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13. Urogenital Pathology > 3. Glomerular diseases > Flashcards

3. Glomerular diseases Flashcards

1
Q

Clinical manifestations of glomerular diseases

A

1) nephrotic syndrome
2) nephritic syndrome
3) rapidly progressive glomerulonephritis
4) microscopic hematuria
5) chronic renal failure

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2
Q

Characteristics of nephrotic syndrome

A
  1. Heavy proteinuria
    - >3.5g of protein loss/24 hours
    - Urine appears frothy
    - May be selective or non-selective in nature
  2. Hypoalbuminemia
    - Plasma albumin <3g/dL
    - Albumin loss in urine overwhelms liver capacity to maintain normal serum albumin
  3. Anasarca
    - Generalized edema due to decrease in plasma oncotic pressure
    - Marked periorbital edema, pedal edema, facial & abdominal swelling
  4. Hyperlipidemia
    - Due to compensatory increase in synthesis of lipoproteins by liver
  5. Lipiduria
    - Due to hyperlipidemia as well as a leaky glomerular filter allowing leakage of lipoproteins into urine
  6. Others
    - Loss of immunoglobulins: increased susceptibility to Staphylococcal & Pneumococcal infections
    - Loss of anticoagulants & antiplasmins: thrombotic & thromboembolic complications
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3
Q

Causes of nephrotic syndrome

A
  1. Primary glomerular diseases
    - Minimal change disease
    - Membranous glomerulopathy
    - Focal segmental glomerulosclerosis
    - Membranoproliferative glomerulonephritis
  2. Systemic disease
    - Diabetes mellitus
    - Amyloidosis
    - Systemic lupus erythematosus
    - Drugs (NSAID, penicillamine, street heroin)
    - Infection (HBV, HCV, malaria, syphilis, HIV)
    - Malignancies (multiple myeloma, lymphoma)
    - Heterozygous Alport disease
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4
Q

Clinical features of nephrotic syndrome

A

Age is important in differential diagnosis of cause of
nephrotic syndrome
- Childhood nephrotic syndrome is almost always sensitive to steroid treatment (minimal change disease)
- Only when the child does not respond to steroid treatment is a renal biopsy performed

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5
Q

Characteristics of nephritic syndrome

A
  1. Oliguria
    - Decrease in urine volume due to poor filtration
  2. Azotemia
    - Elevation of serum creatinine & blood urea nitrogen levels
  3. Gross hematuria
    - Presence of red blood cells in the urine
    - Often with red cell casts under microscopy
  4. Edema
    - Due to fluid retention increasing plasma hydrostatic pressure
    - Usually not as prominent as in nephrotics
  5. Hypertension
    - Due to fluid retention
  6. Proteinuria
    - Mild to moderate, sometimes in nephrotic range
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6
Q

Causes of nephritic syndrome

A
  1. Primary glomerular diseases
    - Post-streptococcal glomerulonephritis
    - IgA nephropathy
  2. Systemic disease
    - Goodpasture syndrome
    - Systemic lupus erythematosus
    - Systemic vasculitis (e.g. polyarteritis nodosa)
    - Infective endocarditis
    - Henoch-Schonlein purpura
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7
Q

Clinical features of nephritic syndrome

A
  1. 3 possible outcomes:
    - Complete resolution with no residual damage
    - Rapid progression to rapidly progressive glomerulonephritis causing acute renal failure
    - Slow progression to chronic renal failure (chronic glomerulonephritis)
  2. Light microscopy often shows focal segmental proliferative glomerulonephritis (hence differential diagnosis depends on the immunofluorescence pattern)
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8
Q

Characteristics of rapidly progressive glomerulonephritis

A
  1. Rapid development of anuria/severe oliguria with a rise in serum creatinine over 3 months or less
  2. Light microscopy exhibits crescents in >50% of glomeruli (thus aka crescenteric glomerulonephritis)
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9
Q

Causes of rapidly progressive glomerulonephritis

A
  1. Type 1 (anti-glomerular basement membrane Abs)
    - Goodpasture syndrome
  2. Type 2 (immune complex)
    - Post-streptococcal glomerulonephritis
    - Systemic lupus erythematosus
    - Henoch-Schonlein purpura
  3. Type 3 (pauci-immune)
    - ANCA-associated
    - Systemic vasculitis (Wegener granulomatosis, microscopic polyangiitis)
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10
Q

Clinical features of rapidly progressive glomerulonephritis

A
  1. Shares common etiologies with nephritic syndrome
  2. Results in acute renal failure
  3. Exclude other causes of acute renal failure:
    - Prerenal causes: shock, renal hypoperfusion
    - Renal causes: acute tubular necrosis, tubulointerstitial nephritis
    - Postrenal causes: urinary tract obstruction
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11
Q

