8. Nephrotic syndrome

Question 1

What is the definition of nephrotic syndrome?

Answer 1

• Severe proteinuria: >3.5g/day
• Hypoalbuminemia
• Edema
• Severe hyperlipidemia (total cholesterol > 10 mM) is often present as well

Question 2

What are the possible causes of nephrotic syndrome?

Answer 2

Nephrotic syndrome is not a diagnosis, thus an underlying cause must be sought. It can be due to a primary renal disease or secondary to different systemic disorders.

Question 3

What is the pathophysiology of nephrotic syndrome?

Answer 3

• Podocytes wrap around glomerular capillaries and maintain filtration barrier, preventing large molecular weight protein from entering the urine
  
  • Effacement of podocyte foot processes or loss of podocytes is the primary cause of proteinuria

Question 4

How can we assess/diagnose nephrotic syndrome?

Answer 4

• Pitting edema (severe, rapid onset) in regions of low tissue resistance (e.g. periorbitally)

Signs:

• Massive proteinuria
• Low serum albumin
• Normal or mildly increased BP
• Normal or mildly decreased GFR

Differential diagnosis:

• CHF (JVP, pulmonary edema, mild proteinuria)
• Liver disease

Diagnosis:

• Renal biopsy for the diagnosis of the underlying cause (may be difficult due to hypercoagulable state and edema)
  
  • The most common cause of nephrotic syndrome is minimal change disease and it is treated with steroids ==> 90% resolution.
    
    • We avoid biopsies in children, unless there is no response to steroids of the clinical features suggest a different disease.

Question 5

What can be the complications of nephrotic syndrome?

Answer 5

• Susceptibility to infections:
  
  • In up to 20% of adult patients because of serum IgG, complement activity and T cell function
    
    • Loss of Ig in urine + immunosppressive treatment
• Thromboembolism:
  
  • 40% develop DVT/PE or renal vein thrombosis.
  • Partly due to clotting factors and platelet abnormalities
• Hyperlipidemia:
  
  • Cholesterol and triglycerides
  • Due to increased lipoprotein synthesis to compensate the proteinuria

Question 6

What is the treatment of nephrotic syndrome?

Answer 6

• Reduce edema:
  
  • Loop diuretics (furosemide) in high doses
    
    • Gut edema may prevent oral absorption so IV route is best
• Reduce proteinuria:
  
  • ACEI, ARB
• Reduce risk of complications:
  
  • ​Anticoagulation in nephrotic proteinuria
  • Statins should be started for cholesterol
• Treat underlying cause:
  
  • Find and treat underlying infections, malignancy or systemic disease
  • Stop causative drugs

Question 7

What is minimal change disease?

Answer 7

• Most common cause of nephrotic syndrome in children
• Can be idiopathic in adults or associated to drugs (NSAIDs) or paraneoplastic diseases (usually Hodgkin’s lymphoma)

Diagnosis:

• Biopsy appears normal under light microscope (hence the name)
• EM shows effacement of podocyte foot processes

Prognosis:

• 90% of children and 70% of adults undergo remission with steroids
  
  • High risk of recurrence
  • Steroid-resistant disease is treated with cyclophosphamide or cyclosporins
  • Only 1% progresses to ESRD

Question 8

What is membranous nephropathy?

Answer 8

• Accounts for 20-30% of nephrotic syndrome in adults and 2-5% in children
• Mostly idiopathic but can be associated with:
  
  • Malignancy
  • Hepatitis B
  • Drugs (gold, pecicillamine, NSAIDs)
  • Autoimmunity (thyroid, SLE)

Diagnosis:

• Biopsy demonstrates diffusely thickened GBM
• Immunofluorescence with IgG and C3 subepithelial deposits on

Treatment:

• Treatment of the idiopathic form involves general measures such as ACEI/ARB and diuretics
• Spontaneous complete remission occurs in up to 30% and in partial remission in 24-40% by 5 years

Question 9

What is mesangiocapillary GN?

Answer 9

• Divides into immune complex-mediated and complement-mediated
  
  • Immune complex-mediated:
    
    • Circulating immune complexes deposit in the glomeruli and activate the complement via classical pathway
    • May be due to hepatitis C, SLE and monoclonal gammopathies
  • Complement-mediated:
    
    • ​Less common
    • Involves persistent activation of the alternative complement pathway

Diagnosis:

• Biopsy demonstrates mesangial and endocapillary proliferation, a thickened capillary basement membrane with tram-track appearance
• Immunofluorescence shows Ig staining, complement staining or light chains depending on cause.
• EM shows electron dense deposits

Treament:

• ACEI/ARB for all
• Treat underlying cause (priority)
• Steroids for rapidly progressing disease
  
  • With cyclophosphamide if rapid deterioration in renal function

Prognosis:

• Poor when no underlying cause is found
• Patients reaching ESRD usually have recurrence in the transplant

Question 10

What is focal segmental glomerulosclerosis (FSGS)?

Answer 10

• May be primary (idiopathic) or secondary (vesicorureteral reflux, IgA nephropathy, Alport’s syndrome, vasculitis, sickle cell disease, heroine use)
  
  • HIV is associated to collapsing subtypes (poor prognosis)
• Patients usually present with nephrotic syndrome or proteinuria
• 50% of patients have an impaired renal function

Diagnosis:

• Biopsy shows glomeruli scarred in some segment (focal sclerosis)
• Immunofluorescence demonstrates IgM and C3 deposits in affected areas

Treatment:

• Corticosteroids in 30% shows response
• Cyclophosphamide or cyclosporine are used if steroid resistance

Prognosis:

• Untreated –> ESRD
• Spontaneous remission < 10% of cases
• Longer course of treatment ==> response in up to 70%
  
  • Those with abnormal renal function –> 30-50% ERSD
• Recurrence in 20% of transplant kidney (may respond to plasma exchange)