Dr Khadijatul Muneer, Dr Mordi Muorah

Alfie is a 5 year old boy who was brought in to the ED by his mother who worried about swelling around the eyes. She first noticed it a week ago and went to the GP who prescribed eye drops for “allergies”.

Mom is unsure if the drops helped as the swelling was not very obvious at times. However, in the last few days, she saw that his tummy was swollen too with imprints of his trousers on them and the eye swelling was more persistent.

Clinically, Alfie was alert and looking generally well. His vitals were normal. He had very obvious periorbital oedema. His chest was clear with normal heart sounds, his abdomen looked slightly distended, was soft, non tender with bowel sounds present. He had scrotal oedema and pitting oedema in the lower limbs.

Alfie was admitted to the paediatric unit.

He was diagnosed to have Nephrotic Syndrome based on history, clinical examination and urine dipstick (proteinuria 4+). His blood results further confirmed the diagnosis.

What is Nephrotic Syndrome?

Nephrotic syndrome (NS) is a triad of

• Proteinuria defined by
  • early morning urine protein : creatinine >200mg/mmol OR
  • dipstick >3+ OR
  • >50mg/kg/day (difficult and rarely used in children as it requires a 24 hour urine collection)
• Peripheral oedema (which may not always be very obvious)

• Hypoalbuminaemia (plasma albumin <25g/L)

You may also see

• Hypercholesterolaemia
• Haemoconcentration and thrombocytosis which may increase the risk of thrombotic disease

To manage NS and avoid complications, you need to have a good understanding of the possible causes – some children (particularly those who might not respond to steroid treatment) can be at risk of chronic kidney disease and even end stage renal disease.

How is NephrOTIC Syndrome different from NephrITIC Syndrome?

Both are clinical terms and sometimes they get mixed up because the names are similar (although they can also co-exist). Nephritic or nephrotic – the easiest way to remember the difference is that it depends on where the damage is.

Damage to podocytes and the glomerular basement membrane (GBM) can cause nephrotic syndrome. Damage to the renal endothelium (intraglomerular inflammation) can cause nephritic syndrome.

Nephritic syndrome is a triad of acute kidney injury (AKI), hypertension (HTN) and glomerular haematuria (red cells and cellular casts). Proteinuria is usually in the sub-nephrotic range.

In Nephrotic syndrome, there is proteinuria and lipiduria but the urine contains very little cells or casts. Nephrotic syndrome would have the classical triad mentioned in the previous section.

Let’s learn about the types of Nephrotic Syndromes that are common in children

Minimal Change Nephrotic Syndrome (MCNS or MCD) is the most common cause of paediatric NS. Children with MCNS generally respond well to steroids. If they are steroid resistant (no response within 4 weeks of steroid therapy), they need a renal biopsy to confirm the pathology – most likely Focal Segmental Glomerulosclerosis (FSGS).

A note on NS in the first year of life

CNS or Congenital Nephrotic Syndrome (birth – 3 months old) such as Finnish type NS (CNF) and Infantile Nephrotic Syndrome (3-12 months old) are usually due to underlying genetic causes. These types of NS are generally unresponsive to steroids and when severe, often progress to end stage renal disease with hypertension.

Rarely the secondary cause can be something transitory such as an infection and resolves naturally.

Tell me more about Minimal Change Nephrotic Syndrome (MCNS)

MCNS makes up 70-90% of NS in children under 10 years of age and 50% of the cases above 10 years of age. MCNS is commonly primary (idiopathic) which is often triggered by viral infection but can sometimes be secondary (Hodgkin’s Lymphoma, leukaemia). Under a microscope, the glomeruli look normal with mild mesangial proliferation (‘minimal change’) and immunofluorescence is negative.

Tell me more about Focal Segmental Glomerulosclerosis (FSGS)

FSGS can be primary, secondary or genetic (to date, over 44 genes linked to FSGS have been identified.) Children with FSGS are resistant to steroids (steroid resistant nephrotic syndrome or SRNS) – if it is suspected, you need to get a renal biopsy to confirm the diagnosis. 85% of steroid resistant NS presents by 3 months and 66% presents in the first year of life.

Under a microscope, you would see segments of mesangial collapse and sclerosis of some glomeruli (‘focal’), with some normal appearing glomeruli in between.