Characteristics of microscopic hematuria

A
  1. Hematuria not visible to the naked eye
    - Detectable only by urinalysis
  2. Usually some degree of hematuria
    - Below nephrotic range
  3. Absence of:
    - Change in urine volume
    - Hypertension
    - Azotemia
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12
Q

Causes of microscopic hematuria

A
  1. Usually milder forms of proliferative GNs
  2. IgA nephropathy
  3. Thin basement membrane syndrome
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13
Q

Clinical features of microscopic hematuria

A

Always exclude lower urinary tract causes of hematuria in differential diagnosis:
- Trauma, tumour, infections, stones

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14
Q

4 stages of progression in chronic renal failure

A
  1. Diminished renal reserve
    - GFR = 50% of normal
    - Normal serum creatinine & blood urea nitrogen
    - Asymptomatic
  2. Renal insufficiency
    - GFR = 20-50% of normal
    - Azotemia appears
    - Anemia, hypertension, polyuria, nocturia
  3. Chronic renal failure
    - GFR < 20-25% of normal
    - Overt uremia (azotemia + GI, neurological & cardiovascular complications)
    - Edema, metabolic acidosis, hyperkalemia
  4. End-stage renal diseases
    - GFR < 5% normal
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15
Q

Characteristics of chronic renal failure

A
  1. Change in urine volume
    - Initial polyuria as tubules cannot concentrate glomerular filtrate
    - Terminal oliguria when little functioning nephrons are left
  2. Consequences of decreased filtration
    - Hypertension & edema
    - Uremia (azotemia + a constellation of signs such as uremic gastroenteritis, uremic fibrinous pericarditis, peripheral neuropathy etc)
    - Metabolic derangements (hyperkalemia, metabolic acidosis)
  3. Decreased endocrine functions of kidney
    - Anemia (decreased erythropoietin production)
    - Secondary hyperparathyroidism (due to decreased Vitamin D activation by renal tubules leading to hypocalcemia)
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16
Q

Causes of renal failure

A
  1. Chronic glomerulonephritis (one of the possible outcomes of glomerular diseases presenting as nephritic syndrome)
  2. Tubulointerstitial diseases
  3. Chronic pyelonephritis
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17
Q

Pathogenesis of Antibody-Mediated Mechanisms resulting in glomerular injury

A
  1. In-situ formation of immune complexes
    - Against native antigen
    i. Goodpasture disease
    - Against planted antigen that localizes in glomerulus
    i. HBV, HCV, Streptococcus, syphilis, malaria
  2. Circulating immune complex deposition in glomerulus
    - Small circulating immune complexes that are formed elsewhere filtered through glomerulus & ending up lodged within it
  3. Anti-neutrophil cytoplasmic antibodies (ANCA)
    - Interacts with neutrophils within glomeruli
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18
Q

Pathogenesis of other pathogenic factors (apart from antibody-mediated mechanisms) that can result in glomerular injury

A
  1. Activation of alternative complement pathway (i.e. no
    antibodies required)
    - Seen in membranoproliferative glomerulonephritis
    type II (aka dense deposit disease)
  2. Platelets
    - Aggregate in glomeruli during immune-mediated injury, can subsequently release eicosanoids & growth factors which promotes inflammation & cellular proliferation
  3. Coagulation system
    - Leakage of fibrin through damaged GBM into Bowman’s space induces proliferation of the parietal layer of Bowman’s capsule (forms crescents)
  4. Cytokines
    - Angiotensin
    - Podocyte-released cytokines
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19
Q

Role of podocytes in the pathogenesis of glomerular injury

A
  1. Podocyte injury results in cytokine release
    - TGFbeta, VEGF, PDGF
    - Results in local proliferation & fibrosis
  2. Podocytes do not normally regenerate after being injured
    - Remaining pool of podocytes become abnormally stretched to maintain an appropriate filtration barrier or become unable to cover some portions of the GBM
    - Results in abnormal protein filtration (leading to proteinuria) & segmental loop dilation of the glomerular capillaries (due to incompletely opposed intracapillary pressures)
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20
Q

Etiology & pathogenesis of minimal change disease

A

Postulated immune-mediated podocyte injury

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21
Q

Clinical presentation of minimal change disease

A

Nephrotic syndrome

  • Usually selective proteinuria (mostly albumin)
  • Most common cause of childhood nephrotic syndrome (good prognosis, typically responsive to steroid treatment)
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22
Q

Renal biopsy of minimal change disease

A
  1. Light microscopy: Normal
  2. Immunofluorescence: No immune deposits
  3. Electron microscopy: Effacement of podocyte foot processes
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23
Q

