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Pathophysiology - Urinary Tract > Pathology of Glomerular Disease > Flashcards

Pathology of Glomerular Disease Flashcards

1
Q

What is the #1 defining characteristic of nephrotic syndrome which causes the majority of the other symptoms?

A

Heavy proteinuria (>3.5 g/day), leading to hypoalbuminemia.

Most of the other symptoms will be as a result of this protein loss.

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2
Q

What are the other general symptoms of nephrotic syndrome other than proteinuria (some will be related).

A

Generalized edema - dependent areas and periorbital, secondary to hypoalbuminemia

  1. Hyperlipidemia - liver increases lipoprotein synthesis to compensate for how thin blood has become due to protein loss
  2. Lipiduria - leakage of plasma lipoproteins into urine
  3. Increased risk of bacterial infections and thromboembolic complications - due to loss of immunoglobulins and antithrombin III, respectively.
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3
Q

Why does generalized edema due to hypoalbuminemia get cyclically worse?

A

Loss of intravascular volume due to loss of albumin from plasma -> decreased renal perfusion -> activation of RAA system for further sodium and water retention

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4
Q

What are the features of nephrotic syndrome on urinalysis?

A

Free fat or oval fat bodies (tubular epithelium filled with resorbed lipoproteins) seen in sediment

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5
Q

Who tends to get membranous glomerulonephropathy, and is it immune-complex mediated or not?

A

Occurs in Caucasian adults, most common cause of nephrotic syndrome in this population. It is due to immune complexes forming in subepithelial space (yes, immune-mediated).

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6
Q

What causes primary membranous glomerulonephropathy?

A

Antibodies to phospholipase A2 receptor, a podocyte antigen

-> autoimmune disease

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7
Q

Where must immune complexes deposit in secondary membranous glomerulonephropathy?

A

Subepithelial - antigens are small or cationic so they can pass all the way into the food processes of the podocytes

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8
Q

What are the causes of secondary membranous glomerulonephropathy?

A
  1. Medications - NSAIDs, penicillamine, captopril
  2. Infections - HBV, HCV, syphilis
  3. Malignancies - solid tumors put new Ags in circulation
  4. SLE - this is the nephrotic presentation of SLE
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9
Q

What is the pathogenesis of membranous glomerulonephropathy, other than the inciting antigen?

A

Immune complexes form / deposit in subepithelial area

  • > activation of complement, especially MAC (although C5a doesn’t seem to recruit more cells)
  • > podocyte and mesangial cell activation and production of injurious substances
  • > capillary wall damage + proteinuria WITHOUT hypercellularity
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10
Q

What does LM and DIF show in membranous glomerulonephropathy?

A

LM - diffuse capillary wall thickening with NORMOcellular glomeruli

DIF - Lumpy bump, granular appearance with immune complex deposition (IgG and complement)

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11
Q

What does EM show in membranous glomerulonephropathy?

A

EM - “spike and dome” appearance as spikes of GBM encircle the immune complexes (membrane is proliferating), with domes of podocyte processes in between them.

Note - immune complexes will appear electron-dense by EM

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12
Q

What is the prognosis of primary and secondary membranous glomerulonephropathy?

A

Primary - not responsive to corticosteroids -> slowly progresses to chronic kidney disease

Secondary - can improve with treatment of underlying cause / inciting antigen

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13
Q

What is the most common cause of nephrotic syndrome in children and what commonly triggers it?

A

Minimal change disease (MCD) - in young children following a recent infection, vaccination, or immune stimulus

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14
Q

What is the pathogenesis of MCD?

A

Usually a primary disease, but may begin secondary to another immune disease, commonly Hodgkin’s lymphoma.

Insult is due to cytokine production -> damage podocytes -> massive proteinuria, mostly albumin.

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15
Q

What are the LM, IF, and EM changes of minimal change disease?

A

LM - normal glomeruli (though lipid may be seen in PCT)
DIF - normal, with no evidence of Ig or complement (damage is cytokine-mediated)
EM - effacement of foot processes, a nonspecific finding for nephrotic syndromes

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16
Q

What is the prognosis of minimal change disease?

