Nephrotic syndrome - Pediatrics

Question 1

Diagnostic triad of nephrotic syndrome (A++)

Answer 1

• Proteinuria > 40 mg/h/m2
• Hypalbuminaemia < 2.5 gm/dl
• Oedema
• Hyperlipidaemia (raised LDL and triglycerides) also occurs in most cases, but is not part of the diagnostic triad.

Question 2

Causes and types of Nephrotic syndrome (A)

Answer 2

Causes
Most cases of nephrotic syndrome are idiopathic and thought due to T cell disorder that leads to glomerular podocyte dysfunction → increased glomerular permeability.

Types of nephrotic syndrome:
1. There are three main types of nephrotic syndrome in childhood:
A. Minimal change disease (85–90%) → No changes seen under normal microscope but podocyte foot process effacement on electron microscopy
B. Focal segmental glomerular → Focal because not all glomeruli affected (usually deeper ones) sclerosis (10–15%) and segmental because only segments of each glomeruli are affected
C. Membranous nephropathy (1–5%) Associated with hepatitis B and malignancy such as lymphomas (more often seen in adults)

2. Congenital nephrotic syndrome (rare)
   * Presenting in utero or within the first month of life.
   * Several mutations have been found, most notably in the nephrin gene (Finnish congenital nephrotic syndrome).
3. Secondary nephrotic syndrome to:
   * GN with heavy proteinuria
   o Systemic lupus erythematosus (SLE)
   o Henoch–Schoenlein purpura (HSP)
   o Infection: PSGN, HBV, HCV, malaria, Bilharzia
   * Drugs as D penicillamine, phenytoin, ….
   * Heavy metals (gold).
   * Anaphylactoid especially bee sting.
   * Tumours: lymphoma/leukaemia.

Question 3

Clinical picture of Nephrotic syndrome (A++)

Answer 3

• Dependent oedema, i.e. Oedema collects at the lowest part, particularly of the face and eyes in the morning.
• As hypoproteinaemia worsens, the oedema becomes widespread and does not improve during the day; sites include the ankles and lower legs, scrotum and sacrum. Ascites can develop and shortness of breath with pleural effusions
• Non-specific symptoms: progressive lethargy and anorexia, occasionally diarrhoea due to GIT oedema.
• Infections, particularly encapsulated organisms such as pneumococcus more likely. Peritonitis also possible (primary or pneumococcal)
• Intravascular hypovolaemia (secondary to hypalbuminaemia) may present with abdominal pain.
• Circulatory collapse/shock or venous thrombosis

Question 4

Initial investigations in Nephrotic syndrome (A)

Answer 4

1) Urine analysis
* Urine Dipstick for proteinuria → will have +3 or +4 proteinuria
* Albumin: creatinine ratio ≥ 2mg/mg
* 24-hr urine protein: 40 mg/m2/hr
* Sodium concentration < 20 mmol/L is an indication of hypovolaemia
* Microscopy: no or minimal cells in uncomplicated nephrotic syndrome (red and white cell casts in glomerulonephritis)

2)Blood:
* CBC: ↑↑ haematocrit (due to hypovolaemia), evidence of infection, ↑↑ ESR
* Urea and creatinine → raised urea may indicate hypovolaemia
* Serum albumin < 2.5 g/dl (by definition)
* Cholesterol, and triglyceride are ↑↑

3) Other investigations if there is a suggestion of overlap with GN:
* Serum complements → C3 and C4 ↓↓ (except in minimal change)
* ASOT, and anti-DNase B → positive if streptococcal infection
* Throat swab culture for streptococcal infection
* Blood screen for hepatitis B and C and for malaria if travel abroad.
* Renal biopsy if:
o No response to steroids after 4–6 weeks (SRNS) or frequent relapses.
o Atypical presentation, e.g. hypertension, gross haematuria, high creatinine, infant < 1 year or > 12 y

Question 5

Differential diagnosis of Nephrotic syndrome (A)

Answer 5

1) Generalized oedema → cardiac, hepatic, nutritional, allergic
2) Other causes of proteinuria
* Orthostatic proteinuria
* Increased glomerular filtration pressure
* Reduced renal mass
* Tubular proteinuria.

Question 6

complications of nephrotic syndrome (A++)

Answer 6

• Intra vascular thrombosis: due to hypovolemia (sluggish circulation), ↑↑ Platelet adhesiveness, and ↓↓ anti-thrombin III, protein S & protein C. in the form of: cerebral cortical veins. renal vein thrombosis. deep venous thrombosis.
• Infections: due to –
  o Loss of immunoglobulins.
  o Loss of complement factor (properdin factor B).
  o Oedema fluid favour infection
  o Immuno-suppressive treatment
  Common organisms: Commonly capsulated bacteria → Pneumococci, E. coli, H. influenza, Staph aureus.
• Acute renal failure: due to: - severe hypovolemia, ↓↓ renal blood flow (prerenal failure), and renal vein thrombosis.
• Relapse:
  Definition: Recurrence of significant proteinuria (≥ 3+) found on 3 consecutive days having been in remission previously.
  If > 4 relapses within 1 year→ frequent relapsing NS.
• Complications of drugs
  o Corticosteroids as hypertension, cataract, infections, growth retardation, diabetes mellitus, osteoporosis, adipose tissue hypertrophy (moon face, buffalo hump, truncal obesity).
  o Cyclophosphamide: alopecia, bone marrow suppression, and cystitis (haemorrhagic).
  o Cyclosporin A: hirsutism, nephrotoxic and hepatotoxic.

Question 7

Treatment of nephrotic syndrome (A++)

Answer 7

❖ Supportive:
* Hospitalization: for follow up of 24 hr urine protein, urinary output, weight gain, and blood pressure.
* Diet control in the form of salt restriction, and increased protein intake. Fluid restriction in case of progressive weight gain.
* Control of infection → either latent UTI, giving pneumococcal and H. influenzae vaccine for chronic cases
* Salt free albumin and diuretics by giving salt free albumin (0.5-1 gm/kg over 4 hrs) followed by frusemide (1-2 mg/ kg)

❖ Curative:
* Induction of remission by Prednisone 2mg/kg/day for 4 weeks in 3 divided doses
* Response either:
- Remission → Steroid sensitive NS → (proteinuria < 4 mg/m2/hr and serum albumin ≥ 3.5 gm/dl) followed by gradual withdrawal over 6 weeks and follow up
- Relapse (10%) that need to restart treatment. Steroid dependent or frequent relapses need to restart treatment until remission followed by alternate day steroid therapy for 12-18 months ± cyclophosphamide 2mg/kg/day or cyclosporin A for 1 year. Rituximab (anti CD 20 monoclonal antibody) can be used in steroid dependent cases.
- Steroid resistance NS → can be given:
1. Calcineurin inhibitors like Cyclosporin A or Tacrolimus.
2. Anti-proteinuria agents like ACE inhibitors and angiotensin II blockers