Minimal Change Disease Clinical Overview
I. The "On-Call" Snapshot
Clinical Significance in Malaysia: This is the single most common cause of nephrotic syndrome in Malaysian children, accounting for over 80% of cases. You will see this. You must be able to diagnose it clinically and initiate management safely to prevent life-threatening complications.
High-Yield Definition (KDIGO): A glomerular disease characterised by diffuse effacement of podocyte foot processes on electron microscopy, with minimal or no changes on light microscopy and negative immunofluorescence.
Clinical One-Liner: This is the classic "puffy-faced kid with frothy urine" who has steroid-responsive nephrotic syndrome.
II. Etiology & Risk Factors
Etiology:
Primary (Idiopathic): This is the vast majority (>90% in children, 70-80% in adults). It is presumed to be an immune/T-cell-mediated disorder.
Secondary: Rare, but must be considered, especially in adults.
Risk Factors / Associations (for Secondary MCD):
Drugs: NSAIDs are a classic cause. Less commonly, lithium, interferons.
Malignancy: Hodgkin lymphoma is the textbook association. Also non-Hodgkin lymphomas, leukaemias.
Infections: Syphilis, HIV (though FSGS is more common).
Atopy: Often associated with a history of asthma, eczema, and allergies.
III. Quick Pathophysiology
The mechanism is not fully known. The current understanding is a systemic T-cell dysfunction leading to a circulating "permeability factor."
This factor targets the glomerular podocytes (the epithelial cells lining the capillaries).
It causes the podocyte foot processes to fuse or efface (flatten).
This disrupts the glomerular filtration barrier, specifically its negative charge and size selectivity.
This leads to massive, selective proteinuria (mostly albumin).
The resulting hypoalbuminemia (<25 g/L) drops plasma oncotic pressure, causing fluid to shift into the interstitium, resulting in edema.
This intravascular depletion triggers RAAS and ADH, causing salt and water retention, which worsens the edema.
IV. Classification
The primary classification is not by histology but by response to steroids, which dictates prognosis and management:
Steroid-Sensitive (SSNS): Achieves remission (urine protein negative) within 4-6 weeks of high-dose steroids. This is the expected course for >90% of children.
Steroid-Resistant (SRNS): Fails to achieve remission despite an adequate course of steroids. This is a red flag and mandates renal biopsy, as it's likely not MCD (e.g., FSGS).
Frequently Relapsing (FRNS): Two or more relapses within 6 months of initial response, or four or more relapses in any 12-month period.
Steroid-Dependent (SDNS): Relapses while on tapering steroids or within 14 days of stopping steroids.
V. Clinical Assessment
🚩 Red Flags & Immediate Actions
Anasarca with Respiratory Distress:
Action: Sit patient up, apply O2, get urgent chest X-ray. Give IV Furosemide (1-2 mg/kg).
Reason: Impending respiratory failure from massive pleural effusion or pulmonary edema.
Tense Abdomen with Fever/Guarding:
Action: High-volume diagnostic ascitic tap, start empirical IV antibiotics (e.g., Cefotaxime) STAT. Call surgical team for review.
Reason: High suspicion for Spontaneous Bacterial Peritonitis (SBP), a life-threatening complication.
Unilateral Leg Swelling, Chest Pain, or Sudden Dyspnea:
Action: High-Alert. Keep NBM, request urgent Doppler U/S or CTPA.
Reason: Suspect DVT or PE. Nephrotic syndrome is a highly hypercoagulable state.
Fever >38°C:
Action: Assume sepsis until proven otherwise. Full septic workup (FBC, RP, CRP, Blood C&S, UFEME, CXR). Start IV antibiotics.
Reason: Patients are immunocompromised (losing Igs in urine, on steroids) and at high risk of encapsulated bacterial infections (e.g., Strep. pneumoniae).
History
Key Diagnostic Clues:
Sudden onset of periorbital edema (puffy face, worst in the morning).
Progression to dependent edema (pedal) and anasarca (scrotal/labial edema, ascites).
Frothy urine (severe proteinuria).
Weight gain (fluid).
Common (>50%): Malaise, lethargy, oliguria, abdominal discomfort/fullness.
Less Common (10-50%): Microscopic hematuria (~20%), dyspnea (from effusions).
Pertinent Negatives:
No gross hematuria.
No significant hypertension.
No renal impairment (at presentation).
No rash, no arthritis, no preceding sore throat (unlike nephritic syndromes).
The presence of these suggests an alternative diagnosis.
Physical Examination (OSCE Approach)
General Inspection: Puffy, pale child. Periorbital edema is striking. Obvious anasarca, abdominal distension. No acute distress unless in respiratory compromise. No rashes.
Vitals: Usually normotensive. May be tachycardic (intravascular depletion). Afebrile (unless infected).
