NEPHROTIC SYNDROME

MODERATOR – DR. NIRVANA HALDER

SPEAKER - DR. VEENA JYOTI

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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 :

 Massive proteinuria, with the daily loss of 3.5 g

or more of protein

 Hypoalbuminemia, with plasma albumin levels

less than 3 g/dL

 Generalized edema

 Hyperlipidemia and lipiduria

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 Hypercoagulibity
Pathophysiology

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Hypercoagulability

 It is due to multifactorial factors that is –

1. Urinary loss of antithrombin III

2. Altered levels of activity of protein C and
S.
3. Increased hepatic synthesis of
fibrinogen.
4. Impaired fibrinolysis
5. Increased platelet aggregation
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Continued…

Hypercoagulability lead to

- Peripheral arterial or venous thrombosis

- Renal vein thrombosis

- Pulmonary embolism

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Other Metabolic Changes
 Protein malnutrition

 Iron-resistant anemia

 Hypocalcemia and secondary

hyperparathyroidism

 ↓ Thyroxine levels

 ↑ Susceptibility to infection
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Causes of Nephrotic Syndrome

 Primary glomerular disease

- Kidney is the only or predominant organ involved.

 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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- Diffuse mesangial sclerosis

SYSTEMIC DISEASES
 Diabetes mellitus
 Amyloidosis
 Systemic Lupus Erythematosus
 Drugs (NSAIDs, Penicillamine)
 Infections (Malaria, Hepatitis B and C,
AIDS)
 Malignant disease (Carcinoma,
Lymphoma)
 Light chain deposition disease

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Membranous Nephropathy
 Most common cause of primary nephrotic syndrome in
adults (30-40%) and rare in children(<5%)

 Diffuse thickening of the glomerular capillary wall due

to the accumulation of deposits containing Ig along the
subepithelial side of the BM.
 It is –
i) Idiopathic/ Primary form (75-80% of cases)
ii) Secondary form(associated with systemic
Disease – SLE
-Hepatitis B & C
-Carcinoma(Lung, Colon), Melanoma
-Drugs (Gold, Penicillamine, NSAIDS)
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Etiopathogenesis

i) Deposition of immune complexes within

subepithelial capillary wall.

ii) Formation of in situ immune complexes.

iii) Activation of the MAC of the complement

system inducing to liberate proteases and
oxidants causing capillary wall injury and
proteinuria.

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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.

MGN Stage III

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STAGE IV:

 Deposits lose their electron density and

the BM becomes vacuolated, folded and
thickened

 Deposits no longer evident

 Glomerular tufts show segmental or total

sclerosis.

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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.

 Microscopic hematuria (up to 30%)

 Hypertension (10-30% at onset, common in late

stage)

 Spontaneous complete remission (up to 40%)

 Repeated relapses and remissions (30-40%)

 Slow progressive decline to ESRD in 10-15 yr (10-

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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.

 Diffuse effacement of foot processes of epithelial

cells in glomeruli that appear virtually normal by
L/M.

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Etiopathogenesis
 Unknown etiology

 Thought to be related to some immune

dysfunction or the effects of cytokines.

 Associated with infectious diseases,

immunization, ingestion of heavy metals,
allergies etc.

 In adults, associated with Hodgkin’s

disease, NSAIDs.
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L/M:
 Glomeruli and Basement membrane appear
normal, no proliferation seen(PAS stain)

IF: No significant finding 25

 E/M: I) Basement membrane appears normal
II) Uniform and diffuse effacement of
the visceral epithelial cell foot processes
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Clinical Course
 Nephrotic syndrome

 Children --- selective proteinuria

 Adults --- non-selective proteinuria

 Microscopic hematuria (20-30% of cases)

 Benign urinary sediment

 Excellent prognosis

 Spontaneous remission in 30-40% of children

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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

 10-15% of childhood nephrotic syndrome

 15-25% of adult nephrotic syndrome

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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

 Nephrotic proteinuria -non-selective

 Hypertension

 Mild renal insufficiency

 Abnormal urine sediment with red cells and

leukocytes

 Relatively poor prognosis

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 Progresses to ESRD in 5-10 yrs

Collapsing glomerulopathy
 Morphological variant of FSGS

 Characterised by widespread collapse of glomerular

capillary loops.

 Usually seen in male African-Americans

 Occurs in 5-10% of HIV-infected patients

 Renal syndrome characterized by progressive renal

failure and proteinuria. 34
Histopathologic Features
 Microcystic dilatation of renal tubules

 Globally sclerotic glomeruli

 Lymphocytic interstitial infiltrates and Interstitial

fibrosis

 Podocyte proliferation and loss of podocyte

differentiation markers

 Endothelial tubuloreticular inclusions seen on EM

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Collapsing FGS and Microcystic
Dilatation of the Tubules

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Membranoproliferative
Glomerulonephritis(MPGN)
 Also known as “Mesangiocapillary GN”

 Usually affects children and young adults

 Characterized by:
(1) Alterations in the basement membrane

(2) Proliferation of mesangial cells

(3) Leucocyte infiltration

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 Classified into -

1. Primary/idiopathic

i) Type 1 MPGN

ii) Type 2 MPGN(Dense-deposit disease)

2. Secondary (common in adults)

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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

 The two types of MPGN are similar by L/M but

differ by E/M and I/F.

