Nephrotic syndrome consist of a triad of oedema, hypoalbuminaemia and proteinuria.

The incidence worldwide is 2-7 in 100,000 and it is the most common glomerular disorder of childhood. It is more common in children of Asian heritage.

It often presents with peri-orbital oedema and abdominal pain and is frequently misdiagnosed in primary care as allergies or hayfever resulting in delayed treatment, so it is important to be able to recognise when a child is presenting for the first time with nephrotic syndrome.

Presentation

• Oedema
  • The first sign of nephrotic syndrome in children is often facial swelling, particularly peri-orbital oedema.
  • This is quickly followed by widespread oedema, most noticeable in the feet and legs and scrotum or labia, and progress to cause ascites and pleural effusions.

Periorbital oedema in a child with nephrotic syndrome

Facial oedema in a child with nephrotic syndrome

• The urine may be described as “frothy”
• Abdominal pain
  • This occurs as a result of severe hypovalaemia which causes mesenteric ischaemia
  • Pain can occur due to distension from ascites
  • Abdominal pain with a fever is a red flag for spontaneous bacterial peritonitis in the context of nephrotic syndrome (Goyal S, 2020)
• Hypovalaemia
  • Can present with hypovalaemic shock with cool peripheries, tachycardia and hypotension
• Nephrotic syndrome can present as a complication of Henoch Schonlein Purpura (HSP) with new onset oedema and proteinuria (which is why follow up for HSP includes regular urine dips and BP monitoring)

Diagnosis

• Urine dip 3+ or more of protein

• Urine protein : Creatinine ratio of > 200mg/mmol

• Plasma albumin < 25g/L

As part of your assessment for nephrotic syndrome you need an up to date weight, height, BP (use height and BP to obtain BP centile) , heart rate, capillary refill time, respiratory rate and temperature.

If the child looks acutely unwell assess A-E.

Examine for fluid status and look for oedema through looking at peripheral perfusion, pulse volume, JVP.

Examine for oedema around face, genitals, feet. Auscultate for pleural effusions and examine for ascites.

Be sure to assess for common complications such as infection, thrombosis and hypovalaemia.

The most common infections are caused by encapsulated organisms in nephrotic syndrome and the most common type of infection is peritonitis.

Thrombosis can occur as a renal vein thrombosis (presents with flank mass, haematuria, hypertension and renal failure), venous sinus thrombosis (would cause neurological signs), deep vein thrombosis (DVT) (causes limb pain and swelling) or a pulmonary embolus (presents with chest pain, tachypnoea, SOB and tachycardia)

Investigations

• Urine dip (early morning sample if possible)

• Urine protein: Creatinine ratio

• U&Es, LFTs (mainly for albumin), FBC

• Varicella antibodies (due to immunosuppression children with nephrotic syndrome who do not have varicella antibodies should avoid contact with chickenpox, and should they come into contact with chickenpox they should seek urgent medical attention for zoster immunoglobulin or high dose aciclovir)

• Lipids and triglycerides

• ASOT, anti-DNAse B

• Complement (C3/4)

• Blood culture and CRP if febrile

• CXR if SOB to look for pleural effusions

• Renal vein dopplers if evidence of renal vein thrombosis

Classifications

Typical Nephrotic Syndrome

• Age 1-12 years

• Normal renal function

• Normotensive

• Microscopic haematuria (occurs in 25%)

• Normal levels of complement

• Responds to steroids within 4 weeks

Atypical Nephrotic Syndrome

• Age < 1 or > 12 yo

• Gross haematuria

• Low C3

• Hypertension

• Renal failure in the absence of severe hypovalaemia

Remission

Urine dipstick negative for protein or trace of protein for 3 consecutive days

Relapse

Dipstick 3+ or more of protein on 3 consecutive days OR dipstick 3-4+ protein with oedema

Frequent relapses

2 or more relapses within 6 months of initial response OR 3 or more relapses within a 12 month period

Steroid dependence

2 consecutive relapses occurring during corticosteroid therapy OR within 14 days of stopping corticosteroids.

Steroid resistance

Failure to achieve complete remission after 8 weeks of prednisolone at 60mg/m2/day

Differentials

Heart failure – would present with oedema, shortness of breath, cyanosis

Allergic reaction  – presents with facial oedema, pruritus. In the case of an allergy there would be a history of recent contact with an allergen and sudden onset of symptoms

Malnutrition (Kwashiorkor) – is rare but can present in children who go on to be exclusively breastfed or whose diet consists mainly of cows milk into the toddler age group. This presents with widespread oedema, abdominal distension, failure to thrive and there may be hypoalbuminaemia, along with iron deficiency anaemia.

