Overview
Nephrotic Syndrome
1. Overview
Nephrotic Syndrome is a clinical syndrome defined by the loss of massive amounts of protein through the kidneys, leading to low levels of albumin in the blood and subsequent fluid retention (edema).
The Diagnostic Triad
- Heavy Proteinuria: >3.5 g/24h (or PCR >300-350 mg/mmol).
- Hypoalbuminaemia: Serum albumin <30 g/L (often <25).
- Oedema: Peripheral, periorbital, or generalized (Anasarca).
Image: The Nephrotic Triad
Note: Hyperlipidaemia is also a classic feature but not essential for definition.
2. Pathophysiology
Image: Podocyte Damage
┌─────────────────────────────────────────────────────────────────────────────┐
│ NEPHROTIC SYNDROME PATHOPHYSIOLOGY │
┌─────────────────────────────────────────────────────────────────────────────┐
│ NEPHROTIC SYNDROME PATHOPHYSIOLOGY │
├─────────────────────────────────────────────────────────────────────────────┤
│ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ GLOMERULAR FILTRATION BARRIER DAMAGE │ │
│ │ • Podocyte Injury (foot process effacement) │ │
│ │ • Loss of negative charge barrier │ │
│ │ • Result: Large proteins (Albumin) leak into urine │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ MASSIVE PROTEINURIA (>3.5g/day) │ │
│ │ • Liver cannot synthesize albumin fast enough to compensate │ │
│ │ • HYPOALBUMINAEMIA (<30 g/L) │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌────────────────────┴─────────────────────┐ │
│ ↓ ↓ │
│ ┌───────────────────────────┐ ┌──────────────────────────┐ │
│ │ "UNDERFILL" THEORY │ │ "OVERFILL" THEORY │ │
│ │ (Classic) │ │ (Modern/Dominant) │ │
│ │ • Low oncotic pressure │ │ • Primary sodium retent- │ │
│ │ pulls fluid into tissue │ │ ion by kidney tubules │ │
│ │ • Intravascular volume ↓ │ │ (ENaC activation) │ │
│ │ • RAAS activation │ │ • Volume Expanded │ │
│ │ • Secondary Na+ retention │ │ • Hypertension common │ │
│ └───────────────────────────┘ └──────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ CLINICAL SEQUELAE │ │
│ │ • OEDEMA (Gravity dependent) │ │
│ │ • HYPERLIPIDAEMIA (Liver pumps out lipoproteins to try and fix │ │
│ │ oncotic pressure) │ │
│ │ • HYPERCOAGULABILITY (Loss of Antithrombin III + Liver pumps out │ │
│ │ Fibrinogen) │ │
│ │ • IMMUNODEFICIENCY (Loss of Immunoglobulins in urine) │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ │
└─────────────────────────────────────────────────────────────────────────────┘
3. Causes (Etiology)
The underlying cause varies significantly by age.
Primary Glomerular Disease (Idiopathic)
Image: Histology Comparison
| Feature | Minimal Change Disease | Membranous Nephropathy | FSGS |
|---|---|---|---|
| Age | Children (peak 2-6y) | Adults (>40y) | Adults (African descent) |
| Light Microscopy | Normal | Thick basement membrane ("Spikes") | Segmental sclerosis |
| Electron Microscopy | Foot Process Effacement | Subepithelial deposits | Effacement |
| Immunofluorescence | Negative | IgG & C3 along loops | IgM / C3 trapped |
| Trigger | URI, Vaccine, Hodgkin's | PLA2R Antibody, Cancer, Lupus | HIV, Heroin, Obesity |
| Response to Steroids | Excellent (>90%) | Poor (needs Cyclophos/Ritux) | Variable/Poor |
- Minimal Change Disease:
- Mechanism: Circulating cytokine factor (unknown) damages charge barrier.
- Course: Relapsing-remitting. Does NOT progress to renal failure.
- Membranous Nephropathy:
- Mechanism: Autoantibodies (Anti-PLA2R) target podocyte antigen. Immune complexes form "under" the podocyte (subepithelial).
- Rule of Thirds: 1/3 Spontaneous Cure, 1/3 Stable Proteinuria, 1/3 Kidney Failure.
- Focal Segmental Glomerulosclerosis (FSGS):
- Mechanism: Scarring (sclerosis) of parts (segmental) of some glomeruli (focal).
- Prognosis: High rate of ESRD. Recurs in transplant.
