🩺 Nephrotic Syndrome (Pediatric)

1. Definition

Nephrotic syndrome is a glomerular disorder characterized by:
1. Massive proteinuria (>40 mg/m²/hr OR urine protein:creatinine >200 mg/mmol)
2. Hypoalbuminemia (<25 g/L OR <2.5g/dL)
3. Hyperlipidemia
4. Edema
It is the most common glomerular disease in children, especially between 2–6 years of age.

2. Causes

Primary (idiopathic) nephrotic syndrome:
- Minimal Change Disease (MCD) – ~90% of cases in children
- Focal Segmental Glomerulosclerosis (FSGS)
- Membranous nephropathy (rare in children)
Secondary causes (rare in children):
- Systemic lupus erythematosus (SLE)
- Infections (Hepatitis B/C, HIV, malaria)
- Drugs (NSAIDs, penicillamine)
- Malignancy (e.g., lymphoma)
- Congenital/genetic forms (e.g., Finnish type)

3. Risk Factors

Age 2–6 years
Male sex
Atopic background
Family history (especially for congenital forms)
Infections (respiratory viruses can trigger relapses)

4. Types

Type	Description
Steroid-sensitive nephrotic syndrome (SSNS)	Responds to steroids within 4 weeks; most common and favorable prognosis
Steroid-resistant nephrotic syndrome (SRNS)	No response to steroids after 4 weeks
Frequent relapser	≥2 relapses in 6 months or ≥4 in 12 months
Steroid-dependent	Relapse during or within 2 weeks of stopping steroids
Congenital nephrotic syndrome	Onset in first 3 months; usually genetic

5. Pathogenesis

Podocyte Injury

Podocyte injury leads to loss of charge and size selectivity in the glomerular filtration barrier.
This results in massive proteinuria, leading to:
- Hypoalbuminemia → ↓ oncotic pressure → edema
- Hyperlipidemia due to hepatic lipoprotein synthesis to compensate loss of protein in urine**
- Immunoglobulin loss → increased infection risk
- Antithrombin III loss → hypercoagulability

Underfill Theory (Volume Depletion Hypothesis)

Cause: Massive proteinuria → ↓ plasma oncotic pressure
Effect: Fluid shifts from intravascular space to interstitium → edema
Compensatory Response:
- ↓ Intravascular volume triggers:
  - ↑ Vasopressin
  - ↑ Aldosterone
  - ↑ Atrial natriuretic peptide (ANP)
- Kidneys retain sodium and water → worsens edema
Clinical Clues:
- Signs of hypovolemia: low BP, tachycardia, delayed capillary refill
- Responds better to albumin + diuretics

Overfill Theory (Volume Overload Hypothesis)

Cause: Primary renal sodium retention, possibly via epithelial sodium channels
Effect: Plasma volume expansion → fluid leaks into interstitium → edema
Clinical Clues:
- Normovolemia or hypervolemia
- May have normal or high blood pressure
- Diuretics alone more effective; albumin may not be required

🎯 Therapeutic Implications

Volume Status	Treatment Approach
Underfill	IV albumin + diuretics, cautious fluid replacement
Overfill	Sodium restriction + diuretics

Always assess clinical volume status before initiating therapy.
Goal: Gradual edema reduction without inducing hypovolemia.

6. Clinical Presentation

Symptoms

Generalized edema (face, periorbital, legs, scrotum)
Frothy urine
Decreased urine output
Fatigue, poor appetite
Abdominal distension

Signs

Pitting edema
Periorbital puffiness (especially in the morning)
Ascites
Hypertension (occasionally)
Pleural effusion in severe cases

Physical Examination

Normal or elevated BP
Weight gain due to fluid retention
Soft, non-tender abdomen with fluid thrill (ascites)

7. Organ & System Complications

System	Complication
Renal	Acute kidney injury (rare in MCD)
Cardiovascular	Thromboembolism (e.g. DVT, renal vein thrombosis)
Respiratory	Pleural effusion, pulmonary edema
Infectious	Peritonitis, cellulitis, sepsis (due to Ig loss)
Endocrine	Growth suppression (from steroids), hypocalcemia
Hematologic	Anemia, hypercoagulability

8. Diagnostic Investigations

Test	Reason
Urine dipstick	Screen for proteinuria
Urine protein:creatinine ratio	Quantify protein loss (>200 mg/mmol significant)
Serum albumin	Hypoalbuminemia (<25 g/L confirms nephrotic state)
Serum cholesterol	Usually elevated (>5.5 mmol/L)
Renal function tests (urea, creatinine, electrolytes)	Assess baseline renal function

