Nephrotic Syndrome
Charles Cho
Proteinuria
Increase in glomerular permeability
that allows the filtration of
nonfiltered maromolecules (albumin)
Heavy proteinura: >3 g/day
Basic Questions
How much protein is being excreted?
Under what conditions is protein
excreted?
What kind of protein is being
excreted?
Amount of protein
excreted
Used to be measured within a 24-
hour urine collection
Total protein-to-creatinine ratio
(mg/mg) on randome urine
Benign forms of isolated proteinurea
< 1-2g/day
Amount also indicates prognosis
Under what conditions is
protein excreted?
Transient Proteinuria
– m/c
– Stress (fever/exercise)
Orthostatic Proteinuria
– Primarily in adolescents
– Increase protein excretion on upright position
– No further workup necessary
Persistent Proteinuria
– Underlying renal or systemic disorder
Definition of Nephrotic
Syndrome
Proteinuria: Nephrotic range
proteinuria
– Protein >3.5 g/day
Hypoalbuminemia (< 3.0 g/dL)
Edema
Hypercholesterolemia
– Fasting level >200 mg/dL
– d/t increased production from liver
Clinical manifestation (1)
Protein loss
– Albumin
– Thyroxine-binding protein
– Cholecalciferol-binding protein
– Transferrin
– Metal biding protein
Clinical manifestation (2)
Hypercoagulable state
Occur when serum albumin <2g/dL
Due to
– urinary loss of antithrombin III
• Factor IX, X, XI, thrombin activity increase
– Protein C, S activity or level decrease
– Hyperfibrinogenemia
– Platelet activation increase
– hyperlipidemia
Venous thromboembolism
– Esp MGN
Clinical manifestation (3)
Increased risk of infection
d/t loss of IgG and complement
S. pneumoniae, E. Coli
Clinical manifestation (4)
Change of phamacokinetics due to
loss of albumins and other drug-
binding proteins
Etiology of
Primary nephrotic
Syndrome
Minimal Change Disease
– = Nil Disease, Lipoid Nephrosis
FSGS (Focal & Segmental Glomerulosclerosis)
MGN (Membranous glomerulonephritis)
MPGN (Membranoproliferative GN)
Mesangial proliferative glomerulonephritis
Others
– Crescentic glomerulonephritis
– Focal and segmental proliferative glomerulonephritis
– Fibrillary-immunotactoid glomerulopathy
Etiology of
Secondary Nephrotic
Syndrome
Infections:
– PSGN, endocarditis, “shunt nephritis”, secondary syphilis, leprosy, Hep
B, AIDS, Infectious mononucleosis, malaria, schistosomiasis, filariasis
Drugs
– Gold, mercury, penicillamine, heroid, NSAID, captopril …
Neoplasia
– Hodgkin’s Dz, lymphoma, leukemia, Wilm’s tumor
Multisystem
– SLE, HS purpura, vasculitis, Goodpasture’s Dz, dermatomyositis,
sarcoidosis, Sjogren’s, RA, MCTD
Heredofamilial
– DM, Alport’s Syndrome, Sickle cell dz, Fabry’s disease
Others
– Thyroiditis, myxedema, RVH, chronic allograft rejection
Complications of NS
ARF
– Drug-iduced interstitial nephritis
– Acute renal vein thrombosis
– Superimposed crescentric GN
– Acute volume depletion
– UTI, Obstruciton
– Uncontrolled HTN
Thromboembolic complications
– Renal vein thrombosis
Infection
– S. Pneumoniae, E. Coli
Principle of therapy (1)
Salt and free water restriction
Diuretics
– Thiazide or loop diuretics.
– Caution for dehydration that can cause ARF
Modest protein restriction
– 0.5-0.6 g/kg/day
Hyperlipidemia treatment
Vitamin D suppliment
Principle of therapy (2)
Modest protein restriciton
High protein diet increases urinary
protein excretion rate => worsen
glomerular lesion
If proteinuria >10g/day
– (-) nitrogen balance & protein
malnutrition
• Need supplimental dietary protein
Primary Nephrotic
Syndrome
MGN > FSGS > MCD
Renal Bx:
– often required in adjust for Dx and treatment plan
Membranous Glomerulonephritis (MGN)
Focal & Segmental Glomerulosclerosis (FSGS)
Minimal Change Disease (MCD)
Membranoproliferative GN (MPGN)
Mesangial Proliferative Glomerulonephritis
Fibrillary-immunotactoid glomerulopathy
Membranous
glomerulonephritis (MGN)
m/c non-DM adult nephrotic syndrome
(30-40%)
Rare in children
Age of 30’s-50’s, Male:Female = 2:1
30-50% => DVT.
Increased risk of RVT
4-11% association to cancer if >60yo
Complement level = normal
Membranous
glomerulonephritis
glomerular basement membrane thickening
with little or no cellular proliferation or
infiltration
Most often idiopathy (85%)
Secondary (15%)
– Hepatitis B, autoimmune disease, throiditis
– Malignancies: breast, lung, colon, gastric,
melanoma, RCC, neuroblastoma
– Drugs: gold penicillamine, captopril, NSAID
– Others: DM, sarcoidosis, sickle cell, Guillain-
Barre, Fnaconi’s, etc.