Primary FSGS might respond to immunosuppression (although not usually steroids) with or without renin-angiotensin system (RAS) blockade. Secondary FSGS (which can be secondary to obesity, infection, obstruction, drugs, etc.) is often managed by RAS blockade alone without immunosuppressive drugs.

How can we explain the symptoms of NS?

Let’s look at the glomerular filtration barrier (GFB). It’s a three layered structure made up of fenestrated endothelial cells, glomerular basement membrane and podocytes. They create a charge-selective and size-selective barrier. The pores between the foot processes are closed by a thin membrane called a slit diaphragm.

The Glomerulus

• Proteinuria injured podocytes = increased loss of macromolecules like albumin
• Hypoalbuminaemia – albumin is lost in the urine
• Hypercholesterolaemia and hypertriglyceridaemia the liver tries to compensate for protein loss by making more albumin, as well as LDL, VLDL and lipoproteins
• Oedema because of lower oncotic pressure (hypoalbuminaemia) and renal sodium retention. Intravascular volume depletion leads to reduced perfusion pressure in the glomeruli. This is detected by baroreceptors which activate the RAAS (Renin Angiotensin Aldosterone System). Aldosterone causes sodium and water to be retained, which increases oedema.
• Risk of infection (especially from encapsulated bacteria) – increased urinary loss and catabolism of IgG, treatment with steroids/immunosuppressants and decreased cellular immunity.
• Risk of clotting and thrombosis – lots of reasons for this, including endogenous anticoagulants being lost in the urine from leaky glomeruli (anti-thrombin III, protein C, protein S, etc); hepatic synthesis of pro-coagulants (factors V, VII, VIII, X, von Willebrand factor, fibrinogen); decreased fibrinolytic activity; abnormal platelet activation and aggregation; intravascular volume depletion; drugs (corticosteroids, diuretics); and changes to the glomerular haemostatic system.

Assessment

Remember the triad (oedema, proteinuria, hypoalbuminaemia). Oedema can be non dependent e.g. periorbital.

These are the things you should be thinking about in terms of severity and complications:

• Intravascular volume depletion in an oedematous child (dizziness, tachycardia, abdominal pain, low JVP, signs of peripheral hypoperfusion, hypertension) including late signs (reduced urine output, hypotension).
• Symptomatic oedema e.g.: discomfort (abdominal, scrotal/vulval oedema), risk of skin breakdown (limb oedema), ascites, tachypnoea and recessions (pleural effusion).
• Infection – sepsis, cellulitis, spontaneous bacterial peritonitis (SBP), ulceration from scrotal oedema, pneumonia.
• Thrombosis (cerebral/pulmonary/renal/femoral vein thrombosis; fall in platelets, rising d-dimers and slow PTT are suggestive). Children with infections are at a higher risk of venous thromboembolism.

I M P O R T A N T

Abdominal pain with NS needs urgent attention. Differentials include renal vein thrombosis, hypovolaemia, surgical complications (appendicitis, intussusception secondary to bowel wall oedema with peristaltic incoordination), and spontaneous bacterial peritonitis (SBP) – this can be difficult to diagnose as steroids can mask fever or cause leukocytosis.

Investigations

• Urinalysis – high albumin concentration (3+ to 4+, 300 to >1000 mg/dL)
• Early morning protein : creatinine ratio (normal value <20mg/mmol, nephrotic value 200 mg/mmol, usually >600 mg/mmol)
• ‘Baseline’ bloods as well as immunoglobulins (IgG, IgA, IgM), complements (C3, C4), zoster immune status, lipid profile, Hepatitis B and C serology
• Second line investigations if atypical (ASO, anti-DNase B, ANA, Anti dsDNA)

Interpretation

• High haematocrit suggests hypovolaemia

• Raised creatinine or urea suggests hypovolaemia, tubular plugging or other nephritis

• Serum cholesterol and triglycerides: often elevated

• IgG usually low

• C3 normal

Risk factors for AKI include hypovolaemia, infection, nephrotoxic drugs, and steroid resistant NS.

Treatment

Don’t forget the possibility of sepsis in a very unwell child!

