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Flashcards in Nephrotic Syndrome Deck (65):
1

_____ have actin filaments that attach to the basement membrane of the glomerular capillaries to govern the diameter of the capillaries.

Mesangial cells

2

What is nephrin?

It is a protein that extends out from each podocyte foot process to prevent protein from getting into the urine.

3

Mutations in ____ and/or _____ (proteins of the slit diaphragm) will lead to proteinuria.

nephrin, podocin

4

Nephrotic syndrome? (5)

  1. Proteinuria (greater than 3.5 g/d) (protein leak causes high urine protein)
  2. Hypoalbuminemia (less than 3.0 g/dl) (serum albumin falls because you're losing albumin in the urine) 
  3. Edema (oncotic pressure falls so fluid starts to move into interstitium)
  4. Hyperlipidemia (elevated cholesterol)
  5. Lipiduria (lipids getting into urine)

5

Nephritic syndrome? (5)

  1. Decreased renal function
  2. Hypertension (decreased renal function means salt retention)
  3. RBC and RBC casts
  4. Edema
  5. Proteinuria (less than 3.5 g/d)

6

Nephrotic syndromes are primarily due to damage of the _____.

What two ways can this happen to cause proteins to leak across the filtration barrier?

podocytes

 

  1. The podocyte can be injured which causes it to swell up and the slit diaphragms are disrupted.
  2. A direct injury or mutation of the slit diaphragm itself.

7

What kind of edema is seen in nephrotic syndrome?

Pitting edema. You can press it with your finger and it stays indented for a while.

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8

What two mechanisms lead to edema in nephrotic syndrome? Explain the mechanisms.

1. Classic mechanism (particularly in children)

Protein is lost in the urine so there is a lower oncotic pressure in blood capillaries. This causes plasma to leak out into the interstitium which causes edema. Furthermore, less volume in the vessels causes the body to release ADH and aldosterone to increase sodium retention to increase fluid retention. This increases the edema as well.

2. More common mechanism

There is a primary defect in Na+ excretion in the distal tubule which causes sodium retention and edema. The low serum albuin also contributes to this effect. However, with this mechanism, there isn't a low serum volume.

 

The big difference is that in the classic mechanism, the patient is edematous with a low serum volume and in the more common mechanism the patient is edematous with a high serum volume.

9

Nephrotic syndrome causes lipiduria. What do lipids look like under polarized light? (2)

"maltese crosses" and "oval fat bodies"

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10

What are 3 additional complications of nephrotic syndrome?

  • Hypercoagulable state
    • When there is low serum albumin, the liver starts to kick out every protein that it can make. This includes coagulation factors (fibrinogen, factors V, VIII, IX, and X).
    • You can lose anti-thrombin III in the urine.
    • Increased platelet aggregation to stimuli (hyperactivated platelets)
  • Infections
    • Loss of immunloglobulins (particularly IgG) and complement proteins (factor B) increases risk for bacterial infections (e.g. peritonitis, pneumonia, etc)
  • Decreased Vitamin D levels (loss of vitamin D binding protein)

11

What is general management of nephrotic syndrome? (6)

  1. Low salt diet (reduce fluid retention)
  2. Diuretics (reduce fluid retention)
  3. BP control
  4. Cholesterol lowering drugs
  5. ACE inhibitors (dilation of efferent arterioles causes less glomerular pressure which decreases proteinuria. This does drop GFR a tiny bit but it's worth the decrease in proteinuria.)
  6. Vitamin D (25-OH Vit D) replacement.

12

True or False: Hereditary nephrotic syndrome is typically seen in adults

FALSE

Hereditary nephrotic syndromes are typically seen in children and young adults. It is typically not seen after the age of 25.

13

What is the etiology of hereditary nephrotic syndrome?

Mutations of slit diaphragm proteins-- Nephrin and/or podocin

14

What is typicaly presentation of hereditary nephrotic syndrome?

Typically seen in children. Sometimes in young adults but not over age of 25.

Presents with ascites, edema, and failure to thrive

15

If you see high protein in amniotic fluid during pregnancy, what nephrotic syndrome would be on the differential dx?

Hereditary nephrotic syndrome.

16

What is treatment for kids with hereditary nephrotic syndrome?

Keep them alive long enough to put them on dialysis (usually after 2 months of age) and then when they get to a certain age (usually 2 years), they can get a kidney transplant which cures their disease.

 

These kids typically don't respond to treatment since it's a mutation but the transplant will cure them.

17

True or False: Minimal change disease typically occurs in children and presents with dramatic and sudden weight gain.

