Steroid-Sensitive Nephrotic Syndrome

Steroid sensitive nephrotic syndrome is nephrotic syndrome (heavy proteinuria, hypoalbuminaemia, oedema and hyperlipidaemia) that remits within 4 to 6 weeks of daily corticosteroid therapy. Minimal change disease is the cause in about 85 to 90% of children who respond.

The incidence is about 2 in 100 000 children each year, and higher in children of South Asian descent. The peak age is 2 to 8 years, with boys affected more often. Most children relapse, and about half have frequent relapses or steroid dependence.

Definitions: nephrotic range proteinuria (urine protein to creatinine ratio over 200 mg/mmol or over 2 mg/mg), serum albumin under 25 g/L, and oedema. Relapse is a urine protein to creatinine ratio over 200 mg/mmol (or 3+ on dipstick) for 3 consecutive days.

Frequent relapse is 2 or more relapses within 6 months of the first episode, or 3 or more in any 12 months. Steroid dependence is 2 consecutive relapses during tapering or within 2 weeks of stopping.

Pathophysiology.

Podocyte injury, possibly from circulating factors or T-cell and B-cell dysregulation, causes foot process effacement and loss of the glomerular filtration barrier to albumin.

Hypoalbuminaemia lowers oncotic pressure, and sodium retention by the kidney causes oedema. Loss of immunoglobulins and clotting regulators, and a rise in hepatic synthesis, cause infection, hyperlipidaemia and thrombosis.

• Periorbital oedema, often mistaken for allergy, then leg, scrotal or labial oedema, ascites, pleural effusions and weight gain.
• Frothy urine, reduced urine output, fatigue, anorexia and abdominal pain.
• Complications: peritonitis, cellulitis, hypovolaemia (abdominal pain, tachycardia, cool peripheries), thrombosis, and acute kidney injury.

Red flags.

• Age under 12 months or over 12 years, macroscopic haematuria, hypertension, impaired kidney function or low C3, suggesting a non-minimal change cause.
• Hypovolaemic shock, peritonitis, severe headache, or limb swelling (venous thrombosis).
• Extrarenal features such as rash, arthritis or a family history of nephrotic syndrome.

• Urine dipstick and protein to creatinine ratio (first morning sample), serum albumin, urea, creatinine and electrolytes, cholesterol, and full blood count.
• Complement C3 and C4, hepatitis B and C and HIV where relevant, varicella antibody, and tuberculosis screening before prolonged immunosuppression.
• Renal biopsy is not needed at presentation in a typical child aged 1 to 12 years. It is done when there are atypical features or steroid resistance.

Differential diagnosis. Steroid resistant nephrotic syndrome, post-infectious glomerulonephritis, IgA vasculitis, lupus nephritis, congenital nephrotic syndrome, protein losing enteropathy, heart failure and liver failure.

Initial episode.

• Prednisolone 60 mg/m2 daily (maximum 80 mg) as a single morning dose until remission (urine protein negative or trace for 3 consecutive days), usually within 4 weeks, and then 40 mg/m2 on alternate days for 4 to 6 weeks, followed by a taper or stop.
• Oedema: moderate dietary salt restriction and no fluid restriction unless hyponatraemia. For severe oedema or anasarca: furosemide 1 mg/kg IV, with 20% albumin 0.5 to 1 g/kg over 4 hours, watching for hypertension and pulmonary oedema. Treat hypovolaemia with 0.9% sodium chloride or albumin.
• Penicillin prophylaxis is optional during relapse. Treat peritonitis and cellulitis with IV antibiotics.
• Thromboprophylaxis with early mobilisation and avoidance of dehydration. Anticoagulate for confirmed thrombosis.
• Vaccinate with pneumococcal vaccines, and give varicella zoster immunoglobulin to non-immune children exposed to varicella during immunosuppression. Delay live vaccines until prednisolone is under 1 mg/kg daily (or 20 mg daily).
• Provide calcium and vitamin D, and monitor blood pressure, growth and eyes for steroid toxicity.

Relapse.

• Prednisolone 60 mg/m2 daily until urine is negative or trace for 3 days, then 40 mg/m2 on alternate days for 4 weeks.
• Parents test urine daily by dipstick at home and begin treatment on early relapse.

Frequent relapse or steroid dependence (steroid sparing agents).

• Low dose alternate day or daily prednisolone for a time, or levamisole 2.5 mg/kg on alternate days.
• Mycophenolate mofetil 1200 mg/m2/day in 2 doses.
• Cyclophosphamide 2 to 3 mg/kg daily for 8 to 12 weeks (maximum cumulative dose 168 mg/kg), with counselling on gonadal toxicity.
• Ciclosporin 3 to 5 mg/kg/day in 2 divided doses (trough 80 to 120 ng/mL) or tacrolimus 0.1 to 0.2 mg/kg/day, with monitoring of kidney function and blood pressure.
• Rituximab 375 mg/m2 IV, 1 to 4 weekly doses, for dependent disease with failure of other agents.

Monitoring. Weight, blood pressure, urine protein, growth and steroid effects. Frequent review in the first 6 months.

Referral and escalation. Refer to a paediatric nephrologist for age under 12 months or over 12 years, atypical features, steroid resistance, frequent relapse or complications.