CASE I - 4-year-old Male with Anasarca (20 marks)

Q.1 - Five Most Common Causes of Anasarca in Children (5 marks)

1. Nephrotic syndrome - most common cause in children; massive proteinuria leads to hypoalbuminaemia and reduced oncotic pressure
2. Congestive cardiac failure - increased hydrostatic pressure from impaired cardiac output
3. Liver disease / hepatic failure - reduced albumin synthesis (hypoproteinaemia), plus portal hypertension
4. Protein-energy malnutrition (Kwashiorkor) - severe hypoalbuminaemia from protein deficiency
5. Severe anaemia - high-output cardiac state causing fluid retention

Q.2 - Differentiate Nephritic Syndrome from Nephrotic Syndrome (5 marks)

Q.3 - Nephrotic Range Proteinuria and Diagnosis of Nephrotic Syndrome (2+3=5 marks)

Nephrotic Range Proteinuria (2 marks)

• In children: proteinuria >40 mg/m²/hour (or urine protein:creatinine ratio >2.0 mg/mg)
• In adults: >3.5 g/24 hours (or >3.5 g/1.73 m²/24 hours)
• On dipstick: 3+ to 4+ protein (~300-2000 mg/dL)
• Spot urine protein:creatinine ratio >2.5 mg/mg is also diagnostic

Diagnosis of Nephrotic Syndrome (3 marks)

1. Massive proteinuria - >40 mg/m²/h or urine P:Cr >2.0 in children (3-4+ on dipstick)
2. Hypoalbuminaemia - serum albumin <2.5 g/dL (<25 g/L)
3. Hyperlipidaemia - elevated serum cholesterol and/or triglycerides
4. Oedema - periorbital, peripheral, ascites, pleural effusion

• Urine microscopy: lipid-laden cells, oval fat bodies, fatty casts; absent or minimal haematuria
• 24-hour urinary protein or spot urine P:Cr ratio
• Serum albumin, total protein, lipid profile, renal function tests (creatinine, urea)
• Complement levels (C3, C4) - to exclude secondary causes
• ANA, anti-dsDNA (SLE), ANCA, HBsAg, anti-HCV as clinically indicated

Q.4 - Classification of Nephrotic Syndrome by Response to Steroid Therapy (3 marks)

1. Steroid-Sensitive Nephrotic Syndrome (SSNS): Patient enters complete remission (urine albumin dipstick 0-trace for 3 consecutive days with resolution of oedema) in response to daily glucocorticoid treatment alone. About 75% respond within 2 weeks; 95% within 4 weeks.
2. Steroid-Resistant Nephrotic Syndrome (SRNS): Failure to enter clinical remission after 4-8 weeks of adequate daily glucocorticoid treatment. These children are at high risk for progressive renal disease and almost always undergo renal biopsy.
3. Frequently Relapsing Nephrotic Syndrome (FRNS): Two or more relapses within 6 months of initial response, OR four or more relapses in any 12-month period.
4. Steroid-Dependent Nephrotic Syndrome (SDNS): Two consecutive relapses occurring during tapering of steroids, or within 14 days of cessation of steroid therapy.

Q.5 - Steroid Prescription for a 15 kg Child with Nephrotic Syndrome (2 marks)

• Prednisolone 2 mg/kg/day (maximum 60 mg/day)
• For 15 kg child: 2 × 15 = 30 mg/day in divided doses (given as 10 mg - 10 mg - 10 mg TID, or 15 mg - 15 mg BD)
• Duration: 6 weeks daily

• Prednisolone 1.5 mg/kg on alternate days (maximum 40 mg on alternate days)
• For 15 kg child: 1.5 × 15 = 22.5 mg on alternate days (round to ~20-22 mg)
• Duration: 6 weeks on alternate days (then gradually taper and stop)

Prescription Summary for 15 kg child:

• Tab. Prednisolone 5 mg
• 30 mg/day (6 tablets/day) for 6 weeks, then
• 22 mg every alternate day for 6 weeks, then taper

CASE III - 4-year-old with Anasarca, Frothy Urine, BP 100/60 (25 marks)

Q.15 - Diagnosis (1 mark)

Q.16 - Investigations (4 marks)

• Urine dipstick - protein 3-4+ (confirms massive proteinuria)
• Urine microscopy - fatty casts, oval fat bodies; rule out RBC casts
• Spot urine protein:creatinine ratio (>2.0 = nephrotic range)
• 24-hour urinary protein (>40 mg/m²/h)

• Serum albumin (low, <2.5 g/dL)
• Total protein
• Serum cholesterol and triglycerides (elevated)
• Serum creatinine and BUN (renal function)
• Complete blood count (haemoglobin, platelets)
• Serum electrolytes (Na, K)
• Complement C3, C4 (rule out secondary causes)
• ANA, anti-dsDNA (rule out SLE, especially if age >10)
• HBsAg, anti-HCV, HIV serology (in high-risk populations)
• Blood glucose

• Renal and bladder ultrasonography (assess kidney size, echogenicity, rule out structural anomalies)

