3. Glomerular diseases Flashcards
(58 cards)
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
2
Q
Characteristics of nephrotic syndrome
A
- Heavy proteinuria
- >3.5g of protein loss/24 hours
- Urine appears frothy
- May be selective or non-selective in nature - Hypoalbuminemia
- Plasma albumin <3g/dL
- Albumin loss in urine overwhelms liver capacity to maintain normal serum albumin - Anasarca
- Generalized edema due to decrease in plasma oncotic pressure
- Marked periorbital edema, pedal edema, facial & abdominal swelling - Hyperlipidemia
- Due to compensatory increase in synthesis of lipoproteins by liver - Lipiduria
- Due to hyperlipidemia as well as a leaky glomerular filter allowing leakage of lipoproteins into urine - Others
- Loss of immunoglobulins: increased susceptibility to Staphylococcal & Pneumococcal infections
- Loss of anticoagulants & antiplasmins: thrombotic & thromboembolic complications
3
Q
Causes of nephrotic syndrome
A
- Primary glomerular diseases
- Minimal change disease
- Membranous glomerulopathy
- Focal segmental glomerulosclerosis
- Membranoproliferative glomerulonephritis - 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
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
5
Q
Characteristics of nephritic syndrome
A
- Oliguria
- Decrease in urine volume due to poor filtration - Azotemia
- Elevation of serum creatinine & blood urea nitrogen levels - Gross hematuria
- Presence of red blood cells in the urine
- Often with red cell casts under microscopy - Edema
- Due to fluid retention increasing plasma hydrostatic pressure
- Usually not as prominent as in nephrotics - Hypertension
- Due to fluid retention - Proteinuria
- Mild to moderate, sometimes in nephrotic range
6
Q
Causes of nephritic syndrome
A
- Primary glomerular diseases
- Post-streptococcal glomerulonephritis
- IgA nephropathy - Systemic disease
- Goodpasture syndrome
- Systemic lupus erythematosus
- Systemic vasculitis (e.g. polyarteritis nodosa)
- Infective endocarditis
- Henoch-Schonlein purpura
7
Q
Clinical features of nephritic syndrome
A
- 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) - Light microscopy often shows focal segmental proliferative glomerulonephritis (hence differential diagnosis depends on the immunofluorescence pattern)
8
Q
Characteristics of rapidly progressive glomerulonephritis
A
- Rapid development of anuria/severe oliguria with a rise in serum creatinine over 3 months or less
- Light microscopy exhibits crescents in >50% of glomeruli (thus aka crescenteric glomerulonephritis)
9
Q
Causes of rapidly progressive glomerulonephritis
A
- Type 1 (anti-glomerular basement membrane Abs)
- Goodpasture syndrome - Type 2 (immune complex)
- Post-streptococcal glomerulonephritis
- Systemic lupus erythematosus
- Henoch-Schonlein purpura - Type 3 (pauci-immune)
- ANCA-associated
- Systemic vasculitis (Wegener granulomatosis, microscopic polyangiitis)
10
Q
Clinical features of rapidly progressive glomerulonephritis
A
- Shares common etiologies with nephritic syndrome
- Results in acute renal failure
- Exclude other causes of acute renal failure:
- Prerenal causes: shock, renal hypoperfusion
- Renal causes: acute tubular necrosis, tubulointerstitial nephritis
- Postrenal causes: urinary tract obstruction
11
Q
Characteristics of microscopic hematuria
A
- Hematuria not visible to the naked eye
- Detectable only by urinalysis - Usually some degree of hematuria
- Below nephrotic range - Absence of:
- Change in urine volume
- Hypertension
- Azotemia
12
Q
Causes of microscopic hematuria
A
- Usually milder forms of proliferative GNs
- IgA nephropathy
- Thin basement membrane syndrome
13
Q
Clinical features of microscopic hematuria
A
Always exclude lower urinary tract causes of hematuria in differential diagnosis:
- Trauma, tumour, infections, stones
14
Q
4 stages of progression in chronic renal failure
A
- Diminished renal reserve
- GFR = 50% of normal
- Normal serum creatinine & blood urea nitrogen
- Asymptomatic - Renal insufficiency
- GFR = 20-50% of normal
- Azotemia appears
- Anemia, hypertension, polyuria, nocturia - Chronic renal failure
- GFR < 20-25% of normal
- Overt uremia (azotemia + GI, neurological & cardiovascular complications)
- Edema, metabolic acidosis, hyperkalemia - End-stage renal diseases
- GFR < 5% normal
15
Q
Characteristics of chronic renal failure
A
- Change in urine volume
- Initial polyuria as tubules cannot concentrate glomerular filtrate
- Terminal oliguria when little functioning nephrons are left - 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) - Decreased endocrine functions of kidney
- Anemia (decreased erythropoietin production)
- Secondary hyperparathyroidism (due to decreased Vitamin D activation by renal tubules leading to hypocalcemia)
16
Q
Causes of renal failure
A
- Chronic glomerulonephritis (one of the possible outcomes of glomerular diseases presenting as nephritic syndrome)
- Tubulointerstitial diseases
- Chronic pyelonephritis
17
Q
Pathogenesis of Antibody-Mediated Mechanisms resulting in glomerular injury
A
- 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 - Circulating immune complex deposition in glomerulus
- Small circulating immune complexes that are formed elsewhere filtered through glomerulus & ending up lodged within it - Anti-neutrophil cytoplasmic antibodies (ANCA)
- Interacts with neutrophils within glomeruli
18
Q
Pathogenesis of other pathogenic factors (apart from antibody-mediated mechanisms) that can result in glomerular injury
A
- Activation of alternative complement pathway (i.e. no
antibodies required)
- Seen in membranoproliferative glomerulonephritis
type II (aka dense deposit disease) - Platelets
- Aggregate in glomeruli during immune-mediated injury, can subsequently release eicosanoids & growth factors which promotes inflammation & cellular proliferation - Coagulation system