Pathophysiology

Around 1 million glomeruli exist in each kidney and these act to filter the blood. The glomerular filtration barrier consists of fenestrated endothelium of the capillary, the glomerular basement membrane and podocyte foot processes. The connection between foot processes are called slit diaphragms. This barrier usually excludes proteins from filtration.

Proteinuria occurs as a result of disease disrupting the filtration barrier, resulting in increased glomerular permeability. The podocyte is usually the component of the barrier that is targeted by pathological processes. (Tapia C, 2023)

A diagram of the glomerular filtration barrier (Daehn IS, 2021)

Children develop hypoalbuminaemia due to the loss of protein in the urine. This causes a positive feedback mechanism with the liver producing more albumin. As well as synthesising more albumin, the liver also increases its production of LDL and VDL and lipoprotein which causes hypercholesterolaemia and hypertriglyceridaemia.

Children become hypercoagulable and are at an increased risk of thrombosis, particularly renal vein thrombosis, but also deep vein thrombosis and pulmonary emboli. This occurs due to loss of anti thrombin III, protein C and protein S in the urine, secondary to proteinuria. There is also increased hepatic synthesis of pro coagulant factors and increased platelet activation.

Oedema occurs as a result of decreased oncotic pressure secondary to hypoalbuminaemia which means more water is filtered through the capillaries and urine output increases. This leads the kidneys to retain sodium in the collecting tubules in order to retain fluid.

Children are also immunocompromised due to loss of immunoglobulins and complement in the urine. Treatment with steroids and biologics compound an infection risk. They are most prone to encapsulated organisms e.g. Strep. pneumoniae, H. influenzae

Aetiology

Minimal Change Disease (MCD) is the cause of 78% of cases of nephrotic syndrome in children. MCD is usually steroid sensitive and its peak incidence is at 2.5 years of age. The main histological finding is podocyte effacement along with growth of microvilli on the podocytes which allows for proteinuria.

The next most common cause of nephrotic syndrome in the paediatric population is focal segmental glomerulosclerosis (FSGS) which accounts for 8% of cases. This is typically steroid resistant and diagnosed on renal biopsy. The histology seen on biopsy includes: distortion of foot processes of podocytes with disruption between the foot processes and of the underlying basement membrane. Increased extracellular matrix within the glomerular tuft and obliteration of the glomerular capillary lumen differentiate FSGS from MCD on light microscopy. (Reidy K, 2007)

Membranoproliferative glomerulonephritis (MPGN) accounts for 6% of cases of nephrotic syndrome in children. It is caused by mesangial cell proliferation and structural changes in the glomerular capillary walls. There are three types of MPGN and all three are related to complement activation. MPGN is usually idiopathic in children. (Alchi B, 2010)

Membranous nephropathy (MN) is characterised by the formation of immune complexes in the space between podocytes and the glomerular basement membrane.

In primary (idiopathic) MN there are subepithelial deposits of IgG and C3 seen in the glomerular basement membrane with immunofluorescence. In secondary MN there may be subepithelial deposits of IgG1, IgG2, IgG3, C1q, IgA, IgM. (Moroni G, 2020)

Congenital nephrotic syndrome is extremely rare and presents within 3 months of birth. The majority of congenital nephrotic syndromes are genetic and the most common type is Finnish (named so because of the higher incidence in Finland) which is autosomal recessive inheritance. It is caused by a mutation in NPHS1 gene which encodes the nephrin protein which forms part of the glomerular filtration barrier. The incidence of Congenital nephrotic syndrome is 1-3 per 100,000 per year but in Finland is 1 per 8200 births. (Jain, 2023)

Management

For a first presentation of typical nephrotic syndrome:

• Prednisolone 60mg/m2 (max 60mg) daily for 4 weeks

• If reaches remission within 4 weeks wean to 40mg/m2 (max 40mg) on alternate days for 4 weeks

• Stop after a total of 8 weeks treatment

• Cover with a PPI (omeprazole) whilst on steroids

• Also prescribe phenoxymethylpenicillin prophylaxis until in remission (125mg BD if < 5yo, 250mg BD if > 5yo)

For a relapse (but not a frequent relapser) the management is the same

For frequent relapsers or steroid dependent: These are referred to nephrology and may be treated with: low dose alternate day steroids, levamisole, cyclophosphamide, tacrolimus, mycophenolate mofetil, rituximab

Indications for admission:

• Parent education

• Any atypical features that require referral to a nephrologist (see below)

• Acutely unwell child.