A

Excellent - responds well to corticosteroids

-> corticosteroids should be the empiric treatment in children with nephrotic syndrome, without renal biopsy

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17
Q

Who tends to get focal segment glomerulosclerosis (FSGS) and what are the associated findings of the nephrotic syndrome + other symptoms?

A

African Americans and Hispanics

Nephrotic syndrome with a nonselective proteinuria, often with associated findings worse than that (hematuria, hypertension)

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18
Q

What is primary FSGS caused by, and what will happen to the glomeruli / ECM?

A

Idiopathic

  • > it is like really bad MCD, caused by a circulating pathogenic factor
  • > damage to podocytes -> leakage of plasma proteins = hyalinosis
  • > hyalinosis -> increased ECM production = sclerosis

Patchy hyalinosis and sclerosis can be seen.

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19
Q

What disorders and comorbidities are associated with causing secondary FSGS?

A
  1. Glomerular hyperfiltration - due to a significant loss in functional nephrons, as described before
  2. Heroin abuse
  3. HIV infection - think of dz association with African American men
  4. Sickle cell disease
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20
Q

What are two causes of inherited forms of FSGS?

A
  1. Mutations in genes encoding proteins in the slit diaphragm (membrane between podocyte foot processes) - i.e. podocin
  2. Genetic risk alleles -> apolipoprotein L1
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21
Q

What pathology can be seen by light microscope in usual FSGS?

A

Hyalinosis of parts of glomeruli (segmental), affecting some but not most glomeruli (focal). Hyalinized areas around mesangial cells and afferent arterioles will undergo progressive ECM expansion (sclerosis)

-> gradually worsens to be accompanied by interstitial fibrosis and tubular atrophy

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22
Q

What is seen by DIF for FSGS?

A

Could be positive or negative, but if positive likely stains for focal deposits of IgM and C3 which have just leaked into extracellular matrix (hyalinosis).

Remember, it is like worsened MCD, which is NOT immune-complex mediated, it is due to cytokine-induced injury

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23
Q

What does TEM show for FSGS?

A

Diffuse effacement of podocytes and focal detachment of podocytes from GBM, with leakage of extracellular material
-> like really bad MCD

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24
Q

What will the HIV-associated variant of FSGS show on light microscopy and what is this variant called?

A

Collapsing variant of FSGS

LM:
Glomerular pathology - retraction of glomerular tuft (collapsing) with proliferation and enlargement of podocytes, typical FSGS pathology elsewhere

Tubular pathology - focal cystic dilatation of tubular cells (HIV can infect tubular cells)with intraluminal proteinaceous material and surrounding fibrosis / inflammation

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25
Q

What does TEM show for collapsing FSGS?

A

Typical changes of FSGS, including podocyte effacement

Endothelial cells of glomeruli have strange inclusions
-> alpha-interferon-modified ER, often seen in HIV-infected individuals

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26
Q

What is the prognosis of FSGS? Collapsing FSGS?

A

Poor, better changes in children to respond to steroids, but often progresses to CKD.

Collapsing FSGS has a very bad prognosis.

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27
Q

What are the symptoms of a nephritic syndrome?

A

Hematuria with RBC casts - inflammatory process, azotemia, oliguria, hypertension, mild-to-moderate proteinuria (not quite nephrotic range proteinuria), edema

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28
Q

Why do azotemia, oliguria, HTN, proteinuria, and edema happen in nephritic syndrome?

A

Reduction in GFR due to hypercellular inflammation blocking filtration
-> azotemia, oliguria, hypertension (sodium retention)

Glomerular membrane damage but not high enough GFR for massive proteinuria
-> RBCs lost, proteins not as much. Proteinuria -> edema from loss of oncotic pressure.

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29
Q

What is the general shared characteristic of nephritic syndrome glomeruli? What is the pathogenesis behind that?

A

Hypercellular, inflamed glomeruli

Immune-complex deposition activates complement; C5a attracts neutrophils, which mediate damage

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30
Q

What is the most common type of acute proliferative glomerulonephritis, postinfectious, and when does it present?

