Nephrotic Syndrome Clinical Overview

Nephrotic Syndrome: A Registrar's Guide for the House Officer

I. The "On-Call" Snapshot

Clinical Significance in Malaysia: This is a core presentation in both medical and paediatric wards. You will be clerking patients with anasarca regularly. Failure to recognise and manage its complications (thrombosis and infection) leads to significant morbidity and mortality.

High-Yield Definition: Nephrotic syndrome is a clinical syndrome defined by the presence of:

1. Heavy Proteinuria: >3.5 g/24 hours (or Urine Protein:Creatinine Ratio [UPCR] >350 mg/mmol or 3.5 mg/mg).

2. Hypoalbuminemia: Serum albumin <30 g/L.

3. Peripheral Edema.

It is typically, though not universally, accompanied by hyperlipidemia and lipiduria.

Clinical One-Liner: The patient's glomeruli are "leaky," spilling massive amounts of protein. This causes low serum albumin, severe edema, high cholesterol, and a high risk of clots and infections.

II. Etiology & Risk Factors

Etiology is broadly divided into Primary (idiopathic) and Secondary causes. The distribution differs significantly by age.

Primary Glomerulonephritis (Most common overall):

• Children: Minimal Change Disease (MCD) is the cause in >90%.

• Adults:

  • Focal Segmental Glomerulosclerosis (FSGS)

  • Membranous Nephropathy (MN)

  • Minimal Change Disease (MCD)

  • Membranoproliferative Glomerulonephritis (MPGN)

Secondary Causes (Always exclude in adults):

• Metabolic: Diabetes Mellitus (Diabetic Nephropathy). This is the most common secondary cause you will see in Malaysian adults.

• Autoimmune: Systemic Lupus Erythematosus (SLE) (Lupus Nephritis Class V).

• Infections: Hepatitis B (very relevant in our population), Hepatitis C, HIV.

• Drugs: NSAIDs, Penicillamine (rare).

• Malignancy (Paraneoplastic): Lymphoma, leukemia, solid tumors (especially in elderly patients presenting with Membranous Nephropathy).

III. Quick Pathophysiology

The primary defect is damage to the glomerular filtration barrier, specifically the podocytes.

1. Podocyte Injury: Leads to effacement (flattening) of foot processes and loss of the slit diaphragm's negative charge.

2. Massive Proteinuria: The barrier becomes permeable to proteins, especially albumin.

3. Hypoalbuminemia: Urinary losses exceed hepatic synthesis.

4. Edema: Low serum oncotic pressure (from low albumin) causes fluid to shift from the intravascular space to the interstitium. This is compounded by primary sodium retention in the distal nephron.

5. Hyperlipidemia: The liver compensates for low albumin by increasing synthesis of all proteins, including apolipoproteins, leading to high VLDL and LDL.

6. Thrombosis Risk: Loss of anticoagulant proteins (e.g., Antithrombin III) in the urine creates a hypercoagulable state.

7. Infection Risk: Loss of immunoglobulins (IgG) and complement factors leads to an immunocompromised state.

IV. Classification

The most clinically relevant classification is histological, as it dictates management. This is obtained via renal biopsy (mandatory for most adults; deferred in children who are treated empirically for MCD).

• Minimal Change Disease (MCD)

• Focal Segmental Glomerulosclerosis (FSGS)

• Membranous Nephropathy (MN)

• Membranoproliferative Glomerulonephritis (MPGN)

• Diabetic Nephropathy

• Lupus Nephritis (Class V)

• Amyloidosis

A second classification is clinical, based on steroid response (mainly for MCD/FSGS):

• Steroid-Sensitive

• Steroid-Resistant

• Steroid-Dependent / Frequently Relapsing

V. Clinical Assessment

🚩 Red Flags & Immediate Actions

• Respiratory Distress / Anasarca:

  • Action: Sit patient up, apply O2, stat portable CXR.

  • Reason: Probable pulmonary edema or massive pleural effusion. Requires urgent diuretics.

• Unilateral Leg Swelling / Pleuritic Chest Pain / Sudden Dyspnea:

  • Action: High-flow O2, STAT ECG, urgent D-dimer & CT Pulmonary Angiogram (CTPA) or Doppler U/L.