Secondary Causes
- Diabetic Nephropathy:
- Kimmelstiel-Wilson Nodules.
- Microalbuminuria -> Macroalbuminuria -> Nephrotic range.
- Autoimmune: SLE (Lupus Nephritis Class V), Amyloidosis (Apple-green birefringence).
- Infections: Hepatitis B/C, HIV, Syphilis.
- Drugs: NSAIDs, Gold, Penicillamine.
- Malignancy: Myeloma (AL Amyloid), Solid tumors (Membranous).
Image: Nephrotic Edema
4. Clinical Features
History Taking
- Frothy Urine: Classic sign of albuminuria.
- Swelling: Eyelids in morning? Ankles in evening?
- Systemic: Rashes/Joint pain (Lupus), Diabetes history, Medications (NSAIDs).
Physical Examination
- Oedema: Pitting. Check sacrum if bedbound. Periorbital (loose tissue).
- Muehrcke's Lines: White bands on fingernails (hypoalbuminemia).
- Xanthelasma: Due to hyperlipidemia.
- BP: Can be high continuous with underlying pathology.
5. Diagnosis
Diagnostic Algorithm
Step 1: Confirm Nephrotic Syndrome
- Urine Dip: ++++ Protein.
- uPCR (Protein:Creatinine): >300 mg/mmol.
- Serum Albumin: <30 g/L.
Step 2: Screen for Cause ("The Nephrotic Screen")
- Blood Sugar/HbA1c: Diabetes.
- Autoimmune: ANA, dsDNA, C3/C4.
- Infection: Hep B, Hep C, HIV.
- Protein Electrophoresis: Myeloma screen (older adults).
- PLA2R Antibodies: Specific for Primary Membranous.
Step 3: Renal Biopsy
- ADULTS: Mandatory in almost all new cases (unless obvious Diabetes with retinopathy, or Amyloid confirmed elsewhere).
- CHILDREN: Not routine. Treated empirically with steroids for Minimal Change. Biopsy only if steroid-resistant.
6. Management Algorithm
┌─────────────────────────────────────────────────────────────────────────────┐
│ NEPHROTIC SYNDROME MANAGEMENT │
├─────────────────────────────────────────────────────────────────────────────┤
│ │
│ 1. GENERAL MEASURES (NON-IMMUNOSUPPRESSIVE) │
│ • FLUID STATUS: Daily weights. │
│ • DIET: Salt Restriction (<2g/day Na). Standard protein (do not │
│ fluid overload with high protein diet). │
│ • DIURETICS: Loop Diuretics (Furosemide). High doses often needed │
│ (gut oedema reduces absorption). │
│ • RAAS BLOCKADE: ACEi/ARB (e.g., Ramipril). Reduces intraglomerular │
│ pressure → Reduces proteinuria. │
│ • STATIN: Treat hyperlipidemia. │
│ │
│ 2. ANTICOAGULATION (CRITICAL) │
│ • Risk of DVT/PE/RV Thrombosis is high. │
│ • Prophylaxis (LMWH) indicated if: │
│ - Albumin <20 g/L │
│ - Other risk factors present │
│ • Especially high risk in Membranous Nephropathy. │
│ │
│ 3. DISEASE-SPECIFIC IMMUNOSUPPRESSION (Based on Biopsy) │
│ • Minimal Change: High dose Steroids (1mg/kg). │
│ • Membranous: "Ponticelli" (Steroids + Cyclophos) or Rituximab. │
│ • Lupus: Mycophenolate / Cyclophosphamide. │
│ • Diabetes: SGLT2 Inhibitors + ACEi (No immunosuppression). │
│ │
│ 4. ANTICOAGULATION PROTOCOL (Detailed) │
│ • **Why?** Loss of Antithrombin III + Liver synthesizes Factor V/VIII + Immobility.
│ • **Risk Calculator**: GEMINI score. │
│ • **Albumin < 20 g/L**: Prophylactic LMWH (Enoxaparin 40mg). │
│ • **Albumin < 20 g/L + High Risk**: Therapeutic Anticoagulation (Warfarin/DOAC).
│ • **Duration**: Until Albumin > 20 or remission. │
│ │
└─────────────────────────────────────────────────────────────────────────────┘
Treating the Edema
"Dry weight" is the target.
- Furosemide: Start 40mg. May need 160mg+ bd.
- Add Thiazide (Metolazone) for synergistic effect (diuretic resistance).