Etiology & pathogenesis of focal segmental glomerulosclerosis

A
  1. Progression from minimal change disease (controversial)

2. Secondary causes

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24
Q

Clinical presentation in focal segmental glomerulosclerosis

A
  1. Nephrotic syndrome
    - Non-selective proteinuria
    - Poor response to steroid therapy
  2. Many progress to chronic renal failure
    - Higher incidence of decreased GFR, hematuria & hypertension than minimal change disease
25
Q

Renal biopsy of focal segmental glomerulosclerosis

A
  1. Light microscopy: Focal segmental glomerular sclerosis & hyalinosis
  2. Immunofluorescence: Focal IgM & C3
  3. Electron microscopy: Effacement of podocyte foot processes
26
Q

Etiology & pathogenesis of membranous glomerulopathy

A
  1. Idiopathic primary cause

2. Secondary causes (10-20% of cases)

27
Q

Clinical presentation in membranous glomerulopathy

A
  1. Nephrotic syndrome
    - Non-selective proteinuria
    - Most common cause of nephrotic syndrome in adults (resistant to steroid treatment)
  2. Unpredictable behaviour
    - Less than half progress to renal failure
28
Q

Renal biopsy of membranous glomerulopathy

A
  1. Light microscopy:
    - Diffuse basement membrane thickening
    - Spikes or string of pearl appearance with silver stain (due to protrusions of growth of GBM between subepithelial deposits)
  2. Immunofluorescence: Granular IgG & C3
  3. Electron microscopy: Subepithelial deposits
29
Q

Etiology & associations of membranoproliferative glomerulonephritis type I

A

Idiopathic (postulated to be due to planted HBV & HCV antigens, associated with chronic antigenemia)

30
Q

Clinical presentation in membranoproliferative glomerulonephritis type I

A
  1. Nephrotic or nephritic

2. Associated with decrease in serum C3 levels

31
Q

Renal biopsy of membranoproliferative glomerulonephritis type I

A
  1. Light microscopy:
    - Mesangial & endocapillary proliferation, giving glomeruli an accentuated lobulated appearance
    - Double contour appearance with silver stain (due to growth of new basement membrane after separation of endothelium from GBM by subendothelial deposits)
  2. Immunofluorescence: IgG, C3
  3. Electron microscopy: Subendothelial deposits
32
Q

Etiology & pathogenesis of membranoproliferative glomerulonephritis type II (dense deposit disease)

A

Activation of alternative complement pathway

33
Q

Clinical presentation in membranoproliferative glomerulonephritis type II (dense deposit disease)

A
  1. Hematuria, chronic renal failure
  2. High incidence of recurrence in renal transplants
  3. Associated with decrease in serum C3 levels
34
Q

Renal biopsy in membranoproliferative glomerulonephritis type II (dense deposit disease)

A
  1. Light microscopy: Similar to MPGN type I
  2. Immunofluorescence: C3
  3. Electron microscopy: Dense deposits in basement membrane
35
Q

Etiology & pathogenesis of post-streptococcal glomerulonephritis

A

Follows infection by nephritogenic strains of Streptococci (classically S. pyogenes) of the throat

  • 1-4 weeks after pharyngitis, in 6-10 year olds
  • Due to planted antigen in glomerulus
36
Q

Clinical presentation in post-streptococcal glomerulonephritis

A
  1. Nephritic syndrome
    - Almost always resolves
    - Small minority will develop RPGN
    - Rarely, might progress to chronic renal failure
  2. Associated with decrease in serum C3 levels & rise in anti-streptolysin O (ASO) titres
37
Q

Renal biopsy of post-streptococcal glomerulonephritis

A
  1. Light microscopy:
    - Diffuse endocapillary proliferation & leukocytic infiltration
    - Red cell casts seen in tubules
  2. Immunofluorescence: Granular IgG, C3
  3. Electron microscopy: Subepithelial humps of electron dense deposits
38
Q

Etiology & pathogenesis of goodpasture disease

A

Autoantibodies produced against Goodpasture antigen (NC1 non collagenous domain of the alpha3 chain of type IV collagen)
- Type IV collagen is found in the basement membrane of the glomerulus & alveolus

39
Q

Clinical presentation of goodpasture disease

A
  1. Rapidly progressive glomerulonephritis
    - Can lead to acute renal failure
  2. Often associated with pulmonary hemorrhage
    - As alveolar basement membrane is attacked too
40
Q

Renal biopsy of goodpasture disease

A
  1. Light microscopy: Crescents
  2. Immunofluorescence: Linear IgG, C3
  3. Electron microscopy: Disruption of basement membrane
41
Q