• Urine protein 3-4+, no RBC casts
• Serum albumin <2.5 g/dL
• Serum cholesterol >200 mg/dL
• Normal C3/C4
• Normal renal function

Q.17 - Causes of Proteinuria in Children (3 marks)

• Fever
• Vigorous exercise
• Orthostatic (postural) proteinuria - common in adolescents; protein only when upright

• Primary glomerular diseases: Minimal Change Disease (MCNS), FSGS, Membranous nephropathy, IgA nephropathy, Membranoproliferative GN
• Secondary glomerular diseases:
  • Infections: HIV, Hepatitis B, Hepatitis C, malaria, post-streptococcal GN
  • Systemic: SLE, Henoch-Schonlein purpura/IgA vasculitis, diabetes mellitus
  • Malignancy: lymphoma, leukaemia
  • Drugs: NSAIDs, gold, penicillamine

• Fanconi syndrome
• Cystinosis
• Lowe syndrome
• Interstitial nephritis

• Multiple myeloma (excess immunoglobulins)
• Myoglobinuria (muscle breakdown)

Q.18 - Treatment of Nephrotic Syndrome (5 marks)

A. General Measures:

• Salt restriction - no added salt diet (restrict NaCl to 1-2 g/day)
• Fluid restriction if severe oedema with hyponatraemia
• Protein intake - normal protein diet (1.5-2 g/kg/day); no benefit from excess protein
• Diuretics for symptomatic oedema:
  • Furosemide 1-2 mg/kg/dose + Spironolactone 1-3 mg/kg/day
  • Albumin infusion (20-25%) if severe hypovolaemia, followed by furosemide
• Monitoring: daily weight, BP, urine dipstick for protein

B. Specific Treatment - Corticosteroids (ISKDC Protocol):

• Prednisolone 2 mg/kg/day (max 60 mg/day) for 6 weeks daily
• Followed by Prednisolone 1.5 mg/kg on alternate days (max 40 mg) for 6 weeks, then taper and stop

C. Treatment of Relapse:

• Prednisolone 2 mg/kg/day (max 60 mg) until urine protein negative for 3 consecutive days
• Then 1.5 mg/kg on alternate days for 4 weeks

D. Steroid-Resistant / Frequent Relapsing / Steroid-Dependent NS:

• Cyclophosphamide (cytotoxic agent)
• Mycophenolate mofetil (MMF)
• Calcineurin inhibitors (Cyclosporine, Tacrolimus)
• Levamisole (immunomodulator)
• Rituximab (anti-CD20 monoclonal antibody)

E. Prophylaxis:

• Vaccinations: Pneumococcal vaccine, varicella vaccine (before steroids if possible; avoid live vaccines during steroid therapy)
• Penicillin prophylaxis during active nephrotic syndrome (due to risk of pneumococcal peritonitis)
• ACE inhibitors/ARBs as antiproteinuric agents in steroid-resistant cases

Q.19 - Likely Cause of Altered Sensorium, Headache, and Monoparesis on Day 5 (2 marks)

Explanation:

• Urinary loss of anticoagulant proteins: Antithrombin III, Protein C, Protein S
• Increased procoagulant factors: Fibrinogen, Factors V, VII, VIII, X
• Increased platelet aggregation and activation
• Altered fibrinolytic system
• Haemoconcentration due to hypoalbuminaemia and reduced intravascular volume

Q.20 - Possible Causes of New Onset Swelling One Month After Discharge (2 marks)

1. Relapse of Nephrotic Syndrome - most likely; relapses occur in 50-75% of children with MCNS; upper respiratory infections are the most common trigger for relapses (~70%)
2. Steroid-induced complications mimicking oedema (Cushing features) if still on steroids
3. New complication such as infection precipitating relapse
4. Inadequate steroid taper leading to relapse
5. Frequently relapsing NS or steroid-dependent NS (if relapse occurs during taper or within 14 days of stopping)

Q.21 - Would You Proceed for Renal Biopsy? Explain with Reason (3 marks)

Reason:

• Macroscopic haematuria (present in the next relapse)
• Age <12 months or >12 years at onset
• Persistent hypertension - this child now has hypertension, which is atypical for MCNS (hypertension is far more common in FSGS and MPGN, not MCNS)
• Systemic or syndromic features
• Persistent creatinine elevation >1-2 weeks
• Low complement levels
• Persistent proteinuria after 4-8 weeks of adequate steroid treatment (steroid resistance)

Q.22 - Other Indications for Renal Biopsy in Nephrotic Syndrome (5 marks)

