Primary Nephrotic Syndrome

Primary nephrotic syndrome is a glomerular disease with heavy proteinuria, hypoalbuminaemia and oedema, in which no systemic cause can be found. Proteinuria is above 3.5 g daily (urine protein:creatinine ratio above 300 mg/mmol; in children above 40 mg/m² each hour or ratio above 200 mg/mmol). Serum albumin is under 30 g/L, with oedema and usually hyperlipidaemia.

The main histological causes are:

• Minimal change disease: about 90% of children under 10 years, about 15 to 25% of adults.
• Focal segmental glomerulosclerosis: about 20 to 35% of adults; higher in people of African ancestry with APOL1 risk alleles.
• Primary membranous nephropathy: about 30% of adults, the commonest cause in adults over 40 in many settings.
• Membranoproliferative or mesangial proliferative disease.

Annual incidence is about 2 to 7 cases in each 100 000 children and about 3 in each 100 000 adults.

Pathophysiology. Injury to the podocyte and glomerular filtration barrier causes massive albuminuria. The injury may come from circulating permeability factors, autoantibodies against the phospholipase A2 receptor, genetic podocyte defects, or immune complexes.

Hypoalbuminaemia, sodium retention through tubular sodium channel activation, and a raised hepatic synthesis of lipoproteins and clotting factors explain the clinical features.

• Oedema (periorbital, then generalised with ascites, pleural effusions and scrotal or labial swelling); frothy urine; weight gain; fatigue.
• Hypoalbuminaemia, hyperlipidaemia (total cholesterol often above 8 mmol/L), lipiduria.
• Blood pressure normal or raised; haematuria is uncommon in minimal change disease and common in focal segmental glomerulosclerosis and membranoproliferative disease.
• Complications: venous and arterial thrombosis (renal vein thrombosis, pulmonary embolism), infection (peritonitis, cellulitis, pneumococcal sepsis), acute kidney injury (from hypovolaemia, tubular injury or renal vein thrombosis), protein malnutrition, vitamin D deficiency, hypothyroidism from urinary loss of thyroid binding globulin.

Red flags

• Flank pain with haematuria and a rise in creatinine: renal vein thrombosis.
• Pleuritic chest pain or dyspnoea: pulmonary embolism.
• Fever with abdominal pain (spontaneous bacterial peritonitis) or erysipelas like skin changes.
• Hypovolaemic shock with oliguria (intravascular depletion, especially in minimal change disease).
• Albumin under 20 g/L, particularly in membranous nephropathy (under 25 g/L).
• Age over 50 with membranous nephropathy: occult malignancy.

• Urine protein:creatinine ratio (or albumin:creatinine ratio), 24-hour urine collection when the ratio is unreliable, urine microscopy, albumin, creatinine, eGFR, lipid profile, glucose or HbA1c, liver tests, full blood count, thyroid function.
• Complement C3 and C4, antinuclear antibodies, anti-dsDNA, hepatitis B and C, HIV, syphilis, serum protein electrophoresis with free light chains (adults over 40).
• Anti-phospholipase A2 receptor antibody is positive in about 70 to 80% of primary membranous nephropathy. A positive result in the right context can allow a diagnosis without biopsy.
• Children under 10 with typical features: empirical steroid treatment without biopsy. Biopsy if age over 10, haematuria, hypertension, low C3, impaired function or steroid resistance.
• Adults: kidney biopsy before treatment (unless the anti-phospholipase A2 receptor result is positive and function is normal).
• Minimal change disease: normal glomeruli on light microscopy, no immune deposits, diffuse podocyte foot process effacement on electron microscopy.
• Focal segmental glomerulosclerosis: segmental sclerosis with podocyte injury.
• Membranous nephropathy: thickened capillary walls, subepithelial deposits with spikes, granular IgG and C3.
• Genetic testing in steroid resistant children, familial disease and adults with early onset disease (NPHS1, NPHS2, WT1, COL4A, APOL1).
• Age appropriate cancer screening in adults over 50 with membranous nephropathy, especially when anti-phospholipase A2 receptor antibody is negative.

Differential diagnosis

• Secondary causes (diabetic kidney disease, lupus, amyloid, hepatitis B and C, HIV, malaria, drugs such as NSAIDs, lithium, interferon and pamidronate, malignancy), IgA nephropathy, C3 glomerulopathy, Alport syndrome, hereditary podocytopathy, and non-glomerular causes of oedema (heart failure, cirrhosis, protein losing enteropathy).

General measures (all patients)

• Sodium restriction under 2 g daily. Fluid restriction only for refractory oedema with hyponatraemia (1 to 1.5 litres daily).
• Loop diuretic: furosemide 40 to 80 mg orally once or twice daily (increase to 120 mg twice daily if resistant).
• For resistant oedema add metolazone 2.5 to 5 mg daily or spironolactone 25 to 50 mg daily. For severe oedema use intravenous furosemide 40 to 120 mg bolus or infusion 5 to 20 mg each hour.
• Weight loss target 0.5 to 1 kg daily. Avoid over diuresis (creatinine rise, hypotension).
• Albumin infusion (20% albumin 100 mL with furosemide 40 mg) only for severe symptomatic hypovolaemia or refractory oedema with albumin under 20 g/L.
• ACE inhibitor: ramipril 2.5 mg daily increased to 10 mg daily; blood pressure below 130/80 mmHg. Check creatinine and potassium at 1 to 2 weeks, accept a rise up to 30%, and stop if potassium exceeds 6.0 mmol/L.
• SGLT2 inhibitor in adults with persistent proteinuria: dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20).
• Statin when hyperlipidaemia persists beyond remission or in adults at risk: atorvastatin 20 mg daily (up to 80 mg).
• Anticoagulation: prophylactic enoxaparin 40 mg subcutaneously daily (20 mg when eGFR is under 30), or warfarin to INR 2 to 3. Use for adults with albumin under 20 g/L (under 25 g/L in membranous nephropathy) plus another risk factor (proteinuria above 10 g daily, immobility, obesity, previous thrombosis, heart failure), provided bleeding risk is low.
• Treat established thrombosis with full dose anticoagulation for at least 6 months and until remission.
• Infection: pneumococcal and influenza vaccination; consider penicillin V 250 mg twice daily prophylaxis in children with relapses and oedema; treat infections promptly.
• Bone health: cholecalciferol 800 to 2000 units daily; calcium intake 1000 mg daily; check vitamin D in prolonged disease.
• Avoid NSAIDs, nephrotoxins and live vaccines during high dose immunosuppression.

