Who, when and what…
Nephrotic syndrome is the most common glomerular disorder of childhood, affecting 1-7 children in 100,000 per year. It most typically affects children aged 2- 12 years of age and is characterized by proteinuria, hypoalbuminaemia and oedema.
Why it happens…
The villain of nephrotic syndrome is the glomerular filtration barrier (GFB). If we peer back at our textbooks, we remember the GFB is composed of two cells, the capillary endothelial cells and the podocytes separated by the glomerular basement membrane. The GFB is responsible for the filtration of water and small solutes but the retention of albumin. Defects in this GFB result in increased permeability to albumin and the subsequent proteinuria that defines nephrotic syndrome.
Idiopathic nephrotic syndrome (INS) is the most common cause of nephrotic syndrome in children. The aetiology is unclear however it could be related to circulating factors that, via immune mechanisms, alter the podocyte function and thus the GFB. The underlying histopathology of INS is minimal change disease (MCD) and less frequently focal segmental glomerulosclerosis (FSGS) which carries a poorer prognosis.
Other, less common causes include genetic mutations (with up to 50 genes affecting various components of the GFB identified to date), membranous glomerulopathy and glomerulonephritis (such as systemic lupus erythematous).
How it presents…
Children often present with a history of intermittent periorbital or pedal oedema. It is not commonly diagnosed until the child develops gross oedema with scrotal or labial oedema, ascites and even pleural effusions which prompts presentation.
Other potential presenting features include sepsis, cellulitis related to oedema, spontaneous bacterial peritonitis and complications of a prothrombotic state such as venous sinus thromboses.
How we investigate it…
It’s important to confirm proteinuria with a urine protein:creatinine ratio. Other investigations include a full blood count to evaluate for evidence of haemoconcentration, biochemistry to assess for hyponatraemia, acute kidney injury and serum albumin levels and a urinary sodium to assist in determining the intravascular fluid status of the patient.
Consideration of an immunologic assessment (ANA, complements) should occur if a patient presents with other systemic symptoms or haematuria. Finally, the patient’s immune status to varicella-zoster is important as it will guide prophylaxis if future exposure occurs.
How we treat it…
There are two main arms to the treatment of nephrotic syndrome. Acutely, the management of severe oedema and chronically, the treatment of the disease for which the basis is corticosteroids.
Management of acute presentation:
When assessing oedema in a nephrotic patient, it’s important to evaluate the intravascular fluid status of the patient. Hypotension, cool peripheries, elevated creatinine and a low urinary sodium are all features consistent with intravascular depletion. Whereas those who are oedematous, well-perfused with hypertension and a urinary sodium > 10mmol/L are likely well hydrated.
Management includes a strict fluid balance with a daily weight, a diet low in salt, the introduction of a fluid restriction (unless there is evidence of intravascular depletion) and consideration of IV albumin with frusemide.
If indicated, 1g/kg (5ml/kg) of 20% albumin should be given over 4-6 hours with 1mg/kg IV frusemide dose either halfway through and/or on completion of the infusion (depending on the patient’s fluid status). Those who have evidence of hypervolaemia may be treated with IV frusemide alone. However, this is a short term strategy and they should be closely monitored for evidence of hypovolaemia.
Another component of the acute management is consideration and treatment of the potential complications including sepsis, cellulitis, spontaneous peritonitis and thrombotic sequelae.
Long term management:
Whilst oedema is being treated it is important to instigate the mainstay of nephrotic syndrome therapy, prednisolone. The initial dose is 60mg/m2 for 4-6 weeks followed by a weaning course (alternate daily dosing) for up to 2 months. Previously, this initial course had been as long as 6 months. There is consistent data in the literature that demonstrates that this shorter regime is non-inferior and leads to a reduction in the side effects of steroids, particularly on growth.
The initial presentation is an invaluable opportunity to provide support to these families who are now presented with a chronic medical illness. This is facilitated by intensive education, dietician review and social work (or equivalent) input.
