What is nephrotic syndrome?
Nephrotic syndrome is the most common glomerular disorder of childhood, affecting 2-7 children in 100,000 per year. It most typically affects children aged 2-12 and is characterised by proteinuria, hypoalbuminaemia and oedema.
Why causes nephrotic syndrome?
The villain of nephrotic syndrome is the glomerular filtration barrier (GFB). If we look back at our textbooks, we remember that 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 and the retention of albumin. Defects in this GFB result in increased permeability to albumin and the subsequent proteinuria that defines nephrotic syndrome.
As albuminaemia develops, plasma colloid oncotic pressure drops. More water is filtered through the capillaries and so interstitial oedema develops. Because there is reduced plasma volume the kidney works hard to retain fluid by retaining sodium.
Primary nephrotic syndrome
Idiopathic nephrotic syndrome (INS) is the most common cause 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 glomerular filtration border (GFB).
Minimal change disease is the most common form of idiopathic nephrotic syndrome.
Focal segmental glomerulosclerosis (FSGS) carries a poorer prognosis and is more common in children of African descent.
Membraneous nephropathy is due to a build-up of immune proteins in the basement membrane.
Congenital nephrotic syndrome/hereditary focal glomerulosclerosis occurs due to mutations in podocyte proteins such as podocin, nephrin, or cation channel 6 protein.
Secondary nephrotic syndrome
Immune disorders – such as IgA vasculitis (Henoch-Schonlein purpura) and lupus
Infective causes – Hepatitis B and C, HIV and malaria
Haematological disease – sickle cell, lymphoma, and leukaemia
Medication – NSAIDs
What is the difference between nephrotic and nephritic syndrome?
Nephrotic syndrome is characterised by excess protein in the urine.
In nephritic syndrome there is usually evidence of an acute kidney injury, hypertension and urinary sediment. This is made up of red cells and red cell casts.
What are the symptoms of nephrotic syndrome?
Children often present with a history of weight gain and swelling. This may be first noticed as intermittent periorbital or pedal oedema. The periorbital oedema is more evident in the morning as the fluid has settled around the eyes. Over the day, the fluid redistributes, so the face becomes puffy. It is not commonly diagnosed until the child develops gross oedema with scrotal or labial oedema, ascites and even pleural effusions.
The proteinuria might present as foamy urine.
Other potential presenting features include sepsis, cellulitis related to oedema, spontaneous bacterial peritonitis and complications of a prothrombotic state such as venous sinus thromboses.
What tests do you need to do?
Nephrotic-range proteinuria is equivalent to 3+ or 4+ on the dipstick. This is the equivalent to 300mg/dL or 3g per day
It’s important to confirm proteinuria with a urine protein:creatinine ratio. Other investigations include a complete blood count to evaluate for evidence of haemoconcentration, biochemistry to assess for hyponatraemia, acute kidney injury and serum albumin levels and urinary sodium to assist in determining the intravascular fluid status of the patient.
Serum albumin may well be low. There may be impairment in renal function and total cholesterol and triglycerides are often raised.
If a patient presents with other systemic symptoms or haematuria, they should have an immunologic assessment (ANA, complements). Finally, the patient’s immune status to varicella-zoster is important as it will guide prophylaxis if future exposure occurs.
What are the indications for a renal biopsy?
The vast majority of cases of nephrotic syndrome in children are due to minimal change disease. Because of this, many paediatric nephrologists will start steroid therapy and only perform a biopsy if the patient is unresponsive to treatment.
- Congenital nephrotic syndrome
- Age less than 12 months
- Gross or persistent microhaematuria
- Low serum C3
- Impaired renal function
- Failure of steroid therapy
What are the complications of nephrotic syndrome?
Because nephrotic syndrome causes peripheral oedema and swelling you might not think that the child in front of you is dehydrated. The problem is that they are intravascularly deplete as fluid leaks from the intravascular space into the interstitium.
This may present as dizziness and light-headedness, coupled with tachycardia, a drop in urine output and cool peripheries
Patients with ascites are at risk of spontaneous bacterial peritonitis. Because complement and immunoglobulins are lost in the urine children are more prone to infection. The immune-modulating drugs that are sometims used to treat the disease also play their part.
It’s not just albumin that leaks out through the glomeruli. Important components of the anti-thrombotic cascade – protein C, protein S and anti-thrombin III are lost whilst there is increased hepatic synthesis of pro-coagulant factors. These, combined with increased platelet activation lead to increased clot formation.
How does nephrotic syndrome cause hypercholesterolaemia?
How do we treat nephrotic syndrome?
There are two primary arms to the treatment of nephrotic syndrome. Acutely, to manage severe oedema and chronically, to treat the underlying disease.