Minimal change disease

• Children: prednisolone 60 mg/m² daily (maximum 60 mg) in divided or single doses for 4 to 6 weeks, then 40 mg/m² on alternate days for 4 to 6 weeks, then taper over 2 to 4 months. About 90% remit within 4 weeks; 60 to 70% relapse.
• Adults: prednisolone 1 mg/kg daily (maximum 80 mg) until remission (median about 3 to 4 weeks, up to 16 weeks), then taper over 24 weeks. Add a proton pump inhibitor and monitor glucose and blood pressure.
• Frequently relapsing or steroid dependent disease (2 or more relapses within 6 months): cyclophosphamide 2 mg/kg orally daily for 8 to 12 weeks (maximum cumulative 168 mg/kg), mycophenolate mofetil 1 g twice daily for 12 to 24 months, or tacrolimus 0.05 to 0.1 mg/kg daily in two divided doses (trough 5 to 8 ng/mL).
• Rituximab 375 mg/m² weekly for 2 to 4 doses, or 1 g on days 1 and 15, is effective at preserving remission.
• In children, levamisole 2.5 mg/kg on alternate days is an option.

Focal segmental glomerulosclerosis (primary)

• Prednisolone 1 mg/kg daily (maximum 80 mg) for 4 to 6 weeks (continue to 16 weeks if partial response), then taper over 6 months.
• Steroid resistant disease: tacrolimus 0.05 to 0.1 mg/kg daily in divided doses (trough 5 to 8 ng/mL) or ciclosporin 3 to 5 mg/kg daily in divided doses (trough 100 to 175 ng/mL) for at least 6 months, with prednisolone 10 to 20 mg daily initially. Stop if no response by 6 months.
• Genetic and APOL1 disease respond poorly; use renoprotection only.

Primary membranous nephropathy

• Low risk (proteinuria under 3.5 g daily, albumin over 30 g/L, normal eGFR): supportive treatment alone for 6 months.
• Moderate and high risk (nephrotic, persistent proteinuria above 4 g daily after 6 months of supportive care, declining eGFR): rituximab 1 g on days 1 and 15 (repeat at 6 months if response is partial), or tacrolimus 0.05 mg/kg daily in divided doses (trough 5 to 8 ng/mL) for 12 months.
• The alternative is cyclophosphamide with steroids for 6 months. Give methylprednisolone 1 g intravenously daily on days 1 to 3, then prednisolone 0.5 mg/kg daily for 27 days in months 1, 3 and 5. Give cyclophosphamide 2.5 mg/kg daily in months 2, 4 and 6 (2 mg/kg if age over 60).
• Monitor anti-phospholipase A2 receptor antibody titre every 3 months; immunological remission precedes clinical remission by months.

Membranoproliferative and mesangial disease. Treat the cause. Primary (immune complex) disease: prednisolone 0.5 to 1 mg/kg daily with mycophenolate mofetil 1 g twice daily or rituximab, with specialist input.

Steroid resistance. No remission after 4 weeks (children) or 16 weeks (adults) of adequate prednisolone. Re-biopsy and arrange genetic testing, and add a calcineurin inhibitor. For children, consider ciclosporin 150 mg/m² daily in two doses with trough 80 to 120 ng/mL.

Prophylaxis during immunosuppression. Co-trimoxazole 480 mg daily (or atovaquone 1500 mg daily if sulphonamide allergy) when on prednisolone 20 mg or more for 4 weeks or with other immunosuppression; hepatitis B screening before rituximab; proton pump inhibitor; vaccination; bone protection.

Monitoring. Weekly weight, urine dipstick (children at home), albumin and creatinine at 2 weeks, then every 4 to 8 weeks; proteinuria monthly until remission, then every 3 months. Relapse is 3 days of 3+ proteinuria (children) or urine protein:creatinine ratio above 100 mg/mmol.

Referral and escalation. Nephrology for all adults, and for children with atypical features, steroid resistance, frequent relapses, infection, or thrombosis. Urgent: suspected venous thrombosis, hypovolaemic shock, peritonitis, acute kidney injury.

Special groups

• Children: the usual cause is minimal change; start steroids without biopsy at age 1 to 10 years; check for infections that trigger relapses.
• Pregnancy: stop ACE inhibitors and mycophenolate before conception; plan pregnancy in remission; low dose aspirin 75 to 150 mg from 12 weeks; the risk of thrombosis and pre-eclampsia is higher.
• Older adults: investigate for malignancy; use reduced steroid doses and calcineurin inhibitor dose adjustments.
• Sub-Saharan Africa: APOL1 associated focal segmental glomerulosclerosis and HIV associated nephropathy are frequent; test for HIV, hepatitis B and C, malaria and schistosomiasis before immunosuppression.