• Manage oedema – daily weights, avoid added salt, daily urine dipstick, strict fluid balance charts with close attention to volume status.
• Hypovolaemia – severe intravascular depletion can be seen due to hypoalbuminaemia, which can be made worse by diarrhoea or diuretics. Indications for treatment with human albumin solution (HAS) and mid-infusion furosemide include symptomatic oedema and intravascular volume depletion. Don’t confuse 4.5% HAS (45 g/L) with 20% HAS (200 g/L). 20% HAS is hyperosmolar and can cause volume overload whereas the 4.5% HAS is similar to that in the normal plasma! 20% HAS should usually be given slowly over 4 – 6 hours.
• Steroid therapy – prednisolone until remission followed by a slow weaning plan to avoid relapse.
• Prophylaxis against complications eg: penicillin V prophylaxis against pneumococcal infection (if penicillin allergic, consider azithromycin), gastritis secondary to steroid therapy.
• Immunisations (particularly pneumococcal) are essential – children with NS are immunocompromised. Avoid vaccines for 3 months after completing a course of high dose corticosteroids. More detailed vaccine guidance for nephrotic syndrome can be found here. Children with NS exposed to chicken pox (varicella) may need IVIG and/or IV aciclovir – discuss urgently with the team monitoring their treatment.
• In severe disease, especially with hypovolaemia (poor perfusion, high Hb, thrombophilia, or abdominal pain), might need to treat with dipyridamole to reduce risk of thrombotic complications.
• Get the paediatric nephrologists involved ASAP if:
• you suspect atypical NS (<1 year or >12 years at first presentation)
• Oedema is difficult to control
• Creatinine rising
• No remission after 4 weeks of steroids
• Low C3/C4, ANA+ or requiring alternative immunosuppressants in the case of steroid toxicity.

Prognosis

• If steroids bring about remission, this is a better predictor of a good long term outcome than the exact renal histology
• MCNS relapse in adulthood is high, and might respond slower to steroids, but has a good prognosis. A small minority develop FSGS with eventual renal failure
• Chronic NS can cause hypothyroidism (or make it worse) due to losing T3, T4 and thyroid binding globulin (TBG) in the urine
• Death is uncommon in NS but usually secondary to complications (infection, thrombosis)
• Abnormalities in bone histology can be seen in chronic NS, because Vitamin D binding proteins are lost in urine (causing low ionised calcium and 25-OH vitamin D3). There’s also a risk of metabolic bone disease with long or repeated steroid courses – think about calcium and vitamin D supplementation.
• Mild microcytic hypochromic anaemia resistant to iron therapy is sometimes seen with NS. This is because transferrin and erythropoietin (EPO) is lost in urine. Subcutaneous injections of EPO can be a treatment option
• Children with atypical NS and persistently high blood pressure are more likely to develop chronic kidney disease. They will benefit from ACE inhibitors or angiotensin II receptor blockers to treat hypertension – these drugs will minimise damage to the kidneys and reduce the urine protein loss.

Top Tip

Assess volume status carefully with all the clues you can get – as well as what has already been mentioned, consider these things:

	Intravascularly depleted	Volume overloaded
Peripheral temperature	Low	Normal
Haematocrit	High	Low
Urinary sodium	Low	Normal / low
Plasma sodium	Low	High / Low / Normal
Plasma creatinine	High	Normal / Low
Urine output	Low	Normal / increased

Back to Alfie

Alfie was discharged after a short stay in hospital (once he was in remission – trace/negative urine protein for 3 days), and he went home on a weaning regime of steroids. Alfie’s mom was given education and support on managing NS, including how to test the first urine of the day using dipsticks, and how to keep a daily proteinuria diary.

Key Learning Points

Nephrotic syndrome is diagnosed based on the presence of heavy proteinuria, hypoalbuminaemia and oedema

Acute complications are hypovolemia, infection and thrombosis

Up to 90% of nephrotic syndrome is idiopathic

If there are atypical features, think about other causes including Systemic Lupus Erythematosus, glomerulonephritis, diabetes, infections (Hepatitis B, malaria) drugs/poisons (lead, mercury, penicillamine) or Henoch Schonlein Purpura

Discharge education (urine testing, corticosteroid diary, follow ups) is extremely important because there is a high risk of relapse

Dr Khadijatul Muneer is a paediatric ST5 doctor. This article was reviewed by Dr Mordi Muorah, Consultant Paediatric Nephrologist at the Birmingham Children’s Hospital