A

Poststreptococcal glomerulonephritis, presents several weeks after a Group A Strept infection of pharynx or skin, usually in children

Note: there are other types of acute proliferative glomerulonephritis, postinfectious which can occur after other bacterial, viral, and parasitic pathogens which are not GAS

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31
Q

What is the pathogenesis of acute post-strept glomerulonephritis (PSGN)? What type of hypersensitivity is it?

A

Infection with nephritogenic strain of GAS -> production of antibodies to microbial antigens, especially strept exotoxins -> formation and deposition of immune complexes within glomeruli -> activation of complement with leukocyte infiltration and proliferation of mesangial cells

  • Type III hypersensitivity reaction
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32
Q

What is seen on LM and DIF for PSGN?

A

LM - diffuse, enlarged, globally hypercellular glomeruli with neutrophils / macs and proliferation of mesangial cells

IF - lumpy bumpy appearance due to IgM / IgG / C3 deposition along GBM and mesangium

33
Q

What is seen on EM for PSGN and how does this differ from nephrotic syndrome in appearance?

A

Large, subepithelial deposits (below podocytes, like membranous glomerulonephropathy), which are LARGER and more interspersed, like humps (vs MGN where they are closer together and smaller).

34
Q

What will serum assay for antistreptococcal and complement titers say in PSGN?

A

ASO and anti-DNase B will be positive

C3 complement titers will be decreased, due to consumption of complement

35
Q

What is the prognosis for PSGN and the worst case scenario?

A

Vast majority recover with conservative management (gotta deal with that cola-colored urine)

Worst case - rapidly progressive glomerulonephritis (RPGN), or slow progression to chronic GN

36
Q

What disease is associated with acute proliferative glomerulonephritis, non-postinfectious?

A

SLE

37
Q

What disease is associated with a mixed nephrotic / nephritic presentation? What disease is it related to?

A

Membranoproliferative Glomerulonephritis (MPGN)

Membrano - nephrotic

Proliferative - nephritic

Related to membranous glomerulonephropathy -> immune deposits are just actually subendothelial or intra-membranous instead of subepithelial

38
Q

What is MPGN, Type I caused by if it is primary or seconday? Where do things deposit?

A

Primary - idiopathic

Secondary - related to SLE, or associated with HBV or HCV, other autoimmune conditions

Subendothelial immune complex deposits

39
Q

What is MPGN type II also called, and what causes it? What will happen to serum complement levels?

A

Dense-deposit disease -> development of an auto-antibody called C3 nephritic factor
-> IgG antibody stabilizes C3 convertase of alternative pathway (C3bBb) for persistent complement activation and decreased C3 levels

40
Q

What does LM show for MPGN, both Types I and II?

A

Both show a “tram-track” or “split” appearance with PAS stain (stains only the glycoproteins in the basement membrane) -> GBM is split through the middle by mesangial cell processes

Glomerulus is hypercellular and proliferative, also appears somewhat lobulated (semidiscretely divided)

41
Q

What do DIF show for MPGN Type I vs Type II?

A

Type I - granular deposition of IgG, C3, C1q, and C4 in the glomerulus diffusely (all complement components, not just alternative)

Type II - C3 deposition would be prominent in GBM adjacent to dense deposits, and in mesangium. C3 nephritic factor is IgG but will not stain because the C3 is formed peripherally. Also C1q and C4 would not be present (classical pathway components)

42
Q

What would TEM show for MPGN Type I vs Type II?

A

Type I - Predominantly subendothelial electron-dense deposits, with duplication of GBM associated with mesangial cell processes coming through

Type II - Extremely electron dense material in the lamina densa (dense-deposit disease) which splits GBM into two layers. No idea whats even accumulating cuz its not even C3.

43
Q

Who tends to get MPGN and what is the prognosis?

A

Adolescents or young adults, poor prognosis (unresponsive to treatments)

44
Q

What causes rapidly progressive glomerulonephritis (RPGN) and what is the prognosis?

A

Usually follows a nephritic presentation, but can follow any severe glomerular injury which involves severe glomerular capillary wall damage -> leakage of fibrin into Bowman space, and formation of crescents (crescentic glomerulonephritis)

Prognosis is poor -> renal failure in days to weeks.

45
Q

How do the kidneys appear grossly in RPGN?

