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Nephrotic Syndrome
Nephrotic Syndrome
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OUTLINES
Introduction
Definition
Classification – Types of Nephrotic
Syndrome
Clinical Features
Etiopathogenesis and Morphology
Nephrotic Nephritic Overlap
Approach to diagnosis
References
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Introduction
The kidney can be divided into
four morphologic components,
1. Glomeruli
2. Tubules
3. Interstitium
4. Blood vessels.
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4
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Definition
Nephrotic syndrome is manifestation of glomerular
disease characterized by :
Generalized edema
Hypercoagulibity
Pathophysiology
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Hypercoagulability
Hypercoagulability lead to
- Pulmonary embolism
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Other Metabolic Changes
Protein malnutrition
Iron-resistant anemia
hyperparathyroidism
↓ Thyroxine levels
↑ Susceptibility to infection
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Causes of Nephrotic Syndrome
Systemic
- Glomerular disease is that associated with
systemic diseases.
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PRIMARY GLOMERULAR DISEASE
Membranous glomerulopathy
Minimal change disease
Focal segmental glomerulosclerosis
Membranoproliferative glomerulonephritis
Ig A nephropathy
Fibrillary glomerulonephritis
Immunotactoid glomerulopathy
Congenital nephrotic syndrome
- Finnish type
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Membranous Nephropathy
Most common cause of primary nephrotic syndrome in
adults (30-40%) and rare in children(<5%)
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Continued…
There are 4 histopathological stages of the
disease.
STAGE I:
- L/M - Glomeruli appear normal
- E/M - small granular sub-epithelial
deposits seen.
STAGE II:
- Capillary wall thickened, many sub-
epithelial deposits separated by BM
extensions(spikes).
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MGN (stage I)
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Subepithelial
deposits are
separated by
projections of the
basement
membrane
Silver preparation
showing spike
formation along the
thickened basement
membrane
(methenamine
silver). MGN stage II 18
STAGE III:
- Deposits are encircled or
engulfed by the newly
formed BM.
- Capillary walls are
markedly thickened with
narrowed lumen.
- BM shows
reduplicated/moth-eaten
appearance.
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STAGE IV:
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I/F MICROSCOPY
Generalized, peripheral granular deposits of IgG & C3
along the glomerular capillary wall.
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Clinical Course
Nephrotic syndrome (>80%) --- non-selective
proteinuria.
20%)
Minimal Change Disease
Accounts for
-70-80% of nephrotic syndrome in children with
a peak incidence between 2 and 6 years of age.
-15-20% in adults.
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Etiopathogenesis
Unknown etiology
Excellent prognosis
cases.
Focal Segmental
Glomerulosclerosis (FSGS)
Characterized by sclerosis of some, but not all,
glomeruli; and in the affected glomeruli, only a
portion of the capillary tuft is involved.
Accounts for
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Etiopathogenesis
(I) Primary: - Unknown cause
- Appears due to a circulating permeability
factor leading to epithelial injury and scar
formation.
- Genetic mutation in genes encoding
nephrin, podocin, α-actinin 4 .
(ii) Secondary:
- Unilateral renal agenesis
- HIV infection
- sickle cell anemia
- Renal ablation-remnant kidney
- Reflux nephropathy
- Heroin addiction
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L/M:
The lesions tend to involve the
juxtamedullary glomeruli
In the sclerotic segments
- Collapse of BM
- Increase in matrix
- Segmental insudation of
plasma proteins along
capillarywall(hyalinosis)
- Lipid droplets and foam
cells are present
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E/M:
Diffuse effacement of
podocytes
Focal detachment of
epithelial cells with
denudation of
underlying GBM
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IF:
IgM and C3 may be present in the
sclerotic areas or in the mesangium 32
Clinical course
Hypertension
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Membranoproliferative
Glomerulonephritis(MPGN)
Also known as “Mesangiocapillary GN”
Characterized by:
(1) Alterations in the basement membrane
1. Primary/idiopathic
i) Type 1 MPGN
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Etiopathogenesis
(1) MPGN-I:
-Immune complex-mediated glomerulonephritis
-Activation of both Classical and Alternative
complement pathways
(2) MPGN-II :
- Activation of Alternative pathway
- Autoantibody (C3 nephritic factor)
Which binds to, and stabilize
C3 convertase lead to persistent C3 &
degradation lead to hypocomplementemia.
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MORPHOLOGY
LIGHT MICROSCOPY
mesangial matrix 40
Continue…
- GBM is thickened, often focally, capillary wall
often shows “tram-track” appearance caused
by duplication of BM due to new BM formation.