Disease-Specific Examination:
Face: Bilateral, pitting periorbital edema.
Abdomen: Distended, shiny skin, everted umbilicus. Fluid thrill and shifting dullness (ascites). Should be soft and non-tender (tenderness = SBP).
Chest: Stony dullness to percussion at lung bases (pleural effusion).
Limbs/Sacrum: Pitting edema (pedal, scrotal, labial, sacral). Check for unilateral leg swelling (DVT).
Pertinent Negatives: JVP is usually normal or low (not high like in fluid overload from CCF/CKD). No malar rash (SLE), no palpable purpura (HSP).
Clinical Pearl: In a child, the diagnosis of MCD is clinical. We treat based on the classic presentation. We do not biopsy typical cases. In an adult, all new-onset nephrotic syndrome gets biopsied.
VI. Diagnostic Workflow
Differential Diagnosis
Focal Segmental Glomerulosclerosis (FSGS):
Points For: Presents as nephrotic syndrome.
Points Against: More likely to have hypertension, renal impairment, and non-selective proteinuria.
Differentiate: Steroid resistance is the key clinical clue. Biopsy is definitive.
Membranous Nephropathy:
Points For: Nephrotic syndrome.
Points Against: The most common cause in adults, rare in children. Often has secondary causes (HBV, SLE, malignancy, drugs).
Differentiate: Biopsy (LM/IF/EM) and serology (anti-PLA2R Ab, relevant in adults).
IgA Nephropathy (Nephrotic Variant):
Points For: Can have nephrotic-range proteinuria.
Points Against: Classic presentation is episodic gross hematuria with a URI.
Differentiate: Biopsy.
Investigations Plan
Bedside / Initial (First 15 Mins):
UFEME: Massive proteinuria (3+ or 4+). Microscopy shows "oval fat bodies" and fatty casts. Minimal or no hematuria.
Urine Protein/Creatinine Ratio (UPCR): A spot urine sample. >200 mg/mmol (or >2 g/g) confirms nephrotic-range proteinuria.
First-Line Labs & Imaging:
FBC: Check Hb/Hct (may be high due to hemoconcentration), WBC (for infection), Platelets (often high, thrombocytosis).
Renal Profile (RP): BUN, Cr. Usually normal. Must check for AKI.
Liver Function Test (LFT): Serum Albumin (diagnostic, <25 g/L).
Lipid Profile: Markedly high cholesterol and triglycerides (hepatic synthetic response).
Complement C3/C4: MUST be NORMAL. Low complement points to other diagnoses (SLE, MPGN, post-infectious GN).
Chest X-ray: To check for pleural effusions.
Confirmatory / Gold Standard:
Renal Biopsy: This is the gold standard, but it is NOT performed in children with a typical presentation.
Indications for Biopsy:
All adults with new-onset nephrotic syndrome.
Children with atypical features:
Age <1 year or >12 years.
Persistent hypertension.
Gross hematuria.
Renal failure (not explained by hypovolemia).
Low C3/C4.
Children who are Steroid-Resistant (SRNS).
Biopsy Findings:
Light Microscopy (LM): Normal glomeruli.
Immunofluorescence (IF): Negative for Igs and complement.
Electron Microscopy (EM): Diagnostic. Widespread, diffuse effacement (fusion) of podocyte foot processes.
VII. Staging & Severity Assessment
Severity is a clinical assessment based on:
Degree of Edema: Mild (periorbital) vs. Moderate (pedal, ascites) vs. Severe (anasarca, effusions).
Serum Albumin: Severely low (e.g., <20 g/L) indicates high risk for complications.
Presence of Complications: Active SBP, VTE, or AKI signifies severe, life-threatening disease.
Management staging is based on the steroid-response classification (SSNS, SRNS, etc.) as detailed in Section IV.
VIII. Management Plan
(Based on Malaysian Paediatric Protocols for Management, 4th Ed)
A. Principle of Management
Induce remission (get urine protein-free).
Manage edema and fluid balance.
Prevent and treat complications.
Minimise steroid toxicity.
B. Immediate Stabilisation (The ABCDE Plan)
Only relevant for severe presentations (see Red Flags).
Airway/Breathing: Sit up, O2 if sats <94%.
Circulation: IV access.
If intravascularly deplete (tachycardia, poor perfusion, low/normal BP): Give 20% Albumin infusion (1 g/kg over 4 hours), followed by IV Furosemide (1-2 mg/kg) mid-way or after.
If intravascularly overloaded (hypertensive, pulmonary edema): Give IV Furosemide (1-2 mg/kg) alone.
Monitor vital signs and strict Input/Output chart.
C. Definitive Treatment (The Ward Round Plan)
First Episode (Induction):
Prednisolone: 60 mg/m²/day OR 2 mg/kg/day (max 60mg) given as a single morning dose for 6 weeks.
