Nephrotic Syndrome
Clinical syndrome characterised by heavy proteinuria (>3.5 g/day or uPCR >350 mg/mmol), hypoalbuminaemia (<25 g/L), peripheral oedema, and hyperlipidaemia. In children, minimal change disease is the most common cause; in adults, membranous nephropathy and FSGS predominate.
Key Facts
Nephrotic syndrome is defined by: proteinuria >3.5g/day, hypoalbuminaemia <25g/L, oedema, and hyperlipidaemia Most common cause in children: minimal change disease (80%); in adults: membranous nephropathy (Caucasian) or FSGS (Afro-Caribbean) Key complications: thromboembolism (loss of antithrombin III), infection (loss of immunoglobulins), hyperlipidaemia, AKI Renal vein thrombosis most commonly associated with membranous nephropathy In children: treat empirically with prednisolone without biopsy if typical presentation (age 1-12, no haematuria, normal complement, normal renal function) Adults: renal biopsy is required for all cases to determine underlying cause Thromboprophylaxis with LMWH or warfarin if albumin <20 g/L or significant additional risk factors
Overview
Key Facts
Nephrotic syndrome results from increased glomerular permeability to protein, predominantly albumin. The underlying cause determines treatment and prognosis.
Epidemiology
- Childhood incidence: 2-7 per 100,000 children/year
- Adult incidence: 3 per 100,000/year
- Males more commonly affected in childhood; equal in adults
Aetiology
Children: MCD (80%), FSGS (10%), membranous (5%), MPGN (5%) Adults: Membranous (25-30%), FSGS (20-25%), MCD (10-15%), MPGN (5-10%), diabetic (25%), amyloid (5%) Secondary causes: diabetes, SLE, amyloidosis, drugs (NSAIDs, gold), infections (HBV, HCV, HIV), malignancy
Pathophysiology
- Glomerular basement membrane damage → loss of charge-selective and size-selective barriers
- Massive albumin loss in urine → hypoalbuminaemia → reduced oncotic pressure → oedema (underfill hypothesis)
- In many patients, primary sodium retention by nephrons also contributes (overfill hypothesis)
- Hepatic response to hypoalbuminaemia: increased lipoprotein synthesis → hyperlipidaemia
- Loss of antithrombin III, protein C/S, increased fibrinogen → prothrombotic state
- Loss of immunoglobulins (especially IgG) → increased infection susceptibility
Clinical Presentation
Classic Features
- Generalised oedema: periorbital (morning), peripheral (dependent), ascites, pleural effusions
- Frothy urine: due to heavy proteinuria
- Weight gain: fluid retention
Complications
- Thromboembolism: DVT, PE, renal vein thrombosis (5-8%)
- Most common with membranous nephropathy
- Suspect RVT: sudden flank pain, worsening proteinuria, haematuria
- Infection: spontaneous bacterial peritonitis (children), cellulitis, pneumonia
- Encapsulated organisms (pneumococcus) particularly dangerous
- Hyperlipidaemia: raised total cholesterol, LDL, triglycerides
- AKI: hypovolaemia, sepsis, bilateral renal vein thrombosis
Red Flags
- Rapidly declining renal function → exclude RPGN or bilateral RVT
- Haematuria with nephrotic syndrome → consider FSGS, MPGN, lupus (not typical MCD)
- Low complement → SLE, MPGN, post-infectious GN
- Adult >60 with nephrotic syndrome → malignancy screening (especially membranous)
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Nephritic syndrome | Haematuria, oliguria, hypertension, modest proteinuria | Urine microscopy, immunology |
| Heart failure | Raised JVP, S3, BNP elevated | BNP, echocardiogram |
| Liver cirrhosis | Ascites, spider naevi, low albumin from hepatic failure | LFTs, liver USS |
| Protein-losing enteropathy | Diarrhoea, oedema, low albumin | Faecal alpha-1 antitrypsin |
| Kwashiorkor | Malnutrition, oedema, depigmented hair | Nutritional assessment |
Diagnosis / Investigation
Bedside
- Urinalysis: 3-4+ protein, assess for blood
- Blood pressure: may be normal or elevated
- Daily weight: monitor fluid status
- Fluid balance: strict input/output
Bloods
- Urine PCR or 24h urine protein: >350 mg/mmol or >3.5 g/day
- Serum albumin: <25 g/L
- Lipid profile: raised cholesterol, triglycerides
- U&Es: renal function
- FBC: haemoconcentration (raised Hb/Hct)
- Immunoglobulins: low IgG
- C3/C4: low in MPGN, lupus; normal in MCD, FSGS, membranous
- ANA, dsDNA: lupus screen
- Anti-PLA2R: membranous nephropathy
- HbA1c: diabetes
- Hepatitis B/C, HIV: infection screen
- Serum/urine electrophoresis: myeloma/amyloid
Imaging
- Renal USS: kidney size, exclude other pathology
- Chest X-ray: pleural effusions
- Renal Doppler: if renal vein thrombosis suspected
Special Tests
- Renal biopsy: mandatory in adults; not routine in typical childhood nephrotic syndrome
Management
Non-pharmacological
- Sodium restriction (<2g/day) and fluid restriction if oedematous
- Dietary protein: adequate but not high-protein diet
- Leg elevation, compression stockings
- Pneumococcal vaccination (loss of IgG)
Pharmacological
Oedema management:
- Loop diuretics: furosemide 40-120mg PO/IV
- Spironolactone 25-100mg as adjunct
- IV albumin 20% (100mL) + IV furosemide: for severe/resistant oedema
Thromboprophylaxis:
- Prophylactic LMWH or warfarin if albumin <20 g/L
- Full anticoagulation if documented VTE
Hyperlipidaemia:
- Statins (atorvastatin 20-80mg): for persistent hyperlipidaemia
Specific treatment:
- Directed by underlying cause (see individual conditions)
- Children: empirical prednisolone for presumed MCD
- Adults: guided by biopsy result
Supportive:
- ACEi/ARB: reduce proteinuria
- Infection prophylaxis: consider prophylactic penicillin V in children
Referral Criteria
- All adults → nephrology for biopsy
- Children not responding to 4 weeks of steroids → paediatric nephrology
- Complications (VTE, AKI, severe infection) → urgent admission
Prognosis
- Depends entirely on underlying cause
- MCD in children: 90-95% remission with steroids; excellent long-term prognosis
- Membranous nephropathy: rule of thirds (remission/stable/progressive)
- FSGS: 50-70% progress to ESRD if untreated
- Diabetic nephropathy: leading cause of ESRD
- Thromboembolic events: major cause of morbidity/mortality in acute phase
- Infection: leading cause of mortality in childhood nephrotic syndrome
Other Relevant Information
Nephrotic vs Nephritic Syndrome
| Feature | Nephrotic | Nephritic |
|---|---|---|
| Proteinuria | >3.5 g/day | <3.5 g/day |
| Haematuria | Usually absent | Present (with casts) |
| Oedema | Severe, generalised | Mild-moderate |
| Blood pressure | Normal or low | Elevated |
| Serum albumin | <25 g/L | Near normal |
| Renal function | Usually preserved | Often impaired |
| Complement | Usually normal | Often low |
Causes by Age Group
| Age Group | Most Common Cause |
|---|---|
| Children (1-12) | Minimal change disease |
| Adolescents/Young adults | FSGS |
| Adults (30-50) | Membranous/FSGS |
| Elderly (>60) | Membranous/amyloid/diabetic |