LIGHT MICROSCOPY

 Glomeruli are large and hypercellular

 Have a lobular appearance accentuated by the

proliferating mesangial cells and increased

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.

- The interposition within the GBM by cellular

elements gives rise to the appearance of
“split” BM.

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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.

 C3 is present in granular or linear foci in the

BM on either side but not within the dense
deposits.

 C3 also present in the mesangium in the

form of mesangial rings.

 IgG as well as C1q and C4 are absent

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MPGN Type II

 Dense homogeneous deposits within the basement

membrane 46
Clinical Features
 Presents as nephrotic or nephritic syndrome

 Slowly progressive course

 Does not respond to corticosteroid therapy

 Progresses to chronic end-stage renal disease

in 10-15 yr

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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%)

 Hematuria, hypertension, renal insufficiency

 Increased incidence of lymphoproliferative

malignancy

 Progress to ESRD in 1 to 10 yr

 No effective therapy

 Transplantation as a viable option in late stage

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IgA Nephropathy
(Berger disease)
 Most common clinically recognized primary
glomerular disease in the world.

 A major cause of asymptomatic glomerular

hematuria.

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Etiopathogenesis :

(1) Evidence suggests a genetic or acquired

immune dysfunction → ↑ mucosal IgA
synthesis in response to respiratory or GIT
exposure to environmental agent.

(2) IgA1 and IgA1-containing Immune complexes

trapped in the mesangium → activation of
alternative complement pathway → initiating
glomerular injury.

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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

 Amyloid - proteinaceous material that

accumulates between cells and produces
atrophy and death of these cells.

 Pts present with nephrotic range proteinuria

with or without renal failure.

 Elevated serum amyloid A protein &

monoclonal light chain in serum and urine.

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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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less frequently for kappa light chains.

Deposits of amyloid exhibiting birefringence under
polarized light (Congo red stain)

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 Amorphous Deposits of Amyloid in the
Mesangium With Patchy Glomerular
Capillary Wall Extension

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Systemic Lupus Erythematosus

 African American women, 2nd to 3rd decade of life

 Systemic disease
Arthralgia, arthritis, skin rashes, inflammation of
serous surfaces
 Clinical evidence of renal disease is present in 50
to 70% of patients with SLE
 Renal disease is less common in drug related
SLE – chlorpromazine, hydralazine. Methyldopa,
procainamide

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Etiopathogenesis

 Deposition of immune complexes

– Mesangial, subendothelial or subepithelial
according to charge, size, affinity,
concentration.
– Local subepithelial formation by planting
antigens in membranous type (histones which are
cationic).
– Cross reaction of antibodies with basement
membrane
antigens(heparansulfate , proteoglycan).

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Continued…

 Activation of complement system by

classical and alternate pathways.
 Release of C3a & C5a with attraction of
leukocytes.
 Macrophages seem to play an important
role.
 Damage of capillary wall by enzymes and
ROS.
 Local formation of cytokines and growth
factors
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Renal involvement
WHO Classification
 Class I - Minimal mesangial lupus nephritis
 Class II - Mesangial proliferative lupus nephritis
 Class III - Focal lupus nephritis
 Class IV - Diffuse lupus nephritis
 Class V - Membranous lupus nephritis
 Class VI - Advanced sclerosing lupus nephritis

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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

Class II Lupus nephritis:

- Seen in 10 – 20% of cases
- Mesangial expansion with patent capillaries
- Mesangial immune deposits
- c/f mild proteinuria; hematuria; normal renal
function. 68
Class III Lupus nephritis

- Focal and segmental endocapillary proliferative

GN < 50% of glomeruli.
- Segmental proliferative lesions show leucocyte
infiltration, fibrinoid material and necrosis.
- Focal areas of necrosis containing fragmented nuclei
(haematoxylin bodies)
- IF : Diffuse deposition of Igs and
complement
- E/M : Mesangial & subendothelial
immune deposits
- C/F : Nephritic urinary sediment;
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proteinuria
Class V Lupus nephritis (10-15%)
- Diffuse thickening of peripheral
capillary walls
- Subepithelial and mesangial
immune deposits
- c/f - nephrotic syndrome

Class VI Lupus nephritis:

- Advanced glomerulosclerosis,
interstitial fibrosis inflammation and
tubular atrophy
- Few immune deposits
- c/f - proteinuria and renal 70
Nephrotic Nephritic Overlap

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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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