Then, Prednisolone: 40 mg/m²/day OR 1.5 mg/kg/day (max 40mg) on alternate days for 6 weeks.
Then, taper off the alternate-day dose over 8 weeks.
Total course is ~5-6 months.
Relapse:
Defined as urine protein 3+ or 4+ for 3 consecutive days.
Restart Prednisolone 60 mg/m²/day daily until remission (urine protein-free for 3 days), then switch to 40 mg/m²/day on alternate days for 4 weeks, then taper.
FRNS / SDNS:
This is where you call your Paediatric Nephrologist.
The goal is to minimise steroid exposure.
Steroid-Sparing Agents: Levamisole, Cyclophosphamide (oral), Mycophenolate Mofetil (MMF), or Calcineurin Inhibitors (Cyclosporine, Tacrolimus). Rituximab is reserved for difficult cases.
D. Supportive & Discharge Plan
Diet:
No-added-salt diet during relapse and while on high-dose steroids.
Fluid restriction is ONLY needed if there is severe edema or hyponatremia.
Diuretics: Oral Furosemide (+/- Spironolactone) for symptomatic edema. Stop once "dry weight" is achieved.
Prophylaxis:
Gastric: PPI or H2 blocker while on daily high-dose steroids.
Infection: Ensure vaccinations are up-to-date (Pneumococcal, Varicella). Live vaccines are contraindicated while on high-dose immunosuppression.
Parent Education:
How to check daily morning urine with a dipstick.
How to keep a diary of urine protein, weight, and steroid doses.
Signs of relapse and complications (fever, abdominal pain).
Follow-up: Close clinic follow-up to monitor for relapse and steroid side effects (weight, height, BP, glucose, cataracts).
IX. Complications
Immediate / Short-Term (Disease-related):
Infection: SBP (Strep. pneumoniae), cellulitis, sepsis. Due to urinary loss of Igs and C3.
Action: High index of suspicion, low threshold to start IV antibiotics.
Thromboembolism (VTE/PE): Due to urinary loss of Antithrombin III, hemoconcentration, and increased hepatic synthesis of pro-thrombotic factors.
Action: Prophylaxis (Clexane) in high-risk adults (Alb <20-25 + other risks). Urgent imaging if suspected.
Acute Kidney Injury (AKI): Usually pre-renal from intravascular depletion.
Action: Careful fluid management with albumin/diuretics. Strictly avoid NSAIDs.
Long-Term (Mainly treatment-related):
Steroid Toxicity: Cushingoid facies, weight gain, striae, hypertension, hyperglycemia, cataracts, osteoporosis, and growth retardation (a major concern in children).
Action: Monitor closely, use steroid-sparing agents for FRNS/SDNS.
X. Prognosis
Children: Excellent renal prognosis. >90% achieve remission with steroids. Most (80%) will relapse, but many will "outgrow" the disease by adulthood. Renal failure is extremely rare if steroid-sensitive. Morbidity is from treatment complications.
Adults: Good renal prognosis, but response is slower. ~80% respond to steroids. Relapses are common. Higher risk of VTE and complications.
Key Prognostic Factor: Steroid responsiveness. SRNS carries a high risk of progression to ESRD (and is likely FSGS).
XI. How to Present to Your Senior
"Sir/Madam, I am calling about [Patient Name], a [Age]-year-old [M/F] in [Ward], with a new presentation of nephrotic syndrome.
S: He presented with 5 days of periorbital edema and ascites. He is clinically edematous but haemodynamically stable, BP [X/Y], HR [X].
B: This is a typical presentation for Minimal Change Disease.
A: His UFEME shows 4+ proteinuria, no hematuria. Serum albumin is [X], Cr is [Y], C3/C4 are normal.
R: My plan is to start supportive management with a no-added-salt diet, daily urine dipstick, and strict I/O. I would like to confirm the plan to start high-dose prednisolone at 2 mg/kg/day."
XII. Summary & Further Reading
Top 3 Takeaways:
MCD is the #1 cause of nephrotic syndrome in children. The diagnosis is clinical (puffy face, anasarca, massive proteinuria, normal BP/Cr/C3) and confirmed by steroid response.
The core pathology is podocyte foot process effacement, leading to selective albuminuria.
Management is high-dose steroids (Prednisolone 2mg/kg/day). You must always be vigilant for the three main complications: Infection (SBP), Thrombosis (VTE), and Steroid Toxicity.
Key Resources:
Primary: Malaysian Paediatric Protocols for Management (4th Edition, 2019) - Chapter on Nephrotic Syndrome.
Guidelines: KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases.
Review: UpToDate - "Treatment of minimal change disease in children" and "Minimal change disease: Etiology, pathogenesis, and diagnosis in adults."