  • Reason: High suspicion for DVT or PE. Patient is hypercoagulable.

• Fever with Abdominal Pain / Tenderness:

  • Action: Blood cultures, diagnostic ascitic tap.

  • Reason: High suspicion for Spontaneous Bacterial Peritonitis (SBP).

History

• Key Diagnostic Clues:

  • Frothy Urine ("Teh Tarik buih"): The classic sign of heavy proteinuria.

  • Periorbital Edema: Often the first sign, prominent in the morning.

  • Progressive Leg Swelling: Pitting edema that ascends.

  • Weight Gain: Due to fluid retention.

• Symptom Breakdown:

  • Common (>50%): Edema (periorbital, pedal, ascites, genital), frothy urine, fatigue, weight gain.

  • Less Common (10-50%): Dyspnea (pleural effusion), abdominal distension/pain (ascites), reduced urine output (if AKI).

  • Rare (<10%): Symptoms of VTE (DVT/PE).

• Pertinent Negatives (To exclude Nephritic Syndrome):

  • No significant hematuria (i.e., not "coca-cola" urine).

  • No active urinary sediment (RBC casts).

  • No rapidly rising creatinine (usually).

Physical Examination (OSCE Approach)

• General Inspection: Patient looks puffy ("puffy facies"), pale. May be in respiratory distress if anasarca is present. Look for malar rash (SLE) or diabetic foot ulcers.

• Vitals: Can be hypertensive (due to fluid overload) or normo/hypotensive (if intravascularly deplete). Tachycardia is a warning sign.

• Disease-Specific Examination:

  • Face: Periorbital edema.

  • Abdomen: Distended, fluid thrill and shifting dullness positive (ascites). Check for tenderness (SBP).

  • Respiratory: Stony dullness to percussion at lung bases (pleural effusion), potential crackles (pulmonary edema).

  • Limbs: Symmetrical, pitting pedal edema (check up to sacrum). Look for signs of DVT (unilateral swelling, calf tenderness, warmth).

• Pertinent Negatives: JVP is usually not raised (unlike in heart failure), unless in severe volume overload. No stigmata of chronic liver disease (jaundice, spider naevi).

• Clinical Pearl: Always check the patient's intravascular volume status. A patient with anasarca can still be intravascularly dry (postural hypotension, tachycardia), which changes your diuretic plan.

VI. Diagnostic Workflow

Differential Diagnosis

1. Nephritic Syndrome:

   • Points For: Edema, hypertension, renal impairment.

   • Points Against: Lacks massive proteinuria; key feature is hematuria (dysmorphic RBCs, RBC casts).

   • How to Differentiate: UFEME (active sediment) and UPCR (sub-nephrotic range).

2. Congestive Cardiac Failure (CCF):

   • Points For: Edema, dyspnea, pleural effusion.

   • Points Against: Will have a raised JVP, orthopnea/PND, S3 gallop, cardiomegaly.

   • How to Differentiate: Check JVP. Confirm with pro-BNP and echocardiogram.

3. Chronic Liver Disease (CLD):

   • Points For: Edema, ascites, hypoalbuminemia.

   • Points Against: Will have stigmata of CLD (jaundice, spider naevi, palmar erythema, caput medusae), coagulopathy (high INR).

   • How to Differentiate: LFT (Bilirubin, AST/ALT, INR) and liver stigmata.

Investigations Plan

• Bedside / Initial (First 15 Mins):

  • UFEME: Look for Protein (+++ or ++++), oval fat bodies ("Maltese crosses" under polarized light). Crucially, note the absence of RBC casts.

  • BP: Check for hypertension.

• First-Line Labs (The "Confirmation" Panel):

  • Urine: Urine Protein:Creatinine Ratio (UPCR). This is the key diagnostic test, replacing the cumbersome 24-hour collection.

  • Blood:

    • Renal Profile (RP): Urea, Creatinine (for baseline e-GFR), Electrolytes.

    • Liver Function Test (LFT): Crucial for Albumin.