9. Other Relevant Investigations

Test	Reason
C3, C4	Rule out lupus nephritis, post-infectious GN
ANA, dsDNA	If autoimmune disease suspected
Hepatitis B/C, HIV	Screen for secondary causes before immunosuppression
Renal ultrasound	Exclude obstruction, assess kidney size
Renal biopsy	Only if steroid resistant or atypical features

10. Terminology

Term	Definition
Complete Remission	Urine protein nil or trace (UPCR ≤ 20 mg/mmol) for at least 3 consecutive early morning specimens
Partial Remission	UPCR > 20 but < 200 mg/mmol and serum albumin ≥ 30 g/dL
Relapse	Urine protein ≥ 2+ (UPCR ≥ 200 mg/mmol) for 3 consecutive early morning specimens, with or without edema in a child who previously achieved remission
Frequent Relapse Nephrotic Syndrome (FRNS)	≥ 2 relapses in first 6 months after initial therapy or ≥ 4 relapses in any 12 months
Steroid Sensitive Nephrotic Syndrome (SSNS)	Complete remission after 4 weeks of prednisolone at standard dose
Steroid Dependent Nephrotic Syndrome (SDNS)	Two consecutive relapses while on 40 mg/m² EOD prednisolone or within 14 days of its discontinuation
Steroid Resistant Nephrotic Syndrome (SRNS)	Failure to achieve complete remission after 4 weeks of daily prednisolone at 60 mg/m²/day
SSNS Late Responder	Achieves complete remission between 4 and 6 weeks of prednisolone therapy (confirmatory period)

11. Treatment

Curative/Definitive

None for idiopathic NS; congenital/genetic forms may require transplant

Empirical

Prednisolone

Initial Corticosteroid

Prednisolone 60 mg/m²/day OD for 4 weeks
Then 40 mg/m² EOD for 4 weeks
Then gradual taper over 4 weeks
~80% achieve remission (urine dipstick negative or trace for 3 days) within 28 days

Initial or Infrequent Relapse

Prednisolone 60 mg/m²/day until remission
Then 40 mg/m² EOD for 4 weeks, then stop

Frequent Relapse

Induction: Prednisolone 60 mg/m²/day (max 60 mg) until remission
Then 40 mg/m² EOD for 4 weeks**
Then taper every 2 weeks to lowest effective EOD dose
Continue low-dose alternate-day steroids for up to 6 months

📌 If relapse occurs while on low-dose steroids → re-induce as above

Steroid-Dependent

If not steroid toxic:
- Re-induce with steroids
- Maintain lowest possible alternate-day dose
If steroid toxic (e.g. growth failure, cushingoid, cataracts):
- Consider steroid-sparing agents

Steroid-sparing Agents

Cyclophosphamide
Levamisole
Calcineurin inhibitors: cyclosporin, tacrolimus
Mycophenolate mofetil (MMF)
Rituximab

Supportive

Salt and fluid restriction during acute phase
Diuretics (e.g., furosemide) for significant edema
Albumin infusion in severe hypoalbuminemia with diuresis
Calcium/vitamin D supplementation
Pneumococcal vaccination, varicella prophylaxis if seronegative

Palliative

Supportive care for complications in refractory cases

12. Long-Term Effects of Treatment

Treatment	Complications	Monitoring	Expected Results
Long-term steroids	Growth suppression, hypertension, Cushingoid features, osteoporosis	Growth chart, BP, glucose, DEXA	Stable growth, normal BP, normal BMD
Calcineurin inhibitors (e.g. cyclosporine)	Nephrotoxicity, gum hypertrophy, hirsutism	Serum creatinine, drug levels, BP	Normal renal function, therapeutic drug level
Cyclophosphamide	Gonadal toxicity, bone marrow suppression	CBC, renal function, fertility counseling	Stable counts, informed fertility management

13. Surveillance for the Disease

Domain	Frequency	What to Monitor
Urine protein	Daily during initial episode, then during URTIs or symptoms	Early detection of relapse
Growth and BP	Every clinic visit	Growth curve, BP percentile chart
Renal function	Every 3–6 months (on treatment)	Urea, creatinine, electrolytes
Lipids & glucose	Annually (if on long-term steroids)	Fasting lipids, blood glucose
Bone health	Every 1–2 years if prolonged steroid use	DEXA scan, Ca/Vitamin D level

14. Malaysia Support Group for Parents

Support Group	Description	Contact/Link
Paediatric Nephrology Club Malaysia (PNCM)	Community of parents and nephrology professionals	Ask your nephrology clinic or follow on Facebook
Hospital-based nephrology clinics	Education, follow-up, social welfare assistance	Available at HKL, HUKM, UMMC, Penang GH, Sabah GH
National Kidney Foundation (NKF)	Resources, financial aid, public awareness	www.nkf.org.my