If a child presents acutely unwell with nephrotic syndrome they are likely to be in hypovalaemic shock, have an infection, or both.

• The best treatment for hypovalaemic shock in these patients is Human Albumin Solution (HAS), as if you give them normal saline or plasma-lyte it will just leak out of the capillaries due to the low oncotic pressure and will not treat the hypovalaemia.

• This is best discussed with a senior registrar or consultant but most A&E departments should have an emergency supply of HAS.

• Indications for HAS are: severe oedema, ascites causing splinting and respiratory distress, pleural effusion causing respiratory distress, poor perfusion, tachycardia, hypotension.

• HAS can be given as 4.5% or 20%. 4.5% HAS is preferable and has less side effects as 20% HAS can cause hypertension and pulmonary oedema if given rapidly.

• 4.5% HAS should be prescribed at 5-10ml/kg over 2 hours IV.

If a child with nephrotic syndrome presents with fever and suspected spontaneous bacterial peritonitis you should cover with broad spectrum IV antibiotics as per your hospital guidelines.

During admission:

• Weight daily

• Daily urine dip

• Regular observations with blood pressure

• Monitor input/output

• Restrict salt intake

• Do not routinely fluid restrict or give diuretics unless instructed to do so by a nephrologist

On discharge:

• Send home with urine dipsticks and advise to dip urine every day to identify when remission starts.

• Give safety net advice to seek urgent medical attention in case of any signs of infection, any contact with chickenpox if no varicella antibodies, any signs of thrombosis, reduced urine output, worsening oedema, shortness of breath.

• Arrange follow up on discharge to be sure the child reaches remission / is managed appropriately if they do not reach remission within 4 weeks.

When to refer to tertiary nephrology

• Macroscopic haematuria

• Persistent hypertension

• Steroid resistance (from 4 weeks onwards)

• Low C3 or C4

• IV albumin required

• Evidence of systemic disease, e.g. HSP or SLE

• Age < 12 months or > 10 years

• Renal failure (Goyder K, 2023)

Bibliography

Alchi B, J. D. (2010). Membranproliferative Glomerulonephritis . Paediatric Nephrology, 1409-1418.

Daehn IS, D. J. (2021). The Glomerular Filtration Barrier: A Structural Target for Novel Kidney Therapies. Nature Reviews Drug Discovery , 770-788.

Goyal S, D. R. (2020). First Episode of Nephrotic Syndrome with Acute Abdominal Pain . Clinical and Experimental Paediatrics, 411-414.

Goyder K, H. S. (2023, July 15). Nephrotic Syndrome in Childhood. Retrieved from Pier Network: https://www.piernetwork.org/uploads/4/7/8/1/47810883/signed_ns_guideline_for_pier.pdf

Jain, J. C. (2023, July 15). Congenital Nephrotic Syndrome. Retrieved from StatPearls: https://www.ncbi.nlm.nih.gov/books/NBK572058/

Liu W, G. C. (2019). Immunological Pathogenesis of Membranous Nephropathy: Focus on PLA2R1 and Its Role. Fronteirs in Immunology.

Moroni G, P. C. (2020). Secondary Membranous Nephropathy. A Narrative Review. Frontiers in Medicine.

Reidy K, K. F. (2007). Pathophysiology of Focal Segmental Glomerulosclerosis . Paediatric Nephrology, 350-354.

Tapia C, B. K. (2023, July 15). Nephrotic Syndrome. Retrieved from StatPearls: https://www.ncbi.nlm.nih.gov/books/NBK470444/#:~:text=Introduction-,Nephrotic%20syndrome%20(NS)%20is%20a%20clinical%20syndrome%20defined%20by%20massive,especially%20infectious%20or%20thrombo%2Dembolic.

Vivarelli M, M. L. (2017). Minimal Change Disease. Clinical Journal of the American Society of Nephrology, 332-345.

Written and edited by Dr Rebecca Evans Paediatric ST3