Etiology & pathogenesis of diabetic nephropathy

A

Advance glycosylated end-products in longstanding hyperglycemia

42
Q

Clinical presentation in diabetic nephropathy

A

Proteinuria (nephrotic range in later stages)

- Often ends up in chronic renal failure

43
Q

Renal biopsy in diabetic nephropathy

A
  1. Light microscopy:
    - Kimmelstiel-Wilson lesions (nodular glomerulosclerosis – PAS-positive nodules of matrix situated in the periphery of glomeruli)
    - Other associated lesions (pyelonephritis sometimes with papillary necrosis, large vessel atherosclerosis)
  2. Immunofluorescence:
    - No immune complex deposition
  3. Electron microscopy:
    - Increased basement membrane thickness
    - Increased in mesangial matrix
44
Q

Etiology & pathogenesis of IgA nephropathy (Berger disease)

A
  1. Associated with pharyngitis (synpharyngitic GN)

2. Most common cause of glomerulonephritis

45
Q

Clinical presentation in IgA nephropathy (Berger disease)

A
  1. Microscopic proteinuria with hematuria
  2. Clinical course waxes & wanes, often associated with
    upper respiratory tract infections
  3. Less than half progress to renal failure
46
Q

Renal biopsy of IgA nephropathy (Berger disease)

A
  1. Light microscopy: Focal mesangial proliferation
  2. Immunofluorescence: IgA in mesangium
  3. Electron microscopy: Mesangial dense deposits
47
Q

Etiology & pathogenesis of lupus nephritis

A

Systemic lupus erythematosus

- 70% of SLE patients will develop renal disease

48
Q

Clinical presentation of lupus nephritis

A

Any clinical presentation possible

  • Aggressive forms typically present with nephritic syndrome & are associated with proliferative changes
  • Those presenting with nephrotic syndrome are associated with membranous change
49
Q

Renal biopsy of lupus nephritis

A
  1. Light microscopy:
    - Class I: normal
    - Class IIa: normal
    - Class IIb: mesangial proliferation
    - Class III: focal proliferations
    - Class IV: diffuse proliferations
    - Class V: membranous change
  2. Immunofluorescence:
    - Full house pattern (2 complements + 3 Igs): C1q, C3, IgG, IgA, IgM
  3. Electron microscopy:
    - Variable
50
Q

Etiology & pathogenesis of Alport syndrome

A

X-linked recessive genetic condition involving mutations in the alpha3, alpha4 or alpha5 chains of type IV collagen

  • Hence type IV collagen in the affected individual is defective, lacking normal cross-linking
  • Type IV collagen required for glomerular basement membrane, lens & cochlea
51
Q

Clinical presentation in Alport syndrome

A
  1. Hematuria +/- proteinuria with progression to chronic renal failure
  2. Other associated conditions (usually seen in male):
    - Deafness
    - Lens discolouration
    - Posterior cataracts
    - Corneal dystrophy
52
Q

Renal biopsy of Alport syndrome

A
  1. Light microscopy:
    - Normal initially
    - Mesangial cell proliferation and sclerosis
  2. Immunofluorescence:
    - Absence of the type IV collagen alpha-3, alpha-4, and/or alpha-5 chains in the basement membrane
  3. Electron microscopy:
    - Splitting and alternating irregular thickening and thinning of the glomerular basement membrane (“basket-weave appearance”)
53
Q

Etiology & pathogenesis of thin membrane disease (benign familial hematuria)

A

Hereditary condition, unclear inheritance pattern

54
Q

Clinical presentation of thin membrane disease (benign familial hematuria)

A
  1. Recurrent hematuria
    - Typically benign clinical course
  2. Unlike Alport syndrome, has no hearing loss, ocular
    abnormalities or family history of renal failure)
55
Q

Renal biopsy of benign familial hematuria

A
  1. Light microscopy:
    - Normal
  2. Immunofluorescence:
    - No immune complex deposition
  3. Electron microscopy:
    - Diffuse thinning of the lamina densa of the GBM (to 150-250nm, normal = 300-400nm)
56
Q

Etiology & pathogenesis of amyloidosis

A
  1. Plasma cell dyscrasia (AL amyloid)

2. Chronic inflammatory diseases or neoplasms (AA amyloid)

57
Q

Clinical presentation in amyloidosis

A

Proteinuria, often nephrotic range

58
Q

Renal biopsy of amyloidosis

A
  1. Light microscopy:
    - Extracellular accumulation of fibrillary proteins (with Congo red stain)
    - Apple green birefringence under polarized light microscopy
  2. Immunofluorescence:
    - No immune complex deposition
  3. Electron microscopy:
    - Variable

13. Urogenital Pathology (12 decks)

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