- A dedicated consult explaining the diagnosis, management, ongoing monitoring requirements and prognosis.
- Provide demonstration of urine dipsticks as this will be required daily for at least a year post-diagnosis and even longer if the patient frequently relapses.
- Supplement with written information and a diary for the family to record urine results, weights and steroid dose.
- A dietetic consult to provide advice around a low salt diet and fluid restriction.
- These restrictions are required whilst the patient is nephrotic and are often reinstated during relapses.
- Education is also provided regarding a healthy balanced diet to avoid significant weight gain on high dose steroids.
- The diagnosis of nephrotic syndrome is often met with considerable anxiety and distress from families who now face a chronic disease for their child.
- A social worker or equivalent support structure is important to assist in acknowledging these concerns and anxieties.
- Provision of information regarding potential financial support is also considered.
- Preventative measures against complications of nephrotic syndrome are equally important.
- Gastritis is a common complication of high dose steroids and can present with epigastric pain or generalized abdominal pain.
- Acid suppression medications such as a proton pump inhibitor (PPI) are recommended whilst children are on high dose steroids.
- These can be ceased when the child moves to alternate-day steroid therapy.
- Penicillin V at 12.5mg/kg BD should be considered for those children who present with ascites as prophylaxis for spontaneous bacterial peritonitis. This therapy is continued until the patient remits (i.e. no longer proteinuric).
- If a child with nephrotic syndrome has contact with a known source of VZV, subcutaneous immunoglobulin should be administered
- Live vaccines are contraindicated whilst the child is nephrotic and/or on high dose steroids
- Ensure yearly influenza vaccine.
- Children who frequently relapse or have persistent nephrotic syndrome qualify for additional pneumococcal vaccine.
The use of aspirin and other anti-thrombotic agents have largely been abandoned given the risks of these therapies. The likelihood of thrombosis is significantly reduced once the child’s oedematous state is appropriately managed
What happens next…
90% of children respond to steroid therapy within 4-6 weeks (i.e. steroid-sensitive). Remission is defined as a negative/trace urine dipstick for three consecutive days. There are a small proportion of children who will not remit in this time period, referred to as steroid-resistant. These children require consideration of a renal biopsy and/or genetic testing (such as rapid genomic sequencing) thus warrant a referral to a paediatric nephrologist.
80% of children with nephrotic syndrome will relapse, often in the context of a concurrent illness. This is the basis for ongoing urine dipstick testing. This will detect a relapse prior to the child becoming oedematous and so may avoid further hospital admission.
Some children will demonstrate steroid-dependence or become frequent relapsers (i.e. ≥2 relapses in the first 6 months following diagnosis or ≥4 in any 12 month period). These patients, in addition to the steroid-resistant group, should be referred to a nephrologist for ongoing management.
Finally, approximately 10% of patients with nephrotic syndrome will continue to relapse in their adult life.
The bottom line…
- Nephrotic syndrome is the most common glomerular disorder of children
- Acute management involves the treatment of oedema and potential complications of the nephrotic state
- Long term management is with prednisolone
- Equally important at diagnosis is education, social support and dietetic review
- Referral to nephrology is required if a child demonstrates any of the following
- Steroid resistance
- Steroid dependence
- Frequent relapses
- Atypical presentation (e.g. microscopic haematuria, acute kidney injury etc…)
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- Hahn D, Samuel S, Willis N, Craig J, Hodson E. (2020). Corticosteroid therapy for nephrotic syndrome in children. Cochrane database of systematic reviews, accessed 11 October 2020, doi.org/10.1002/14651858.CD001533.pub6.
- Hodson E, Wong S, Willis N, Craig J. (2016) Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane database of systemic reviews, accessed 11 October 2020, doi.org/10.1002/14651858.CD003594.pub5.
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- McCaffrey J, Lennon R, Webb N. (2016) The non-immunosuppressive management of childhood nephrotic syndrome. Paediatric Nephrology, 31, 1383-1402 doi: 10.1007/s00467-015-3241-0