risk of FSGS and renal failure in individuals of African descent.

Front 22

What is shown here?

Back 22

Focal segmental glomerulosclerosis:
One involved, two uninvolved glomeruli, illustrating that it is focal.
Involved glomerulus has a large area of disease, illustrating that it is segmental.

Front 23

What is shown here?
Green arrow?
Black arrows?

Back 23

Focal segmental glomerulosclerosis:

Hyalinosis: accumulation of leaked plasma proteins and lipids.

Large accumulation = green arrow
Small accumulation = black arrow

Front 24

What is shown here? What is each arrow pointing to?

Back 24

Focal segmental glomerulosclerosis

Left = adhesion of involved segment to Bowman capsule

Bottom = hyalinosis

Front 25

What is this?

Back 25

Normal glomerulus

Front 26

What is this?

Back 26

Focal segmental glomerulosclerosis = foot process effacement (similar to minimal change disease)

Front 27

What are the five subtypes of FSGS? In order of frequency.

In which two will you see heavier proteinuria? Which of these has the worst survival and which is more likely to obtain remission?

Back 27

Not specified
Perihilar
Tip
Collapsing
Cellular

Collapsing = worst
Tip = remission

Front 28

What is the stain? What is the type of FSGS?

Back 28

Silver stain = collapsed BM and two adhesions
Collapsing type FSGS

Front 29

What is shown here?

Back 29

Electron microscopy of collapsing type FSGS.

Front 30

In MCD and FSGS what will immunofluorescence microscopy be?

What might you see in FSGS?

Back 30

Front 31

How do you treat FSGS?
Which is most commonly used?

What are other treatment options?

Back 31

Steroid and immunosuppressive therapy.

Front 32

What is shown here? Does proteinuria remit with treatment? What is more likely on the biopsy? Prognosis?

Back 32

Front 33

What is shown here? Does proteinuria persist despite treatment? What is more likely on biopsy? Prognosis?

Back 33

Front 34

True or false:
MCD and FSGS may be part of the same disease spectrum.

Why is sampling error possible in some cases?

Back 34

True

FSGS is focal and localized more to the deep juxtamedullary glomeruli

Front 35

What may develop in children with repeated relapses of MCD with steroid responsive nephrotic syndrome?

Back 35

FSGS secondary to repeated renal injury supporting an evolution process.

Front 36

Non-scarred glomeruli of patients with FSGS resemble those of what?

Back 36

MCD

Front 37

Loss of glomerular capillary charge barrier in both MCD and FSGS leads to what? What is the difference between the two?

Back 37

Heavy proteinuria --> may be less selective is FSGS secondary to large pores

Front 38

What is shown in bright red? Weird orange/red color?

How do they appear?

Why can't large circulating immune complexes deposit in the subepithelial regions?

Filtered antibody interacts with what?

What may the endogenous antigen be?

Back 38

1. Post infectious glomerulonephritis
2. Membranous nephropathy

May be assembled locally by "in situ" interaction or deposited antigen with filtered antibodies Large circulating immune complexes cannot deposit in the subepithelial regions as they are too big to pass through the glomerular basement membrane (GBM)
Filtered autoantibody interacts with a locally generated endogenous antigen
Endogenous antigen may be a protein or glycoprotein expressed on the podocyte cell membrane

Front 39

What are the two models of membranous nephropathy (in situ formation)?

Back 39

1. Filtered "cationic" antigen
2. Autoimmunity model

Front 40

Explain the filtered cationic antigen model of membranous nephropathy (in situ).

Provide an example:

Back 40

Deposits --> cross endothelium and GBM --> localize in SUBEPITHELIAL SPACES as restricted by size of slit diaphragm --> antibodies localize and cause nephritis

Endostreptin, NSAP, SPEB in acute post-streptococcal glomerulonephritis (APSGN)

Front 41

Explain the autoimmunity model of membranous nephropathy (in-situ):

Which one do you see in primary MN? Congenital MN?

Back 41

Autoimmunity model --> locally generated antigen and filtered antibody

Primary = M-type phospholipase A2 receptor (PLA2R)
Congenital = Neutral endopeptidase, NEP

Front 42

What is the autoantibody in idiopathic (not secondary MN)?

Back 42

Autoantibodies to M type phospholipase A2 receptor (PLA2R)

Front 43

Where is PLA2R expressed?

Back 43

Expressed by podocytes in normal human glomeruli and was co-localized with IgG4 in immune deposits in glomeruli of patients with idiopathic MN.

Front 44

Two types of MN?

Causes of secondary:
Infection
Autoimmune
Drugs
Maligancy

Back 44

Primary and secondary

Infection = Hep B, syphilis, malaria
Autoimmune = SLE
Drugs = gold, penicillamine, captopril, NSAID
Malignancy = lung cancer, colon cancer, melanoma

Front 45

What is the most common cause of nephrotic syndrome in Caucasian adults?
When is the peak incidence?
Male/Female?
What percent spontaneously resolve? What percent progress to renal failure? What percent proteinuria with variable renal dysfunction?

Back 45

Front 46

What are some risk factors for loss of renal function in MN?

Back 46

Front 47

What is shown here?

Back 47

MN
Thickened basement membrane without increased cellularity

Front 48

What is shown here?

Back 48

MN: immunofluorescence

Granular deposits of immunoglobulin (IgG) and complement (not shown but would look the same)

Front 49

What is shown here?

Back 49

Membranous Nephropathy:

Diffusely thickened basement membrane with subepithelial deposits separated by spikes of new GBM (“spike and dome” pattern).

Front 50

What is shown here?

Back 50

MN:
Thickened basement membrane with
subepithelial deposits (colored blue here) separated by spikes of new GBM (“spike and dome" pattern)

Front 51

Is MN nephrotic or nephritic? Why? Comment on the resolution of subepithelial deposits if the disease is secondary.

Back 51

Front 52

What occurs in the prescence of subepithelial deposits?

What is the mechanism?
What is washed away into urinary space?

Back 52

Retraction and effacement of podocyte foot processes

Complement dependent process mediated by membrane attack complex (C5b-9)
Intermediate chemotactic fragments (C3a and C5a)

Front 53

What are some indications of post-infectious glomerulonephritis?

Back 53

Dark color urine, weight gain, decreased urine output
BP increased
Pitting edema
High creatinine
Low albumin
3+ proteinuria
Urine protein ratio about 3

Front 54

Again, indications of PIGN?

Back 54

Front 55

What are common lab results in PIGN?

Back 55

Low C3 and normal C4 (alternative pathway activation)
Elevated anti-streptolysin O (ASO) titers if preceded by throat infection
Elevated anti-DNAse B titers if preceded by skin infection
Positive blood culture in sepsis

Front 56

What is shown here?

Back 56

Post streptococcal glomerulonephritis
Diffuse endocapillary proliferation and infiltration by numerous neutrophils

"polys" look like ants

Front 57

What is shown here?

Back 57

Immunoflourescence of post-streptococcal glomerulonephritis: Diffuse granular deposits in capillary walls and mesangium (especially IgG and C3)

Front 58

What is shown here?

Back 58

PSGN
"Dome shaped" subepithelial humps in blue!

Front 59

How do you treat PIGN? Supportive measures?

Back 59

Supportive = control hypertension (antihypers and diuretics), renal replacement therapy (if severe kidney dysfunction)

Treatment = treat underlying infection

Front 60

Prognosis of PIGN?

Back 60

Good prognosis with resolution of hypertension
Normal C3 levels by 6 weeks
Resolution of hematuria within 12 months