MGN
Stage IV: thickening of the
glomerular basement
membrane together with
segmental or global
glomerulosclerosis are
detectable by light
microscopy
Membranous
glomerulonephritis
Treatment and Prognosis
Steroid: Not effective as MCD
ACEi
Anticoagulation d/t increased risk of DVT
Prognosis
– 20-30%: complete recovery without Tx
– 25%: persistent proteinuria, normal kidney
finction
– 20-30%: progress to CRF
– Poor Prognosis indicator:
• male, old age, HTN, severe proteinuria >10g/d
• hyperlipidemia, worsening renal function,
• interstitial fibrosis on renal Bx => req. immunosupp.
Tx
Focal & Segmental
Glomerulosclerosis (FSGS)
15% of Nephrotic syndrome in adult
7-10% of nephrotic syndrome in children
Characterized for nonselective proteinuria
The most common primary glomerular
disease underlying end-stage renal disease
Microscopic hematuria (80%)
HTN, poor renal function (BUN, Cr ↑)
Differ from MCD
Severe tubulointerstitial damage
FSGS: Etiology
Mostly primary
Secondary
– AIDS, DM, Fabry’s disease, Charcot-Marie-
Tooth Dz
– d/t persistent glomerular capillary HTN
• Congenital oligonephropathy: solitary kidney
• Acquired nephron loss: surgery, GN or
tubulointerstitial nephritis
• Others: sickle cell nephropathy, obesity, heroin
abuse
FSGS: Pathology
LS: focal segmental sclerosis
EM: diffuse fusion of the epithelial
cell foot processes, similar to that
seen in minimal change disease
IF: deposition of IgM and C3 around
sclerotic segment
FSGS
collagenous sclerosis runs across
the middle of the glomerulus.
FSGS: Treatment and
Prognosis
Rare spontaneous recover, poor prognosis
Steroid responsive in 40%
Cyclophosphamide, cyclosporine
– 50-60% partial/complete remission in steroid
responsive patients
– No effect on steroid-resistent patient
ACEi:
– decrease proteinuria,
– delay progression of renal failure
Most progress to ESRD in 5-10 years
No transplantation: recur in 50%
Membranoproliferative GN
(MPGN)
5-10% of idiopathic NS in children
Rare in adult (<5%)
Proteinuria, hematuria, azothemia,
edema, HTN
Mostly type I: 1/3 has recent URI
Hx
70% has decreased complement (C3)
C3 nephritic factor: decrease C3
MPGN: Pathology
Type I: immune-complex GN
– LM: subepithelial deposits & mesangial hypertrophy
– EM: subendothelial & mesangial deposit
– IF:
• C3 in mesangium,
• IgG, IgM deposits in capillary loop
Type II: double deposit Dz
– LM: similar to type I
– EM: electron dense deposit in GBM lamina densa
Type III: mesangial & subendothelial &
subepithelial deposits
MPGN: Type I
The "classic" form is
characterized by massive
mesangial proliferation,
mesangial matrix expansion and
diffuse thickening of the
glomerular basement membrane
‘
’
MPGN: Type II
Type II MPGN is characterized by a dense homogenous
deposition along the glomerular basement membrane and in the
mesangium. Deposits can be different, in dimension and
diffusion, even among the glomeruli of a given biopsy. When
deposition is mild, ultrastructural examination is fundamental
for diagnosis.
MPGN: Etiology
Primary
Secondary:
– SLE, mixed cryoglobulinemia, Sjogren’s SD
– Hep B and C, HIV, subacute bacterial
endocarditis, sepsis. P. falciparum,
Schistosomiasis
– Cnacer: leukemia, lymphoma
– Others: heroin abuse, sarcoidosis, inherited C2
deficiency, rhtombotic microangiopathies
MPGN: Tx and Prognosis
No effective therapy
Very rare spontaneous recovery
Type I: benign, 70-85% survive
Type II: variable course,
– may lead to ESRD in 5-10 years
Minimal Change Disease
(MCD)
m/c idiopathy NS in children (>90%)
m/c in 6-8 years old
15-20% in adult
Male > female
Highly selective proteinuria
– Mostly albumin
Microscopic hematuria (20%)
Complement level: normal
No HTN, azothemia (normal BP, BUN, Cr)
MCD: Etiology
Mostly primary
Secondary
– Drug induced: NSAID, rifampin,
interferon
– Lymphoproliferative malignancy
(Hodgkin’s)
– AIDS, Fabry’s Disease, Sialidosis
– DM, IgA nephropathy, Heroin use
– Iron dextran administration
MCD: Pathology
LM: normal
EM: foot process effacement
(fusion)
IF: mostly normal
– Rarely IgM and C3 deposition
MCD: Tx and Prognosis
(1)
Children: 30-40% recover spontaneously
High-dose steroid: 8weeks
– 90% response in children
– No need to do Bx in children
– Adult: 50% respond
• 90% remission if used for 20-24 weeks
– Recur 50% if steroid is stopped
If no response to steroid => suspect FSGS
MCD: Tx and Prognosis
(2)
Cytotoxic agent
– Cyclophosphamide, chlorambucil
– Cyclosporine => nephrotoxic, high
recurrence rate
– Ix: No response to steroid, steroid
dependent, requiring high dose steroid,
frequent relapse
10 year survival: >90%
– Rarely progress to CRF
