Nephrotic syndrome is a kidney disorder characterized by excessive urinary protein loss due to damage of the glomerular filtration barrier, resulting in generalized body swelling (oedema). It is defined by severe proteinuria, usually:

• Adults: ≥3.5 g/day of proteinuria

Nephrotic syndrome occurs due to a wide range of glomerular diseases, which may be primary kidney disorders or secondary manifestations of systemic diseases. Persistent glomerular injury can lead to progressive glomerulosclerosis, chronic kidney disease (CKD), and eventually end-stage kidney disease.

The diagnosis and management of nephrotic syndrome require identification of the underlying glomerular pathology. Kidney biopsy is generally required in adults to establish the diagnosis and guide treatment. In children, biopsy is usually reserved for specific situations such as steroid-resistant disease or atypical clinical features.

Epidemiology

Nephrotic syndrome occurs worldwide and affects both children and adults. The causes differ according to age group and geographical region.

In children, minimal change disease is the most common cause and frequently responds well to corticosteroid therapy. In adults, common causes include focal segmental glomerulosclerosis, membranous nephropathy, diabetic kidney disease, and secondary glomerular disorders.

The burden of nephrotic syndrome is significant because prolonged protein loss, immune dysfunction, infections, thrombosis, and progressive kidney damage contribute to morbidity and mortality.

Risk Factors

Common risk factors include:

• Primary glomerular diseases.

• Diabetes mellitus.

• Systemic lupus erythematosus (SLE).

• Chronic infections including hepatitis B, hepatitis C, and HIV.

• Hypertension.

• Obesity.

• Family history of kidney disease.

• Certain medications causing kidney injury.

• Malignancies associated with paraneoplastic glomerular disease.

• Autoimmune disorders.

Pathophysiology

The glomerular filtration barrier normally prevents excessive protein loss into urine. Damage to this barrier causes increased permeability, resulting in leakage of large amounts of protein, especially albumin.

Loss of albumin causes:

• Reduced plasma oncotic pressure.

• Movement of fluid from blood vessels into tissues.

• Generalized oedema.

The liver responds by increasing protein synthesis, including lipoproteins, leading to:

• Hyperlipidaemia.

• Increased risk of cardiovascular disease.

Urinary loss of immunoglobulins contributes to increased susceptibility to infections, while urinary loss of anticoagulant proteins such as antithrombin III increases the risk of thrombosis.

Clinical Presentation

Patients may present with:

• Generalized oedema.

• Facial swelling, especially in the morning.

• Lower limb swelling.

• Ascites.

• Weight gain due to fluid retention.

Other clinical features include:

• Heavy proteinuria.

• Hypoalbuminaemia.

• Hyperlipidaemia.

• Fatigue.

• Reduced appetite.

• Frothy urine.

• Increased susceptibility to infections.

Diagnostic Criteria

Diagnosis is based on the presence of:

1. Heavy proteinuria

   • Adults: ≥3.5 g/day.

2. Hypoalbuminaemia

3. Generalized oedema

4. Hyperlipidaemia

Kidney biopsy is usually required in adults to determine the underlying histological pattern.

In children aged 1–18 years:

• Initial treatment with corticosteroids is recommended.

• Kidney biopsy is indicated in:

  • Steroid-resistant nephrotic syndrome.

  • Failure to respond after initial steroid response.

  • Atypical clinical features.

  • Progressive decline in kidney function.

Differential Diagnosis

Conditions that should be considered include:

1. Nephritic syndrome

   • Usually presents with haematuria, hypertension, reduced kidney function, and less severe proteinuria.

2. Diabetic kidney disease

   • Diabetes-associated kidney damage causing albuminuria and progressive CKD.

3. Heart failure

   • Can cause generalized oedema due to fluid retention.

4. Chronic liver disease

   • May cause oedema due to reduced albumin production.

5. Protein-losing enteropathy

   • Gastrointestinal protein loss causing hypoalbuminaemia and oedema.

6. Acute kidney injury

   • May present with fluid retention and reduced kidney function.

7. Hypothyroidism

   • Can cause generalized swelling and mimic oedematous states.

8. Malnutrition

   • Severe protein deficiency causing low serum albumin and oedema.

Investigations

Investigations aim to confirm nephrotic syndrome, assess complications, and identify the underlying cause.

Urine investigations

• Urinalysis.

• Urine protein quantification:

  • Urine protein-creatinine ratio (UPCR).

  • Urine albumin-creatinine ratio (UACR).

• Urine microscopy.

Blood investigations

• Serum albumin.

• Serum creatinine.

• Blood urea nitrogen (BUN).

• Electrolytes.

• Lipid profile.

• Full blood count.

Additional investigations

Depending on clinical suspicion:

• Kidney biopsy with histological examination.

• Autoimmune screening:

  • ANA.

  • Anti-dsDNA.

  • Complement levels.

• Viral screening:

  • Hepatitis B.

  • Hepatitis C.

  • HIV.

Management

Management depends on the underlying glomerular disease and should be individualized according to kidney biopsy findings and specialist assessment.

Main objectives include:

• Reducing proteinuria.

