Approach
Nephrotic syndrome (NS) is an important chronic disease in children, most of which is attributable to minimal change disease (MCD). Peripheral oedema associated with nephrotic-range proteinuria (first morning or 24-hour protein-creatinine ratio ≥200 mg/mmol or ≥2 mg/mg or ≥3+ dipstick), hypoalbuminaemia (serum albumin <3 g/dL), and hyperlipidaemia is the hallmark of this syndrome.[3] As it is not always practical to perform 24-hour urinalysis in children, early morning spot urine for the urine protein to creatinine ratio (≥200 mg/mmol) is an alternative diagnostic test.[3][Figure caption and citation for the preceding image starts]: Diagnostic algorithm for MCD nephrotic syndromeCreated by authors [Citation ends].
History and physical examination
Children with underlying MCD are usually between the ages of 1 and 12 years. Parents typically give a history of facial swelling, with or without puffy hands and/or feet. Abdominal swelling with or without abdominal pain may also be a presenting complaint.[4] Nausea and vomiting, although non-specific, can occur. Onset is gradual, ranging from a few days to several weeks, and often follows a recent viral illness (suggesting immune system involvement). A history of Hodgkin's lymphoma or leukaemia may suggest MCD NS (focal segmental glomerulosclerosis [FSGS], membranoproliferative glomerulonephritis [MPGN], and membranous nephropathy have also been associated with leukaemia).[22]
Facial or generalised oedema on physical examination are typical findings. A few patients may present with signs of complications including hypertension or respiratory distress (a consequence of pleural effusion or pneumonia).[4]
Adults with MCD also present with NS (oedema, nephrotic-range proteinuria, hypoalbuminaemia, and hyperlipidaemia), but differ from children in that they are more likely to have hypertension (25% to 50%), haematuria (20% to 30%), and acute kidney injury (20% to 25%) at the time of diagnosis.[24][25]
Screening for nephrotic syndrome
All children presenting with a first episode of generalised or facial oedema must have urinalysis to check for protein. Typical results show 3+ to 4+ proteinuria on dipstick.[3] The urine sediment in idiopathic NS is usually benign except for occasional hyaline casts and oval bodies. Other types of cellular casts are uncommon. Microscopic haematuria can be found in patients with MCD or FSGS. In the International Study of Kidney Disease in Children (ISKDC), haematuria was seen in 23% of patients with MCD, 49% of patients with FSGS, and 50% of patients with MPGN.[20] If proteinuria is absent or <3+ on dipstick, a diagnosis other than NS should be considered (e.g., kwashiorkor, congestive heart failure, cirrhosis). If haematuria is significant, acute glomerulonephritis is more likely.
Laboratory investigations
Having established the presence of significant protein on urinalysis, the proteinuria should then be measured by either a first morning urine protein/creatinine ratio or 24-hour urine protein. The protein/creatinine ratio is more easily obtained. In children a protein/creatinine ratio ≥200 mg/mmol is considered nephrotic-range proteinuria.[3] Nephrotic-range proteinuria can vary depending on the age and size of the child. For example, a ratio of 1 (about 1 g/24 hours) in a 20 kg patient may signify nephrotic-range proteinuria, whereas in an adolescent patient a ratio of 1 represents mild to moderate proteinuria.[4][20] If measuring 24-hour urine protein, nephrotic range proteinuria is defined by a result ≥1000 mg/square metre of body surface area/day.[2]
Initial investigations also include serum albumin, lipid, and complement levels, as well as a full blood count and electrolyte panel.[1] GFR should be estimated and is usually normal in MCD NS. LFTs (including liver enzymes) are necessary, as elevated serum aspartate aminotransferase and alanine aminotransferase levels may suggest underlying hepatitis. If they are elevated, an acute hepatitis profile should be obtained to include hepatitis B and C studies.
Serum albumin levels are typically <30 g/L (<3 g/dL) and, in some cases, the serum albumin can be as low as 10 g/L (1 g/dL).[2][3] Serum triglyceride and cholesterol levels are elevated. There is an inverse relationship between the serum albumin level and the total cholesterol level: the lower the serum albumin level, the higher the cholesterol level.
Serum complement levels in idiopathic NS (MCD, FSGS, membranous nephropathy) are normal. C3 levels are low in MPGN, postinfectious glomerulonephritis, and systemic lupus erythematosus. If the C3 level is low, additional tests should be performed to differentiate these conditions, including antinuclear antibody, anti-double-stranded DNA antibody, antistreptolysin O antibody, anti-DNase antibody, and CH50 levels.
The haemoglobin level and haematocrit may be elevated in NS if the patient is volume contracted. The platelet count may also be elevated.
The serum sodium level may be low partly due to depressed free water excretion (volume contraction may stimulate antidiuretic hormone secretion) or partly due to hyperlipidaemia (pseudohyponatraemia). Urea may be slightly elevated in volume-contracted states.
Imaging
Although, in uncomplicated NS, imaging studies may not provide useful information, kidney ultrasound does help confirm the presence of two kidneys, and assesses their size and structure.[2] In NS, the kidneys typically appear normal. In some patients with severe oedema, the kidneys may be echogenic and show loss of corticomedullary differentiation. The kidneys may also be enlarged.
A chest x-ray is indicated in patients with respiratory symptoms to exclude pneumonia or pleural effusion, which may occur as a complication. Chest x-ray should also be obtained in cases of suspected MCD associated with lymphoma.[2] In some countries where tuberculosis is endemic, it is a routine practice to obtain chest x-ray before initiation of corticosteroid therapy to rule out tuberculosis.[26]
Kidney biopsy
In children aged <12 years, biopsy is usually reserved for those patients who do not respond to corticosteroids, have an atypical clinical presentation (e.g., persistently elevated serum creatinine, significant haematuria) and relapse frequently despite the addition of corticosteroid-sparing therapy. In addition, kidney biopsy should be considered when there are factors at presentation that suggest histology other than MCD, as treatment may differ. For example, MCD is uncommon in infants aged <1 year; congenital (Finnish type) NS or FSGS is more likely. Therefore, all infants aged <1 year presenting with NS should have a kidney biopsy and/or genetic testing if available.[2] Podocyte effacement on electron microscopy confirms the diagnosis of MCD.
In adults, a kidney biopsy is required for diagnosis of MCD and in children aged ≥12 years, a biopsy should be considered.[2][3]
If biopsy is indicated and two healthy kidneys are present, an ultrasound-guided, closed needle biopsy under conscious sedation (or general anaesthesia in the case of an infant or child) is a relatively low-risk procedure. If there is a single kidney, an open laparoscopic biopsy by a surgeon should be considered. If the kidneys are small or obstructed, a biopsy may be contraindicated.
Genetic testing
In infants aged <1 year who present with NS, genetic testing is becoming more common, where available, either as an alternative to or in addition to kidney biopsy.[2] Around 50% of children with infantile-onset NS (aged 3-12 months) have a genetic cause of NS.[2]
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