A

Swollen, pale kidneys with petechial hemorrhages

-> due to little glomerular injuries

46
Q

What is the characteristic light microscopic finding of RPGN?

A

Crescents formed by proliferating parietal epithelial cells (of Bowman’s capsule), infiltrating monocytes / macrophages, and fibrin
-> causes compression of glomerular tufts

47
Q

Why will RPGN cause oliguria?

A

Decreased GFR due to compression of the glomerular tufts

48
Q

What does TEM show in RPGN?

A

Irregular, wrinked GBM with focal discontinuities -> holes allowing leaking of fibrin and severe glomerular injury

49
Q

What type of RPGN will show a linear, diffuse immunofluoresence pattern and who does it classically affect?

A

Anti-GBM antibody, against NCI in Type IV collagen
-> IgG staining of basement membrane of glomerulus and tubules

Classically presents in young adult males

50
Q

What is it called if you have an anti-GBM antibody and it presents with hematuria and hemoptysis? What type of hypersensitivity is it?

A

Goodpasture syndrome - Type II hypersensitivity

Noninherited auto immune disease, when you have anti-GBM antibodies against your lungs as well
-> associated with pulmonary hemorrhage

51
Q

What is the treatment for anti-GBM antibody, and what “type” of RPGN is this?

A

RPGN Type I - anti - GBM antibody

Treatment is plasmapheresis and immunosuppression

52
Q

What is Type II RPGN and what does it follow?

A

Immune-complex RPGN
-> follows another glomerulonephritis which causes immune complex damage, allowing fibrin leak

i.e. Post-streptococcal GN, glomerulonephritis due to SLE, IgA nephropathy

53
Q

What will DIF show for Type II RPGN and how is it treated?

A

DIF - granular, lumpy bumpy staining

Treated by treating the underlying disease

54
Q

What is Type III RPGN also called and what are the causes?

A

Pauci-immune = immune-negative, usually do to a type of small vessel vasculitis, but can be idiopathic.

All are associated with development of an ANCA, either c-ANCA or p-ANCA

55
Q

What small vessel vasculidities are associated with Type III RPGN and what antibodies cause them?

A

Granulomatosis with polyangiitis - WeCener - c-ANCA - proteinase-3 antibody (P doesn’t go with P)

Microscopic Polyangiitis - p-ANCA- anti-MPO

56
Q

What does IF show for Type III RPGN?

A

No staining for IgG or C3 -> immune negative = pauciimmune

57
Q

What is the most common glomerular disorder worldwide?

A

IgA nephropathy - Berger disease (NOT Buerger)

58
Q

What is the clinical presentation of IgA nephropathy?

A

Usually in older children or young adults - persistent microhematuria with episodes of macrohematuria following a mucosal infection (usually respiratory)

59
Q

What is the pathogenesis of Berger disease? Include the type of cell which is most damaged.

A

Susceptible individuals increase IgA synthesis following infection (or with celiac disease or decreased IgA clearance in hepatobiliary diseases)

  • > increased polymeric IgA
  • > deposition in mesangium of glomeruli
  • > activation of alternative complement pathway wiht primary mesangial injury
60
Q

What is seen on LM and IF for Berger disease?

A

LM - variable focal / segmental mesangial proliferation + increased matrix

IF - granular deposition of IgA and C3, predominant in the mesangium. No C1q or C4 since it’s alternative pathway activation, and no IgM/IgG.

61
Q

What does TEM show for Berger disease?

A

Mesangial immune complex deposits of IgA

62
Q

What is the inheritance of Alport syndrome, and what is the major defect?

A

X-linked, defect in Type IV collagen alpha chains

-> defective assembly and dysfunction of the GBM

63
Q

What are the clinical manifestations of Alport syndrome?

A

Can’t see, can’t pee, can’t hear a bee

  1. Renal disease - hematuria with RBC casts, which progressively worsens to chronic kidney disease
  2. Sensorineural hearing loss (involves BM of ear)
  3. Ocular involvement - retinal flecks, anterior lenticonus (weird lens shape)
64
Q

What does LM and DIF (what are we looking for?) show for Alport syndrome?