• Controlling oedema.

• Preventing complications.

• Treating the underlying glomerular disorder.

• Preserving kidney function.

Non-pharmacological Treatment

General measures include:

• Provide adequate calories.

• Maintain adequate protein intake:

  • Approximately 1 g/kg/day protein.

• Avoid added salt to reduce fluid retention.

• Monitor body weight and fluid balance.

• Reduce cardiovascular risk factors.

• Avoid nephrotoxic medications.

Pharmacological Treatment

Treatment is guided by the histological pattern identified through kidney biopsy.

Specialist-directed treatment may include:

• Corticosteroids.

• Immunosuppressive therapy.

• Renin-angiotensin system blockade.

• Other targeted therapies.

Histology-Based Treatment of Glomerular Diseases

1. Minimal Change Disease

Children

Steroid-sensitive disease

Initial treatment:

Prednisolone:

• 60 mg/m²/day or

• 2 mg/kg/day (maximum 60 mg/day)

Duration:

• 6 weeks.

If remission occurs by 4 weeks, continue full initial treatment for 6 weeks.

Continuation phase:

Prednisolone:

• 40 mg/m², or

• 1.5 mg/kg on alternate days for 6 weeks.

Then taper gradually over approximately 6 weeks.

Relapsing steroid-sensitive disease

Prednisolone:

• 60 mg/m²/day or

• 2 mg/kg/day (maximum 60 mg/day)

Continue until complete remission for 3 days.

Then:

Prednisolone:

• 40 mg/m² or

• 1.5 mg/kg on alternate days for at least 4 weeks.

Frequent relapse or steroid-dependent disease

Options include:

• Levamisole 2.5 mg/kg orally on alternate days for 12 months.

• Cyclophosphamide 2 mg/kg/day for 10–12 weeks.

• Cyclosporine 4–5 mg/kg/day.

• Tacrolimus 0.1 mg/kg/day.

• Everolimus 0.5–2 mg every 12 hours.

• Sirolimus 1–3 mg every 12 hours.

• Mycophenolate mofetil 1200 mg/m²/day in two divided doses.

• Rituximab 375–1000 mg/m².

Steroid-resistant nephrotic syndrome

Options:

• Mycophenolate mofetil 1200 mg/m²/day in two divided doses.

• Mycophenolate sodium with high-dose prednisolone.

Adults

Prednisolone:

• 1 mg/kg/day orally (maximum 80 mg/day).

Alternative:

• 2 mg/kg on alternate days (maximum 120 mg).

Treatment duration:

• Continue up to 16 weeks if remission is not achieved.

• Slowly taper after remission over 6 months.

Monitor:

• HbA1c monthly.

• Osteoporosis risk.

2. Focal Segmental Glomerulosclerosis (FSGS)

For idiopathic disease:

Prednisolone:

• 1 mg/kg/day (maximum 80 mg), or

• Alternate day dose 2 mg/kg (maximum 120 mg).

Duration:

• 4–16 weeks.

If steroid intolerance or resistance:

• Cyclosporine 3.5–5 mg/kg/day in two divided doses.

• Tacrolimus 0.1 mg/kg/day in two divided doses.

Exclude secondary causes before treatment.

3. Membranous Nephropathy

Treatment applies mainly to idiopathic disease.

Children

Alternating monthly regimen:

Months 1, 3, and 5:

Methylprednisolone:

• 10 mg/kg/day intravenously for 3 days.

Then:

Prednisolone:

• 0.5 mg/kg/day for 27 days.

Months 2, 4, and 6:

Cyclophosphamide:

• 2 mg/kg/day for 30 days.

Alternative regimens:

• Cyclosporine 3.5–5 mg/kg/day with prednisolone.

• Tacrolimus 0.2 mg/kg/day in two divided doses.

Adults

Options:

• Cyclophosphamide with prednisolone.

• Monthly intravenous methylprednisolone.

Alternative:

• Tacrolimus 0.1 mg/kg/day for 6 months.

• Cyclosporine 3.5–5 mg/kg/day.

If albumin <25 g/L with thrombosis risk:

• Warfarin according to DVT anticoagulation guidelines.

4. Membranoproliferative Glomerulonephritis (MPGN)

Treatment depends on the underlying cause, severity of kidney involvement, and histological findings.

Management options include:

• Cyclophosphamide.

• Mycophenolate mofetil 1200 mg/m²/day in two divided doses.

• Mycophenolate sodium.

These may be combined with:

• Prednisolone.

Patients should undergo evaluation for secondary causes, including:

• Chronic infections.

• Autoimmune diseases.

• Complement disorders.

5. Immunoglobulin A (IgA) Nephropathy

Management focuses on reducing proteinuria, controlling blood pressure, and treating progressive disease.

Initial supportive treatment (3–6 months)

For persistent proteinuria:

• Enalapril 10–20 mg orally once daily.

OR

• Lisinopril 2.5–10 mg orally once daily.

Other registered ACE inhibitors or angiotensin receptor blockers may be used according to hypertension management guidelines.

Patients with persistent proteinuria:

• Proteinuria ≥1 g/day for 6 months despite supportive therapy.

