Ben Reynolds. Nephrotic syndrome, Don't Forget the Bubbles, 2013. Available at:
Ella is a 3-year-old girl, who presents with bilateral lower leg oedema and facial puffiness. Dipstick of her urine shows 3-4+ of protein. Her BP is normal.
- Nephrotic syndrome should be referred to tertiary nephrology if:
- It’s not steroid response
- The patient is hypertensive
- There is derranged renal function
- There is significant PERSISTENT microscopic haematuria, or any macroscopic haematuria
- It’s an atypical presentation e.g. teenage girl
- Steroid treatment is immunosuppressant, and patients should be managed accordingly
- Major complications are thrombosis, immunosuppression, and dehydration
- Peritonitis is rare, but important.
What is nephrotic syndrome?
Traditionally a triad of proteinuria, hypoalbuminaemia, and oedema. Loss of albumin in the urine leads to low serum albumin, which drops oncotic pressure, and hence the formation of peripheral oedema. In fact, it’s much more complicated than that, but that is a simple view! Nephrotic syndrome is one of the commonest kidney diseases of childhood, affecting 2-7/100,000.
What causes it?
Who knows? There are various genetic mutations that predispose to the development of nephrotic syndrome, most affecting podocyte function. It is often triggered by viral illness, particularly relapses of established nephrotic syndrome.
Who gets it?
1-10 year olds, Asian>Caucasian>Afro-Caribbean.
Development of nephrotic syndrome in infancy suggests congenital nephrotic – was there a big placenta?
Development in teenage girls demands exclusion of Frasier syndrome; karyotype should be checked.
What does it look like?
Children can be massively oedematous. Common sites are peri-orbital, pedal/shins, sacral oedema, and scrotal/penile oedema. Labial oedema can occur in girls. Abdominal ascites can be significant.
Referrals may include children with ‘hayfever’ (persistent peri-orbital/facial oedema) or with lymphoedema – does inguinal lymphoedema actually originate from the ankles?
Assessment of fluid status is difficult! Oedematous children may still be intravascularly dry, and approaching shock – check cap refill, peripheral warmth, pulses, conscious state.
Investigations for first presentation
BP – are they hypertensive? Refer to nephrology if so
Urinalysis – at presentation there should be at least 3+ of protein (though beware the very dilute urine)
Urinary electrolytes, protein:creatinine ratio, osmolality – urinary Na may give an indication of intravascular state, though this is challenged!
U+Es – normal renal function? If not, refer
Varicella zoster immune status – in case of subsequent exposures
FBC – are they dry/haemo-concentrated?
Some authorities recommend checking C3/C4 at initial presentation, others only if there are atypical features or no steroid response. If checked and abnormal, the child should be referred.
- Fluid resuscitation if intravascularly depleted.
- Oral prednisolone 60mg/m2 for 4-6 weeks then 40mg/m2 alternate days for 6 weeks up to 5 months. Various regimes differ, but the risk of relapse appears to be lessened with a longer course of steroids at first presentation. Alternate day steroids have less impact on subsequent growth.
- 80% of paediatric nephrotic syndrome will be steroid-responsive. Steroid resistance is a failure to remit after eight weeks of high-dose steroid.
- Gastro-protection – rantidine during steroid therapy.
- Penicillin V prophylaxis – not recommended by all, against spontaneous bacterial peritonitis. Risk:benefit probably in favour of pen V, especially if there is significant ascites, younger age, or previous infection.
- Low salt diet is vital to prevent accumulation of fluid.
- Anti-coagulation – subcutaneous tinzaparin is used by some centres as nephrotic patients are pro-thrombotic, but only indicated if mobility also affected, or previous history of thrombosis. Thrombosis complicates ~3% of childhood nephrotic syndrome.
- The indications and usage of IV albumin remain contentious. Some authorities suggest IV albumin can cause more harm than good, though there is a notable absence of any really good studies, and the last study of any significance was in the early 1990s! Certainly, it has no role in inducing remission, and is used to prevent complications arising from severe oedema. Low serum albumin alone is NOT an indication. Significant hypovolaemia, or oedema causing actual skin breakdown or clinical distress are indications. Beware pulmonary oedema – this can cause mortality in nephrotic children! Hypertension is a common side-effect of albumin administration, and may persist, requiring anti-hypertensives. Detection of hypovolaemia can be tricky in the oedematous child. Be guided by urinary osmolality and fractional excretion of sodium – though also be wary that these may be affected by the disease process itself.
- Furosemide 2mg/kg should be given half way through the infusion, which is 5ml/kg of 20% albumin.
- Nephrotic steroid treatment is immunosuppressive. Contact with varicella needs prophylaxis/treatment. Live immunisations are contra-indicated during treatment. Influenza vaccination should be considered during winter.
The end is in sight…
Remission is 3 days of dipstick-negative urine for protein. Pen V and the low salt diet can stop. If there is no remission at 28 days, nephrology referral is indicated.
Relapse = 3+ of protein on dipstick for 3 days (or 2+ for 7 days). Treatment is 60mg/m2 until protein clears, then 40mg/m2 for 4 weeks. Frequent relapsers (>2 in 6 months, or >4/year) should be referred.
What’s the prognosis?
Minimal change disease generally has a good prognosis, and the majority of children will eventually ‘grow out of it’ – though not as many as previously thought.
Long-term studies have suggested complete resolution of relapses in 44% at one year increasing to 84% at 10 years. There continues to be a cohort of patients with minimal change childhood-onset nephrotic syndrome with ongoing relapses in adulthood. Risk factors for ongoing relapses include frequent relapsing and steroid dependence, plus the need for additional immunosuppression to control relapses. Even in adult relapsers, overall morbidity is not particularly high.
Steroid responsiveness also influences prognosis in focal segmental GS. Steroid responding FSGS has a risk of end-stage renal impairment of 15%, compared to 60% lifetime risk for children with steroid resistant FSGS.
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