A

LM - Interstitial foam cells with progressive sclerosis of glomeruli, interstitium, and vasculature

DIF - Absence of normal GBM staining using antibodies against collagen alpha-chain

65
Q

What does TEM show for Alport syndrome?

A

Irregular basement membranes of glomeruli and tubules, with alternating areas of thickening and thinning.

Along with interspersed breaking apart of lamina dense giving a “Basket-weave” appearance

66
Q

What is the most common cause of asymptomatic familial hematuria? What is the prognosis?

A

Thin basement membrane disease - seen in individuals who are heterozygous for alpha-chain of Type IV collagen abnormalities

  • > diffuse thinning of GBM
  • > hematuria +/- proteinuria

Normal renal function and excellent prognosis

67
Q

What is Chronic Glomerulonephritis?

A

End-stage renal disease caused by any type of glomerular disorder

  • > each entity has a different chance of progressing here, with RPGN being the highest
  • > think of it as the congestive heart failure of the kidney
68
Q

What is the gross appearance of chronic glomerulonephritis?

A

Two tiny little scarred kidneys

-> thinned cortex

69
Q

What is the microscopic appearance of chronic glomerulonephritis?

A

Progressive hyalinosis and sclerosis of the glomeruli, arterioles, and interstitium, with tubular atrophy and chronic inflammatory infiltrate

70
Q

What is IgA vasculitis?

A

Henoch-Schonlein Purpura (HSP)

Skin + GI + IgA nephropathy

  • > IgA nephropathy the same as discussed before
  • > HSP is just the systemic manifestation of this disease
71
Q

What are the systemic symptoms of HSP?

A

Palpable purpura on buttocks, dorsal legs, and arms

Intestinal bleeding and abdominal pain (GI)

Renal abnormalities (hematuria, proteinuria, hypertension, edema) -> nephritic

72
Q

What are the six classes of renal pathology associated with SLE? Which one is most common presenting type?

A

Class I - minimal mesangial lupus glomerulonephritis
Class II - mesangial proliferative lupus glomerulonephritis
Class III - focal proliferative lupus glomerulonephritis
Class IV - diffuse proliferative glomerulonephritis - most common presenting type
Class V - membranous lupus glomerulonephritis
Class VI - advanced sclerosing lupus glomerulonephritis

73
Q

How does LM look for classes I and II lupus glomerulonephritis?

A

Class I - minimal mesangial lupus glomerulonephritis
-> normal appearance

Class II - mesangial proliferative lupus glomerulonephritis
->expansion of mesangium cell number + matrix (proliferative)

74
Q

How does LM look for classes III and IV lupus glomerulonephritis?

A

Class III - focal proliferative lupus glomerulonephritis
-> scattered glomeruli with increased cellularity, inflammatory cell infiltrates, and fibrinoid necrosis / thrombosis

Class IV - diffuse proliferative glomerulonephritis

-> Majority of glomeruli with the features of Class III

Wire looping of capillaries is common in both types.

75
Q

What is class V lupus glomerulonephritis by LM?

A

Class V - membranous lupus glomerulonephritis

  • > this is the secondary membranous glomerulonephropathy from earlier
  • > leads to a nephrotic / nephritic presentation

-> Widespread thickening of glomerular capillary walls

76
Q

What does DIF show for glomerulonephritis of lupus?

A

Granular appearance with lumpy-bumpy deposition of immune complexes in mesangium and glomerular capillary walls

77
Q

Where will the immune complexes deposit via TEM in Class III, IV, and V lupus glomerulonephritis?

A

III & IV - proliferative picture -> subendothelial deposits

V - membranous picture -> subepithelial deposits

78
Q

What special LM finding is seen most often with Types III and IV lupus glomerulonephritis and why?

A

Types III & IV are both commonly seen to have “wire looping” of capillaries
-> rigid thickening of glomerular capillary walls, especially due to subendothelial immune complex deposition.

Think “wire lupus”.

Can happen in other types as well, but less common.

79
Q

Are immune complex deposits of lupus in the kidney limited to the glomerulus?

A

No -> immune complexes commonly deposit within tubular basement membranes as well

Pathophysiology - Urinary Tract (14 decks)

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