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MPGN type I
Glomerulus with silver stain shows tram
tracking or reduplication of the GBM.
(Jones silver methenamine)
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MPGN type I
Glomerulus with crescent (PAS)
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MPGN type I
I/F -
TYPE I
- Subendothelial electron dense deposits
C3, IgG, C1q and C4 are present
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TYPE II
The lamina densa of the GBM is transformed
into an irregular, ribbon-like, extremely
electron-dense structure due to deposition
of dense material.
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MPGN Type II
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Fibrillary GN and Immunotactoid
Glomerulopathy
Rare variants of GN.
Characterized by
- Extracellular deposition of non-branching, randomly
arrayed fibrils approx. 20nm in diameter
(Fibrillary GN)
- Deposits consist of organized microtubular structures
30-50nm diameter (Immunotactoid glomerulopathy)
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Clinical Course
Nephrotic syndrome (>50%)
Progress to ESRD in 1 to 10 yr
No effective therapy
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Etiopathogenesis :
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Morphology
LM:
- Mesangial expansion by increased matrix and cells
- Some cases show diffuse proliferation cellular crescent.
- Interstitial inflammation
- Areas of glomerulosclerosis 52
EM:
-Electron-dense deposits in mesangium
I/F:
-Mesangial deposition of IgA and C3
-IgG deposition in 50% of cases
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Clinical Course
Children and young adults are commonly affected.
Hematuria and/or proteinuria
-short-lived gross hematuria following respiratory or GI
infection, UTI, vaccination, strenuous exercise
-Microscopic hematuria with or without proteinuria
(30%)
Nephrotic syndrome (~10%)
Hypertension (20-30%)
Nephritic syndrome
Progressive loss of renal function and ESRD in 20 yr
(20-50%). 55
Diabetic Nephropathy
Most common cause of nephrotic
syndrome in adults.
Leading cause of ESRD in USA
30% of patients with Type I and 20% of
patients with Type II DM develop diabetic
nephropathy.
Initially microalbuminuria followed by
heavy proteinuria and decline in renal
function.
Diagnosis usually made on clinical grounds
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Pathogenesis
Metabolic defects are responsible for
biochemical alteration in diabetic GBM which
include Increased synthesis of collagen type
IV and fibronectin.
Decreased synthesis of proteoglycans
Non enzymatic glycosylation of proteins lead
to advanced glycosylation end products and
causes glomerulopathy.
Hemodynamic changes asso. with glomerular
hypertrophy also contribute to development
of glomerulosclerosis. 57
The 3 main morphologic
changes in the glomeruli
include -
1. Capillary basement
membrane thickening
2. Diffuse glomerulosclerosis
3. Nodular glomerulosclerosis
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NODULAR GLOMERULOSCLEROSIS
Sclerotic nodules in one or more
mesangial regions of the
glomerular tuft known as
“Kimmelstiel-Wilson lesions”
Acellular, spherical often
laminated, situated in the
periphery of the glomeruli
These nodules can be surrounded
by a patent peripheral capillary
loop.
Nodular regions are frequently
accompanied by accumulation of
hyaline material in capillary loops
“fibrin cap” or adherent to 59
Bowman’s capsule “capsular drop”
Renal Amyloidosis
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Gross:
- Kidney may appear normal in size or it may be
enlarged.
- In advanced cases, it may be shrunken and
contracted.
L/M
- Renal amyloid always involves the glomeruli
- Amyloid appears as a homogeneous eosinophilic
mesangial and capillary loop deposits.
- Congo red birefringence is the most specific stain
for amyloid by L/M .
I/F
-Amyloid usually shows +ve result for lambda and
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Amorphous Deposits of Amyloid in the
Mesangium With Patchy Glomerular
Capillary Wall Extension
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Systemic Lupus Erythematosus
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Etiopathogenesis
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Continued…
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Class I Lupus nephritis:
- Seen in < 5% of cases
- Renal biopsy appears normal by L/M, IF and E/M
- Minor non-specific changes by E/M
- c/f usually asymptomatic
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Approach to Diagnosis
24 hour urine collection for estimating protein
Chemical test/Dipstick : protein, glucose, etc
Urine microscopy : RBCs, WBCs, Casts
Serum electrolytes, BUN, creatinine, lipid profile,
serum albumin
Serological work up - depends upon the clinical
presentation –common serological tests done are
- ANA; Anti-ds DNA
- Complement levels (C3, C4)
- Hepatitis B and C serologies
Renal Ultrasound
Renal Biopsy
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RERERENCES
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Thank yo
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