Nephrotic syndrome in children

Overview

Nephrotic syndrome (NS) is the most common kidney disease of childhood in Akbar's account. The glomerular filter becomes leaky to protein, albumin pours into the urine and the child swells. Most young children have minimal change disease (MCNS), which responds to steroids and rarely damages the kidneys, but the illness tends to relapse for years. The main dangers are infection, thrombosis, low circulating volume and the side effects of long steroid courses.

Definition

NS is the combination of:

Normal protein loss is under 4 mg/m²/hour, with a spot ratio under 0.2. Values between 0.2 and 2 are raised but not nephrotic.

Classification

By cause

• Primary (idiopathic): no outside cause; about 90% of childhood NS.
• Secondary: due to a systemic disease, infection, cancer or drug (see table below).
• Congenital and infantile: onset in the first year (see later).

By age of onset (Akbar)

By histology (primary NS)

By response to steroid

Pathophysiology

• The glomerular wall (endothelium, basement membrane, podocytes) normally carries a negative charge that repels albumin. In MCNS this charge is lost, so albumin leaks: selective proteinuria (mainly albumin). In other lesions larger globulins also leak.
• A T-cell disorder is thought to release a factor that raises glomerular permeability; NS often follows a viral respiratory infection.
• Oedema:
  • Underfill idea (fits MCNS): low albumin lowers plasma oncotic pressure, fluid moves into tissues, blood volume falls, and renin-angiotensin-aldosterone and ADH are switched on, so salt and water are retained.
  • Overfill idea (other lesions): the kidney itself holds on to salt and water and the circulation is expanded.
• High lipids: low albumin makes the liver produce more lipoprotein and their breakdown falls.
• Clotting tendency: urine loss of antithrombin III, plus raised clotting factors, raised platelets, haemoconcentration, steroids and diuretics.
• Infection risk: urine loss of immunoglobulin and complement, plus steroids.

Clinical features

• Typical child: boy aged 2 to 6, often after a flu-like illness.
• Puffy eyes in the morning that spread over days to generalised oedema (anasarca): ascites, pleural effusion, scrotal or labial swelling, pitting leg oedema.
• Reduced urine output, mild abdominal pain, poor appetite, tiredness; diarrhoea from gut wall oedema; breathlessness with large effusions or ascites.
• Blood pressure is usually normal or low normal; Nelson notes it can be raised in up to a quarter at presentation.
• A child can present with a complication (peritonitis, thrombosis, shock).

Typical MCNS versus atypical features

Investigations

Management

General measures

• Most children can be treated as outpatients; counsel parents about the long, relapsing course, steroid side effects and home testing.
• Diet: no added salt (under about 2 g/day while oedematous); generous protein (Akbar suggests 130 to 140% of the recommended amount); limit saturated fat.
• Home urine testing: dip the first morning urine daily and keep a diary to catch relapse early.
• Diuretics are not routine: careless use can cause shock, AKI and thrombosis. Use cautiously only for severe anasarca with breathing difficulty or tense scrotal skin.
• Albumin infusion for severe oedema: salt-poor 20 to 25% albumin about 0.5 to 1 g/kg over 1 to 2 hours with intravenous furosemide. Its effect is brief because the albumin is soon lost in the urine.

Steroid course for the first episode

Over 90% of responders do so within 4 weeks (Nelson).

Treating a relapse

• Prednisolone 2 mg/kg/day (60 mg/m²) daily until the dipstick has been negative for 3 days, then 1.5 mg/kg (40 mg/m²) on alternate days for 4 weeks, then stop.
• Most relapses follow viral respiratory infections. If a child already on alternate-day steroid relapses with a cold, giving the same dose daily for a week may restore remission.

Frequent relapses and steroid dependence

• Keep the lowest alternate-day prednisolone that holds remission, or add a steroid-sparing drug:

Steroid-resistant NS

• Renal biopsy before further treatment: usually FSGS (about 80%), then mesangioproliferative GN, MCNS and MPGN.
• Calcineurin inhibitors are the first choice; mycophenolate helps some.
• ACE inhibitors or ARBs reduce proteinuria; control blood pressure tightly.
• About half progress to end-stage kidney disease within 5 years (Akbar).

Steroid side effects to watch

Cushingoid look and weight gain, hypertension, short stature, behaviour change, infection, gastritis, osteoporosis, posterior subcapsular cataract, raised glucose, raised intracranial pressure, proximal myopathy and adrenal suppression.

Complications

Immunisation

• Pneumococcal vaccine and yearly influenza vaccine are advised (influenza also for household contacts).
• Live vaccines are deferred until prednisolone is below 1 mg/kg daily (or 2 mg/kg on alternate days); they are contraindicated on cyclophosphamide or ciclosporin.
• After close contact with chickenpox, give varicella-zoster immune globulin.

Secondary nephrotic syndrome

These usually present with atypical features. Treat the cause and stop any suspected drug.

Congenital and infantile nephrotic syndrome

• Congenital NS: onset at birth or within 3 months (Nelson: first 2 months). The Finnish type is autosomal recessive, due to a mutation in nephrin, a protein of the filtration slit.
• Clues: massive oedema at birth, a large placenta (over a quarter of birth weight), raised maternal and amniotic alpha-fetoprotein antenatally.
• Problems: severe hypoalbuminaemia, infections (low immunoglobulin), hypothyroidism from urine loss of thyroxine-binding globulin (so thyroxine is given), thrombosis, poor growth.
• Not steroid responsive. Treat with albumin, diuretics, nutrition, ACE inhibitors, ARBs or prostaglandin synthesis inhibitors to cut protein loss, then nephrectomy, dialysis and transplantation (the definitive treatment).
• Secondary congenital NS follows congenital infections (syphilis, CMV, toxoplasmosis) and is treated by treating the cause.
• Infantile NS (3 to 12 months) is mostly steroid resistant: biopsy first.

Prognosis

• Most children eventually go into lasting remission; relapses become less frequent with age.
• Nearly 80% of MCNS cases relapse at least once (Nelson).
• Children who respond quickly and have no relapse in the first 6 months tend to follow an infrequently relapsing course.
• Steroid-sensitive NS rarely causes chronic kidney disease; steroid-resistant NS (especially FSGS) carries a poor kidney outlook.

Quick revision

• Proteinuria above 40 mg/m²/hour, low albumin, oedema, high cholesterol.
• MCNS: boys 2 to 6 years; normal light microscopy; foot-process fusion on EM; selective albuminuria; normal C3.
• Typical case: steroid without biopsy; biopsy if atypical, under 1 or over 12 years, or steroid resistant.
• Prednisolone 2 mg/kg/day (maximum 60 mg) daily, then 1.5 mg/kg alternate days; total at least 12 weeks.
• Relapse: 2+ protein for 3 days; frequent relapser: 4 or more a year; dependent: relapse within 2 weeks of stopping.
• Steroid sparing: levamisole, cyclophosphamide, calcineurin inhibitors, mycophenolate, rituximab.
• SRNS: FSGS mostly; calcineurin inhibitors, ACE inhibitors; poor outlook.
• Complications: pneumococcal peritonitis, thrombosis (antithrombin III loss), hypovolaemia, steroid toxicity.
• Congenital Finnish type: nephrin, autosomal recessive, large placenta, high alpha-fetoprotein, transplant.

Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).

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