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