May receive:

• Prednisolone 1 mg/kg/day orally for 6 months.

Treatment decisions should consider:

• Kidney function.

• Risk of progression.

• Histological findings.

6. Lupus Nephritis

Lupus nephritis is a kidney manifestation of systemic lupus erythematosus requiring specialist management.

General treatment

All patients:

• Hydroxychloroquine 6 mg/kg/day orally as maintenance therapy.

Treatment depends on histological class.

Class II Lupus Nephritis

For patients with proteinuria >3 g/day:

Treat as minimal change disease using corticosteroid-based therapy.

Class III and Class IV Lupus Nephritis

Initial treatment (first 6 months)

Methylprednisolone:

• 250–1000 mg intravenously over 30 minutes for 3 days monthly.

Plus one of:

Cyclophosphamide:

• 500–1000 mg/m² intravenously monthly.

OR

Mycophenolate mofetil:

• 500 mg–1 g orally every 12 hours, increasing to 1.5 g every 12 hours if tolerated.

OR

Mycophenolate sodium.

Maintenance therapy

Options include:

• Azathioprine 1.5–2.5 mg/kg/day.

• Mycophenolate mofetil 500 mg–1 g every 12 hours.

• Mycophenolate sodium.

• Cyclosporine 4–5 mg/kg/day.

• Tacrolimus 0.1 mg/kg/day.

Duration and choice depend on response, tolerance, and specialist assessment.

Alternative shorter EURO-Lupus cyclophosphamide regimen

Cyclophosphamide:

• 500 mg intravenously every 2 weeks for 6 doses.

Class V Lupus Nephritis

For persistent nephrotic-range proteinuria:

Management is similar to Class II and Class IV lupus nephritis depending on clinical severity.

7. Pauci-Immune Focal and Segmental Necrotizing Glomerulonephritis

This group commonly includes ANCA-associated vasculitis and requires urgent specialist management.

Initial induction therapy

Cyclophosphamide:

Option 1:

• 15 mg/kg intravenously every 2 weeks for 3 doses, then every 3 weeks for 3–6 months.

OR

Option 2:

• 1.5–2 mg/kg/day orally for 3–6 months.

Plus:

Methylprednisolone:

• 250–1000 mg intravenously over 30 minutes for 3 days as induction therapy.

Then:

Prednisolone:

• 1 mg/kg/day initially.

• Reduce to 30 mg within one week.

• Gradually taper to 5 mg by 4–6 months.

Severe disease

Rituximab:

Option 1:

• 1 g intravenously followed by another 1 g after 14 days.

OR

Option 2:

• 375 mg/m² weekly for 4 weeks.

Plus:

Methylprednisolone:

• 250–1000 mg intravenously over 30 minutes for 3 days.

Then:

Prednisolone:

• 1 mg/kg/day initially.

• Taper gradually as above.

Maintenance therapy

Options include:

• Azathioprine 1–2 mg/kg/day for 18 months.

OR

• Mycophenolate mofetil 1 g every 12 hours.

OR

• Mycophenolate sodium.

Special interventions

In selected severe cases:

• Haemodialysis.

• Plasmapheresis.

may be required.

Referral

All patients with suspected nephrotic syndrome should be referred to a nephrologist, especially:

• Adults requiring kidney biopsy.

• Children with steroid-resistant nephrotic syndrome.

• Patients with declining kidney function.

• Persistent nephrotic-range proteinuria.

• Suspected secondary glomerular disease.

• Patients requiring immunosuppressive therapy.

Referral is essential because treatment depends on histological diagnosis and specialist interpretation.

Complications

Potential complications include:

Thromboembolic complications

Due to urinary loss of anticoagulant proteins:

• Deep vein thrombosis.

• Pulmonary embolism.

• Renal vein thrombosis.

Infectious complications

Due to loss of immunoglobulins:

• Bacterial infections.

• Severe infections.

Metabolic complications

• Hyperlipidaemia.

• Malnutrition.

• Vitamin D deficiency.

Kidney complications

• Acute kidney injury.

• Chronic kidney disease.

• End-stage kidney disease.

Treatment-related complications

Due to immunosuppression:

• Opportunistic infections.

• Bone complications.

• Metabolic abnormalities.

Prognosis

The prognosis depends on:

• Underlying histological diagnosis.

• Degree of proteinuria.

• Kidney function at diagnosis.

• Response to therapy.

• Presence of complications.

Children with minimal change disease generally have a favorable prognosis with steroid therapy. However, patients with focal segmental glomerulosclerosis, membranous nephropathy, lupus nephritis, or pauci-immune glomerulonephritis may progress to chronic kidney disease without appropriate treatment.

Early diagnosis, specialist management, and monitoring improve long-term kidney outcomes.

Prevention

Preventive strategies include:

• Early diagnosis of kidney disease.

• Control of diabetes and hypertension.

• Prompt treatment of infections.

• Avoidance of nephrotoxic medications.

• Regular monitoring of kidney function and urine protein levels.

• Early referral for suspected glomerular disease.

• Patient education on medication adherence and follow-up.