- Salt restriction is key: Diuretics won't work if patient eats salt.
7. Complications
- Thromboembolism (VTE):
- Loss of Antithrombin III + increased clotting factors.
- Renal Vein Thrombosis: Flank pain + Haematuria + Worsening renal function.
- PE is a major cause of death.
- Infection:
- Loss of IgG + Opsonins.
- Encapsulated bacteria risk (Pneumococcus).
- Vaccinate: Pneumoccal, Influenza.
- Acute Kidney Injury (AKI):
- Prerenal (over-diuresis) or ATN (interstitial edema).
8. Prognosis
- Minimal Change: Excellent (remission >90%), but relapses common.
- Membranous: Rule of thirds (1/3 remit spontaneously, 1/3 stable, 1/3 progress to ESRD).
- FSGS: Variable, often poor. High recurrence rate in transplant.
- Diabetes: Progressive.
9. Special Considerations
Pregnancy
- Risk: Pre-eclampsia is harder to diagnose (proteinuria is already present).
- VTE Risk: Pregnancy + Nephrotic = EXTREME risk. Needs high dose LMWH.
- Biopsy: Avoid if possible (bleeding risk).
- Drugs: ACEi/ARB contraindicated. Switch to Labetalol/Nifedipine.
Vaccination
- Patients are immunocompromised (by disease and treatment).
- Pneumococcal vaccine is essential.
- Avoid live vaccines if on high dose immunosuppression.
Diuretic Resistance
- Gut edema prevents absorption of oral furosemide.
- Albumin helps transport furosemide to tubule.
- Solution: IV Furosemide or albumin-primed diuresis (rarely used now).
10. Key Clinical Pearls
Exam-Focused Points
- Triad: Proteinuria + Hypoalbuminemia + Edema.
- Biopsy Rule: Kids = No (Steroids first). Adults = Yes (Biopsy first).
- VTE Risk: Albumin <20 = Heparin prophylaxis.
- Infection: Specifically Pneumococcus (Peritonitis in kids).
- Frothy Urine: Pathognomonic for proteinuria.
- Membranous: Associated with malignancy (Lung/Colon) - check for cancer in older adults.
- Minimal Change: Fusion of foot processes on Electron Microscopy.
Common Exam Scenarios
- 4yo boy with puffy eyes. Management? (Steroids. No biopsy).
- 50yo man with nephrotic syndrome. Management? (Biopsy. Rule out cancer).
- Nephrotic patient with sudden flank pain and haematuria. Dx? (Renal Vein Thrombosis).
11. Patient Explanation
What is Nephrotic Syndrome?
"Your kidneys act like a sieve to clean your blood. Normally, the holes in the sieve are small enough to keep goodies (like protein/albumin) in the blood while letting waste out. In this condition, the holes have become too big.
Important proteins are leaking out into your urine. Because protein acts like a sponge to hold water in your blood vessels, losing it means water leaks out into your tissues, causing swelling."
Why do I need a kidney biopsy?
"In adults, there are many different reasons for the sieve to become leaky (inflammation, scar tissue, antibodies). We cannot tell which one it is just by blood tests. We need a small sample of the kidney to look under the microscope so we can choose the right medicine."
Can I just drink less water?
"No, the problem is salt. Salt holds onto water. You must stop adding salt to your food, or the swelling will not go away even with water tablets."
12. Evidence & Guidelines
Key Guidelines
| Guideline | Organization | Year | Key Points |
|---|---|---|---|
| Glomerular Diseases | KDIGO | 2021 | Global gold standard for GN management. |
| Glomerulonephritis | UK Kidney Association | 2019 | UK specific guidance. |
Landmark Trials
MENTOR (2019):
- Rituximab vs Cyclosporine for Membranous Nephropathy.
- Result: Rituximab was non-inferior for induction and SUPERIOR for maintaining remission.
- Shifted practice towards Rituximab.
PODO Trial:
- Studied steroid withdrawal in Minimal Change Disease.
Evidence-Based Recommendations
| Recommendation | Evidence Level |
|---|---|
| ACEi for proteinuria reduction | High |
| Anticoagulation for Alb <20 | Moderate (Observational) |
| Rituximab for Membranous | High (MENTOR) |
| Steroids for Minimal Change | High |
13. References
- KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276.
- Fervenza FC, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy (MENTOR). N Engl J Med. 2019;381(1):36-46.
- Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. BMJ. 2008;336(7654):1185-1189.