    • Lipid Profile: Total cholesterol, TG, LDL will be high.

• Second-Line Labs (The "Etiology" Workup):

  • Autoimmune Screen: ANA, Anti-dsDNA (for SLE).

  • Infectious Screen: HBsAg, Anti-HCV, HIV screen.

  • Glucose Screen: HbA1c, Fasting Blood Sugar (for DM).

  • Complements: C3, C4 (Low in SLE nephritis, MPGN).

  • In older adults (>50): Serum protein electrophoresis (SPEP) / Urine free light chains (for Myeloma/Amyloidosis).

• Confirmatory / Gold Standard:

  • Renal Biopsy: This is the definitive test in adults to determine histological type and guide specific immunosuppressive therapy.

VII. Staging & Severity Assessment

Severity is not "staged" like cancer. It is assessed based on:

1. Degree of Hypoalbuminemia: (e.g., <25 g/L is severe).

2. Severity of Edema: (e.g., mild pedal edema vs. anasarca with pulmonary edema).

3. Presence of Renal Impairment: (i.e., concurrent AKI or underlying CKD).

4. Presence of Complications: (e.g., active VTE, SBP, severe hyperlipidemia).

VIII. Management Plan

A. Principle of Management

1. General: Manage the complications (edema, thrombosis, hyperlipidemia).

2. Specific: Induce remission (stop proteinuria) with immunosuppression or by treating the secondary cause.

B. Immediate Stabilisation (The ABCDE Plan)

• A (Airway): Usually patent.

• B (Breathing): If dyspneic, sit patient up, give high-flow O2. Check for pleural effusion / pulmonary edema.

• C (Circulation):

  • Secure IV access.

  • Diuretics: This is key. Start with IV Furosemide 40-80mg. Patients are often diuretic-resistant (due to albumin-binding in tubule, poor GFR). You may need high doses, infusions, or combination with Metolazone.

  • Albumin Infusion: Use with caution. Only if patient is intravascularly deplete (hypotensive, tachycardic) or to potentiate diuretics in severe hypoalbuminemia (<20). Give 20% Human Albumin Solution (HAS) 100ml, followed immediately by IV Furosemide.

• D (Disability): GCS usually normal.

• E (Exposure): Check for fever (infection), DVT. Insert urinary catheter and start strict I/O charting. Record daily weights.

C. Definitive Treatment (The Ward Round Plan)

1. General / Supportive Management (For all patients)

• Edema:

  • Low Salt Diet: Crucial. Inform patient and family.

  • Fluid Restriction: Usually 1.0-1.5L/day if severe edema or hyponatremia.

  • Diuretics: Convert to oral Furosemide once edema improves.

• Thromboprophylaxis:

  • Start prophylactic dose SC Clexane (Enoxaparin) if Albumin is <20-25 g/L, or if other VTE risk factors are present.

• Anti-Proteinuric:

  • ACE Inhibitors (e.g., Perindopril) or ARBs (e.g., Losartan). These are mandatory. They reduce intraglomerular pressure and proteinuria. Start low, titrate up. Hold if patient develops AKI.

• Hyperlipidemia:

  • Statin (e.g., Atorvastatin 20-40mg ON).

• Infection Prophylaxis:

  • Vaccinations: Give Pneumococcal (Pneumovax) and Influenza vaccines (once stable/off high-dose steroids).

2. Specific / Immunosuppressive Management

• Paediatrics (Presumed MCD):

  • As per Paediatric Protocol: Oral Prednisolone 60mg/m²/day for 4-6 weeks, then taper slowly.

• Adults (Biopsy-guided):

  • MCD: Oral Prednisolone 1mg/kg/day.

  • FSGS: Prednisolone +/- Calcineurin inhibitors (e.g., Cyclosporin).

  • Membranous Nephropathy: Risk-stratify. Can be Prednisolone + Cyclophosphamide (Ponticelli regimen), or Calcineurin inhibitors, or Rituximab.

  • Secondary Cause: Treat the underlying disease (e.g., tight glycemic control for DM, antiviral for Hep B, hydroxychloroquine/MMF for SLE).