- Leakage of fibrin through damaged GBM into Bowman’s space induces proliferation of the parietal layer of Bowman’s capsule (forms crescents) - Cytokines
- Angiotensin
- Podocyte-released cytokines
19
Q
Role of podocytes in the pathogenesis of glomerular injury
A
- Podocyte injury results in cytokine release
- TGFbeta, VEGF, PDGF
- Results in local proliferation & fibrosis - 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)
20
Q
Etiology & pathogenesis of minimal change disease
A
Postulated immune-mediated podocyte injury
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)
22
Q
Renal biopsy of minimal change disease
A
- Light microscopy: Normal
- Immunofluorescence: No immune deposits
- Electron microscopy: Effacement of podocyte foot processes
23
Q
Etiology & pathogenesis of focal segmental glomerulosclerosis
A
- Progression from minimal change disease (controversial)
2. Secondary causes
24
Q
Clinical presentation in focal segmental glomerulosclerosis
A
- Nephrotic syndrome
- Non-selective proteinuria
- Poor response to steroid therapy - Many progress to chronic renal failure
- Higher incidence of decreased GFR, hematuria & hypertension than minimal change disease
25
Renal biopsy of focal segmental glomerulosclerosis
1. Light microscopy: Focal segmental glomerular sclerosis & hyalinosis
2. Immunofluorescence: Focal IgM & C3
3. Electron microscopy: Effacement of podocyte foot processes
26
Etiology & pathogenesis of membranous glomerulopathy
1. Idiopathic primary cause
| 2. Secondary causes (10-20% of cases)
27
Clinical presentation in membranous glomerulopathy
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
Renal biopsy of membranous glomerulopathy
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
Etiology & associations of membranoproliferative glomerulonephritis type I
Idiopathic (postulated to be due to planted HBV & HCV antigens, associated with chronic antigenemia)
30
Clinical presentation in membranoproliferative glomerulonephritis type I
1. Nephrotic or nephritic
| 2. Associated with decrease in serum C3 levels
31
Renal biopsy of membranoproliferative glomerulonephritis type I
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
Etiology & pathogenesis of membranoproliferative glomerulonephritis type II (dense deposit disease)
Activation of alternative complement pathway
33
Clinical presentation in membranoproliferative glomerulonephritis type II (dense deposit disease)
1. Hematuria, chronic renal failure
2. High incidence of recurrence in renal transplants
3. Associated with decrease in serum C3 levels
34
Renal biopsy in membranoproliferative glomerulonephritis type II (dense deposit disease)
1. Light microscopy: Similar to MPGN type I
2. Immunofluorescence: C3
3. Electron microscopy: Dense deposits in basement membrane
35
Etiology & pathogenesis of post-streptococcal glomerulonephritis
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
Clinical presentation in post-streptococcal glomerulonephritis
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
Renal biopsy of post-streptococcal glomerulonephritis
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
Etiology & pathogenesis of goodpasture disease
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
Clinical presentation of goodpasture disease
1. Rapidly progressive glomerulonephritis
- Can lead to acute renal failure
2. Often associated with pulmonary hemorrhage
- As alveolar basement membrane is attacked too
40
Renal biopsy of goodpasture disease
1. Light microscopy: Crescents
2. Immunofluorescence: Linear IgG, C3
3. Electron microscopy: Disruption of basement membrane
41
Etiology & pathogenesis of diabetic nephropathy
Advance glycosylated end-products in longstanding hyperglycemia
42
Clinical presentation in diabetic nephropathy
Proteinuria (nephrotic range in later stages)
| - Often ends up in chronic renal failure
43
Renal biopsy in diabetic nephropathy
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
Etiology & pathogenesis of IgA nephropathy (Berger disease)
1. Associated with pharyngitis (synpharyngitic GN)
| 2. Most common cause of glomerulonephritis
45
Clinical presentation in IgA nephropathy (Berger disease)
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
Renal biopsy of IgA nephropathy (Berger disease)
1. Light microscopy: Focal mesangial proliferation
2. Immunofluorescence: IgA in mesangium
3. Electron microscopy: Mesangial dense deposits
47
Etiology & pathogenesis of lupus nephritis
Systemic lupus erythematosus
| - 70% of SLE patients will develop renal disease
48
Clinical presentation of lupus nephritis
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
Renal biopsy of lupus nephritis
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
Etiology & pathogenesis of Alport syndrome
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
Clinical presentation in Alport syndrome
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
Renal biopsy of Alport syndrome
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
Etiology & pathogenesis of thin membrane disease (benign familial hematuria)
Hereditary condition, unclear inheritance pattern
54
Clinical presentation of thin membrane disease (benign familial hematuria)
1. Recurrent hematuria
- Typically benign clinical course
2. Unlike Alport syndrome, has no hearing loss, ocular
abnormalities or family history of renal failure)
55
Renal biopsy of benign familial hematuria
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
Etiology & pathogenesis of amyloidosis
1. Plasma cell dyscrasia (AL amyloid)
| 2. Chronic inflammatory diseases or neoplasms (AA amyloid)
57
Clinical presentation in amyloidosis
Proteinuria, often nephrotic range
58
Renal biopsy of amyloidosis
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