True

18

What is typical presentation for minimal change disease nephrotic syndrome? (4)

Edema

Ascites

Weight Gain

Normal blood pressure

19

What is typical age of incidence for minimal change disease (nephrotic syndrome)?

2-10 y/o

20

What are the lab findings for minimal change disease (nephrotic syndrome)? (4)

  1. Renal function normal or slightly depressed
  2. Urinalysis with 4+ protein
  3. hyaline casts
  4. microscopic hematuria is rare.

21

Minimal change disease (a nephrotic syndrome) can be sometimes associated with what 3 things?

  1. history of allergy
  2. hodgkin's lymphoma
  3. nonsteroidal drugs (idiosyncratic reaction)

22

What is the pathophysiology of minimal change disease?

The proposed mechanism is that there is something in their blood (a circulating factor) that is triggering podocyte injury disrupting the slit diaphragm and causing proteinuria.

23

True or False: Minimal change disease (a nephrotic syndrome disease) is difficult to cure.

False

It's easily treated. Patients are put on corticosteroids (prednisone) and improve quickly. Within weeks to months, the urine protien drops to normal levels. However, some patients relapse. Relapses are treated the same way but if they relapse more than a couple times, you want to give a short course of oral cytoxan (12 weeks).

24

What does minimal change disease look like under light microscopy, electron microscopy, and immunofluorescence?

Basically, everything is normal except for foot process fusion in electron microscopy.

 

With light microscopy, the glomerulus looks normal.

With Immunofluorescence, there aren't any findings.

With electron microscopy, there is foot process fusion.

 

The fused foot processes just show that the podocytes are damaged. So, some cross sections will show the fused foot processes while other cross sections will have nothing appearance of podocytes at all. This was in response to someone asking "if they are fused, how to proteins pass?"

 

25

Recently discovered, the podocytes are not just cells that hold back proteins from crossing the filtration barrier, they are actually antigen presenting cells. How can this be used to differentiate between minimal change disease and other nephrotic diseases?

Antigen CD80 is highly expressed on the podocytes in minimal change disease. When patients are treated with prednisone, the CD80 expression drops dramatically.

 

CD80 is actually excreted in the urine and you can detect it to know that it's minimal change disease.

26

You find CD80 antigens in the urine. What is the disease?

Minimal change disease

27

What is the most common primary nephrotic syndrome in children?

Minimal change disease

28

What is the most common primary nephrotic syndrome for people in their 20s?

Focal segmental glomerulosclerosis (FSGS)

29

Why is Focal Segmental Glomerulosclerosis named that way?

There is scarring (sclerosis) in some glomeruli but not all (focal). And it's called segmental because the scarring in glomeruli is spotty, not global.

30

In FSGS, does the protein pass through the filtration barrier in the glomeruli with sclerosis or the normal ones?

The normal ones.

 

The places that are scarred are not functional (dead kidney)

31

What is the etiology or associated causes of focal segmental glomerulosclerosis (FSGS)? (4)

Idiopathic (75% of cases)

HIV associated nephropathy (HIVAN)

Sickle Cell Disease

Obesity

32

What is the most common cause of nephrotic syndrome in African Americans?

Focal Segmental Glomerulosclerosis (FSGS)

33

What is the peak incidence age range for FSGS?

20-40 years old

34

What are the lab findings for FSGS?

Renal function is normal or slightly depressed

Urinalysis has 4+ protein, hyaline casts, and microscopic hematuria

35

True or False: FSGS improves easily with treatment

False. This disease is harder to manage and usually progresses over time.

36

What is the associated genetic factor that can cause FSGS?

APOL1 mutation is associated with FSGS in african americans.

 

APOL1 mutation in african americans actually protected against sleeping sickness from the Tsetse fly. This explains how APOL1 mutation has been preserved but unfortunately this sometimes leads to kidney damage by increasing risk factor or accelerating existing risk factors (HTN, HIV, etc)

37

HIV nephropathy is a typic of FSGS that typically presents in people with full-blown AIDS (low CD4 counts). How is this treated?

Treated with anti-retroviral agents

38

HIV nephropathy looks slightly different from other FSGS in histologic findings. What are the 2 characteristic findings?

  1. Tubular dilation (microcysts)
  2. Reticulo-endothelial inclusions

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39

What is the most common primary nephrotic syndrome in patients in their 40s or 50s?

Membranous nephropathy

40

Are the age ranges for primary nephrotic syndromes hard rules?

Of course not.. You can still get minimal change disease as an 80 year old but it's just not common. The age groups just help you narrow things down to what is typical.

41

What is the clinical presentation of membranous nephropathy (a type of nephrotic syndrome disease)?