D. Long-Term & Discharge Plan

• Education: Low salt diet, medication compliance, home urine dipstick monitoring, "sick day" rules (e.g., hold ACEi if D/V).

• Follow-up: Under Nephrology clinic for long-term monitoring of BP, renal function, and proteinuria.

• Steroid Complications: Prescribe bone protection (Calcium/Vit D) and gastric protection (PPI) if on long-term steroids.

IX. Complications

• Thromboembolism (DVT, PE, Renal Vein Thrombosis):

  • Cause: Loss of Antithrombin III, increased pro-thrombotic factors.

  • Action: High index of suspicion. Prophylaxis with Clexane. Therapeutic anticoagulation (e.g., Warfarin) if VTE occurs.

• Infection (SBP, Cellulitis, Sepsis):

  • Cause: Loss of IgG and complement.

  • Action: Low threshold to start empirical antibiotics (e.g., IV Ceftriaxone/Cefotaxime) if fever or localized pain. Vaccinate.

• Acute Kidney Injury (AKI):

  • Cause: Intravascular volume depletion (e.g., over-diuresis), progression of GN.

  • Action: Monitor RP. Hold diuretics/ACEi if creatinine rises. Careful fluid balance.

• Long-Term:

  • End-Stage Renal Failure (ESRF): Especially with FSGS, diabetic nephropathy.

  • Atherosclerotic Cardiovascular Disease (CVD): From chronic hyperlipidemia, hypertension.

  • Complications of Treatment: Cushing's syndrome, PUD, osteoporosis from chronic steroid use.

X. Prognosis

• MCD (Children): Excellent renal prognosis. >90% respond to steroids, but relapses are very common.

• MCD (Adults): Good response to steroids (~80%), but slower than children.

• FSGS: More guarded. High rate of progression to ESRF, especially if steroid-resistant.

• Membranous Nephropathy: Rule of thirds: ~1/3 spontaneous remission, 1/3 partial remission (proteinuria persists), 1/3 progress to ESRF.

• Diabetic Nephropathy: Poor prognosis. Relentless progression to ESRF without tight glycemic and BP control.

Key Prognostic Factors: The histological subtype, response to steroids, and degree of persistent proteinuria.

XI. How to Present to Your Senior

"Sir/Madam, referring a patient from A&E."

S: "This is Mr. Tan, a 45-year-old male with new-onset frothy urine and bilateral leg swelling for 2 weeks, now with anasarca."

B: "He has no known medical illness. Clinically, he is fluid overloaded with periorbital edema, ascites, and pitting edema up to the sacrum. BP is 160/100. Lungs are clear. No fever."

A: "His UFEME shows protein 4+. Labs show UPCR 1000 mg/mmol, serum albumin 18 g/L, and creatinine 90 µmol/L. Lipid profile is high. My impression is new-onset Nephrotic Syndrome. I have sent the full nephrotic screen (Hep B/C, ANA, C3/C4). The main complications to watch for are VTE and infection."

R: "I have admitted him, started a low salt diet, strict I/O chart, and IV Furosemide 80mg STAT. I plan to start prophylactic Clexane and an ACE inhibitor once stable. Requesting your review and plan for referral to Nephrology for a biopsy workup."

XII. Summary & Further Reading

Top 3 Takeaways

1. Diagnosis: The triad is massive proteinuria (UPCR >350), hypoalbuminemia (<30), and edema.

2. Complications: Always think Thrombosis (prophylax!) and Infection (low threshold to treat!).

3. Management: In adults, workup for secondary causes (DM, SLE, Hep B) is mandatory. Treatment is biopsy-driven (immunosuppression) plus general care (diuretics, ACEi, statin).

Key Resources

1. Malaysian Paediatric Protocols (4th Ed., 2019): Chapter on Nephrotic Syndrome (for paeds management).

2. Malaysian CPG on Management of Glomerulonephritis (3rd Ed., 2011): Provides framework, but supplement with newer data.

3. UpToDate: "Overview of nephrotic syndrome in adults" and "Treatment of nephrotic syndrome in children."

4. Amboss: "Nephrotic syndrome."