1. Steroid-resistant nephrotic syndrome (SRNS) - failure to achieve remission after 4-8 weeks of adequate steroid therapy (most important indication)
2. Age <12 months or >12 years at initial presentation (atypical age group for MCNS)
3. Macroscopic (gross) haematuria - suggests nephritic component, not typical of MCNS
4. Low complement levels (C3, C4 low) - suggests secondary GN: post-streptococcal GN, MPGN, lupus nephritis
5. Systemic features - rash, arthritis, signs of SLE, vasculitis, etc.
6. Persistent azotaemia/elevated creatinine >1-2 weeks without explanation
7. Persistent hypertension disproportionate to the degree of nephrotic syndrome
8. Family history of kidney disease (genetic nephropathy, Alport syndrome)
9. Suspected secondary nephrotic syndrome (SLE, amyloidosis, malignancy)
10. Frequently relapsing or steroid-dependent NS - when considering long-term immunosuppressive therapy (cyclophosphamide, cyclosporine) to guide treatment decisions

Note: In a child aged 1-12 years with classical features of nephrotic syndrome (facial oedema, no haematuria, normal BP, normal complement) - empirical steroid treatment is started WITHOUT biopsy, as MCNS is overwhelmingly the most likely diagnosis (85% of idiopathic NS in children).

CASE II - 4-year-old with Generalised Body Swelling, Frothy Urine (15 marks)

Q.1 - Most Probable Cause of Swelling (2 marks)

• Age 4 years (peak age for MCNS: 2-6 years)
• Swelling started from face (periorbital oedema) then spread to whole body
• Frothy urine (massive proteinuria)
• Pitting oedema and ascites on examination
• No anaemia, no jaundice (rules out liver disease, malnutrition)
• BP 90/60 (normal for age - not hypertensive, typical of MCNS)
• CVS normal (rules out cardiac cause)
• Urine protein 4+ with NO RBCs (classic nephrotic - proteinuria without haematuria)

Q.2 - Differential Diagnosis of Anasarca (2 marks)

1. Nephrotic syndrome - most likely (massive proteinuria, hypoalbuminaemia)
2. Congestive cardiac failure - raised JVP, cardiomegaly, S3 gallop; CVS normal here, so less likely
3. Liver disease (cirrhosis/hepatic failure) - jaundice, hepatomegaly, spider naevi; absent here
4. Protein-energy malnutrition (Kwashiorkor) - skin/hair changes, nutritional history
5. Severe anaemia - pallor, hyperdynamic circulation; no anaemia here
6. Hypothyroidism - non-pitting (myxoedema), bradycardia, other features
7. Protein-losing enteropathy - diarrhoea, malabsorption features
8. Severe nephritic syndrome/RPGN - but would have haematuria, RBC casts, hypertension

Q.3 - Investigations and Expected Findings (4 marks)

Q.4 - Treatment of Nephrotic Syndrome (4 marks)

General/Supportive:

• Diet: Normal protein (1.5-2 g/kg/day), salt restriction (no added salt), adequate caloric intake
• Fluid restriction only if severe hyponatraemia (Na <125 mEq/L)
• Diuretics for symptomatic oedema:
  • Furosemide 1-2 mg/kg/dose ± Spironolactone 1-3 mg/kg/day
  • IV 20-25% albumin infusion (0.5-1 g/kg over 2-4 hours) followed by furosemide if severe hypovolaemia
• Monitoring: daily weight, BP, urine dipstick for proteinuria
• Infection prevention: Penicillin prophylaxis, pneumococcal vaccine

Specific Treatment - Corticosteroids (ISKDC Protocol):

• Prednisolone 2 mg/kg/day (maximum 60 mg/day), given as single morning dose or divided doses
• Duration: 6 weeks (daily dose)
• Then 1.5 mg/kg on alternate days (maximum 40 mg) for 6 weeks (then taper and stop)
• Monitor urine protein daily with dipstick

Outcome in MCNS:

• ~95% of MCNS respond to steroids within 4-8 weeks
• Response to steroids is both therapeutic AND diagnostic (confirms likely MCNS)

Q.5 - Common Complications of Nephrotic Syndrome (3 marks)

• Spontaneous bacterial peritonitis (SBP) - classically due to Streptococcus pneumoniae (gram-positive)
• Cellulitis, urinary tract infections, septicaemia
• Mechanism: urinary loss of IgG and complement factor B, impaired T-cell function

• Renal vein thrombosis (flank pain, haematuria)
• Deep vein thrombosis, pulmonary embolism
• Cerebral venous sinus thrombosis (headache, altered sensorium, focal neurology)
• Mechanism: loss of Antithrombin III, Protein C & S; elevated fibrinogen; increased platelet activity

• Reduced intravascular oncotic pressure causes shift of fluid to interstitium
• Manifests as abdominal pain, tachycardia, cold peripheries, oliguria
• May progress to acute tubular necrosis in severe cases

• Hypercholesterolaemia and hypertriglyceridaemia
• Long-term risk of atherosclerosis

• Cushingoid appearance, growth retardation, cataracts, osteoporosis
• Hypertension, gastric ulcers, immunosuppression, insulin resistance, mood swings

References: Brenner and Rector's The Kidney (2-Vol Set), 9th ed.; The Harriet Lane Handbook, 23rd ed. (Johns Hopkins Hospital); Robbins & Kumar Basic Pathology; Comprehensive Clinical Nephrology, 7th ed.; Symptom to Diagnosis: An Evidence-Based Guide, 4th ed.