Edema (sometimes subtle)

Variable BP (usually a little on the high side)

4+ proteinuria

Microhematuria

42

While membranous nephropathy is sometimes idiopathic, it is currently observed that membranous nephropathy is associated mainly with _____. It is also associated with what other things? (3)

Cancer (GI, lung, breast)

Heavy metals (mercury)

Hepatitis B

Lupus (type V)

43

How do you diagnose membranous nephropathy?

Renal biopsy showing thickening of the glomerular basement membrane, normocellularity, and granular immune complex deposits that are in the subepithelial regions.

 

The thickened basement membrane is why it's called membranous nephropathy.

44

What are findings on light, IF, silver stain, and EM for membranous nephropathy?

Light - thick glomerular basement membrane

IF - granular deposits

Silver stain - projections (little spike things)

EM - subepithelial deposits

 

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45

What is the pathogenesis of membranous physiology?

Mediated by antibodies to the phospholipase A2 receptor (antigen) on podocytes.

46

A 52 year old executive with 30 year smoking history presents with a hilar mass and nephrotic syndrome. What nephrotic syndrome is it likely to be?

Membranous nephropathy

47

Patients who are found to have membranous nephropathy should be evaluated for what?

Cancer. Cancer is present in 6-11% of these cases so patients w/ membranous nephropathy are screened for cancer (colonoscopy, mammogram, CXR, CBC, history and physical).

48

What is the example of mercury exposure that was talked about in class that can cause membranous nephropathy?

Mercury in skin cream used to lighten skin (seen in Asia/India)

49

Membranous nephropathy that's caused by hepatitis B is typically associated with what demographic?

Children

50

What is seen in hepatitis B associated membranous nephropathy? (aside from the things usually seen)

Hepatitis B immune deposits (HBsAg+, HBeAg+, anti-HBc +)

51

How do you treat hepatitis B virus associated membranous nephropathy?

Treat with interferon(antiviral). Patients typically do well from this.

52

What is the prognosis for membranous nephropathy?

50% of untreated subjects progress to end stage renal disease over 20 years.

70% of treated patients respond.

53

How do you treat membranous nephropathy?

Corticosteroids and cyclophosphamide

54

True or False: Type 1 MPGN is classic membranoproliferative glomerularnephritis.

True

55

How do patients with membranoproliferative glomerularnephritis (type 1) present?

Nephrotic syndrome (with mixed nephritis syndrome - mildly reduced renal function), and hypertension

56

MPGN (type 1) is typically associated with ____. (3)

Hepatitis C (HCV) - may be associated with systemic symptoms (weakness, arthralgia, palpable purpura - red raised spots that come and go which are from immune complexes depositing in the skin) and circulating cryoglobulins that contain HCV virus. Positive rheumatoid factor, low serum complements (C3 and C4).

Low grade systemic infection - ventriculoatrial shunts, subacute endocarditis

Idiopathic - rare, occurs mainly in children

57

What is the pathology of membranoproliferative glomerulonephritis (type 1)?

GBM thickening (that's why it's called membrano)

Hypercellularity (That's why it's called proliferative)

Granular immune complex deposits

EM with subendothelial deposits

58

How do you treat membranoproliferative glomerulonephritis (type 1)?

Treat the hepatitis C. Or if it's progressing rapidly, use steroids to suppress the immune system.

For infection associated, treat the infection.

For idiopathic, use steroids.

59

Where are the immune depositis in membranoproliferative glomerulonephritis (type 1)? How is this different membranous?

The deposits are on the endothelial side of the basement membrane and that allows the WBCs to see the deposits which causes inflammation and injury. In membranous nephropathy, the cells are on the other side of the basement membrane (subepithelial) where the WBCs can't reach.

60

Membranoproliferative glomerulonephritis type II is a _____ disorder

complement

61

Membranoproliferative GN type II typically presents in what age group?

Children

62

How does membranoproliferative glomerulonephritis type 2 appear in histology?

Hypercellularity and thickened basement membrane (like type I).

However, there are complement deposits in the basement membrane which looks like ribbon like deposits that replace the basement membrane.

63

Low serum complements are in both type 1 and type 2 membranoproliferative glomerulonephritis. What's the difference between the two?

Type 1 has low C3 and C4.

Type 2 has low C3 but normal C4 (due to alternative pathway of complement due to presence of C3 nephritis factor)

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64

Is membranoproliferative glomerulonephritis type 1 or type 2 easier to treat?

Type 1.

Type 2 often responds poorly to therapy.

65

What are 3 systemic diseases that can cause nephrotic syndrome?

Diabetes

Amyloid and light chain disease

SLE (membranous)