Management of acute presentations
It’s essential to evaluate the intravascular fluid status of the patient when managing oedema. Hypotension, cool peripheries, elevated creatinine, and low urinary sodium are all consistent with intravascular depletion. Conversely, those who are oedematous, well-perfused, hypertensive and have a urinary sodium > 10mmol/L are likely well-hydrated.
The patient should maintain a strict fluid balance, measuring their weight daily. They should have a diet low in salt, a degree of fluid restriction (unless they are intravascularly depleted), and potentially IV albumin with frusemide.
- Fluid restriction
- Sodium restriction
- Fluid restriction
- Sodium restriction
- Loop diuretic
- Potassium-sparing diuretic if prolonged treatment needed
- Fluid restriction
- Sodium restriction
- loop diuretic +/- potassium-sparing diuretic
- Thyazide diuretic
- Albumin followed by furosemide bolus.
If indicated, 1g/kg (5ml/kg) of 20% albumin should be given over 4-6 hours with 1mg/kg IV furosemide dose either halfway through and/or on completion of the infusion (depending on the patient’s fluid status).
Those who are hypervolaemic may be treated with IV furosemide alone. This is a short-term strategy, however, and they should be closely monitored for worsening hypovolaemia.
It is also worth considering potential complications, including sepsis, cellulitis, spontaneous peritonitis and thrombotic sequelae.
The mainstay of treatment is prednisolone.
The initial dose of prednisolone is 60mg/m2/day for 4-6 weeks followed by a weaning course (alternate daily dosing) for up to 2 months.
In the past, this initial course lasted as long as six months. However, the literature suggests that this shorter regime is non-inferior and reduces steroid side effects – particularly in its impact on growth. Steroid-sparing agents such as cyclophosphamide, mycophenalate, calcineurin inhibitors and levamisole may be useful in frequently relapsing or steroid-dependent patients.
The first presentation is an invaluable opportunity to support these families who are now presented with a chronic medical illness. This is facilitated by intensive education, a dietician review and social work (or equivalent) input.
How can we support a young person with nephrotic syndrome?
- A dedicated consult explaining the diagnosis, management, ongoing monitoring requirements and prognosis of nephrotic syndrome.
- Demonstrate how to use urine dipsticks. They will be needed every day, for at least a year. post-diagnosis and even longer if they relapse frequently.
- They should also get written information and a diary. Here, the family to record urine results, weights and steroid doses.
A dietetic consult can provide advice about 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 children. Parents and carers need information about potential financial support.
Gastritis is a common complication of high-dose steroids and can present with epigastric pain or generalised abdominal pain. Acid suppression medications such as a proton pump inhibitor (PPI) are recommended when 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 is no longer proteinuric. If a child with nephrotic syndrome has contact with a known source of VZV, subcutaneous immunoglobulin should be given
Live vaccines are contraindicated whilst the child is nephrotic and/or on high-dose steroids. Patients need 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 has 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 a negative/trace urine dipstick for three consecutive days. A small proportion of children will not remit in this period, which is referred to as steroid-resistant. These children require consideration of a renal biopsy and/or genetic testing (such as rapid genomic sequencing) and thus warrant a referral to a paediatric nephrologist.
Remission: trace/no protein on dipstick for three consecutive days
Relapse: 3+ or 4+ urine protein for three consecutive days having achieved remission
Frequent relapser: four or more relapses in 12 months
Steroid-dependent: two consecutive relapses while on steroids or within 14 days of discontinuation
Steroid-resistant: preoteinuria (+2 or more) on daily steroid therapy after 8 weeks
Most patients, with minimal change disease, will go into remission following steroid treatment.
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 before the child becomes oedematous and so may avoid further hospital admission.
Patients with focal-segmental glomerulosclerosis have a much poorer prognosis. The majority will develop end-stage renal disease and require dialysis and a kidney transplant.
Some children will demonstrate steroid dependence or become frequent relapsers . These patients should be referred to a nephrologist for ongoing management.
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
Atypical presentation (e.g. microscopic haematuria, acute kidney injury etc…)
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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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Pasini, A., Benetti, E., Conti, G., Ghio, L., Lepore, M., Massella, L., Molino, D., Peruzzi, L., Emma, F., Fede, C. and Trivelli, A., 2017. The Italian Society for Pediatric Nephrology (SINePe) consensus document on the management of nephrotic syndrome in children: Part I-Diagnosis and treatment of the first episode and the first relapse. Italian journal of pediatrics, 43, pp.1-15.
Tapia C, Bashir K. Nephrotic Syndrome. [Updated 2022 Jun 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470444/
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