Nephrotic Syndrome Diagnosis and Classification in Children

The diagnostic criteria for nephrotic syndrome in children are three documented findings: nephrotic-range proteinuria, low serum albumin and oedema. Classification then rests on two things the doctor observes over time: how quickly the child responds to steroids, and how often the child relapses. Getting both right at the first episode decides every treatment step that follows.

This article sets out the diagnostic criteria and definitions Dr. Shraddha Lohia, then Consultant, Paediatric Nephrology at Fortis Memorial Research Institute, Gurgaon, India, taught to doctors across Africa, applies them to the cases she presented, and covers the first investigations and the management of oedema. The complete guide to difficult nephrotic syndrome gives the overview, and the steroid-sparing agents article covers what to do once a child is classified as frequently relapsing, steroid dependent or steroid resistant.

Diagnostic criteria for nephrotic syndrome in children

Nephrotic syndrome is diagnosed only when all three of its components are documented, not on clinical appearance alone. Dr. Lohia opened with a seven-year-old who had a week of fever, no obvious focus of infection and generalised oedema. The blood count was unremarkable, but urine protein was 2+. Is that nephrotic syndrome? Not yet. The diagnosis needs documented evidence of each component:

• Nephrotic-range proteinuria. Measured by urine protein to creatinine ratio (UPCR), by dipstick, or as a timed urine protein of 40 mg/m² per hour or more. A dipstick reading of 3+ or 4+ is in the nephrotic range.
• Hypoalbuminaemia. A serum albumin below 3 g/dL (30 g/L).
• Oedema. Typically starting around the eyes.

Hypercholesterolaemia used to be part of the definition. The current guideline has removed it, so nephrotic syndrome is now proteinuria, hypoalbuminaemia and oedema, with or without raised cholesterol. Clinical identification is not enough: the proteinuria and the low albumin have to be documented.

Primary or secondary

The second question is whether the disease is primary (idiopathic, not caused by another illness) or secondary. Age is the strongest clue. Between about 2 and 12 years, nephrotic syndrome is usually idiopathic, most often minimal change disease, and responds well to steroids. Under one year, congenital nephrotic syndrome is the concern. Above about 12 years, a secondary cause such as systemic lupus erythematosus (SLE) becomes more likely.

Nephrotic syndrome definitions: remission, relapse and steroid response

Remission, relapse, frequent relapses, steroid dependence and steroid resistance each have a precise definition. Dr. Lohia stressed that several have changed recently, and that the current versions should be used.

The frequent-relapse definition is the recent change: the threshold over any twelve months has come down from four relapses to three.

Why steroid resistance is defined at four to six weeks

The cut-off for steroid resistance is contested. Some authorities use four weeks, some six, and the definition keeps changing. Dr. Lohia asks doctors to remember the curve instead: 93% of children are in remission by the fourth week and 97% by the end of the sixth. A child who has not responded by week four is already outside the usual pattern. That is the point at which she begins counselling parents about a kidney biopsy, so that a biopsy report is available by the end of week six. Children who respond between weeks four and six are classed as late responders.

Complete and partial remission

For difficult nephrotic syndrome, KDIGO (Kidney Disease: Improving Global Outcomes) adds a further distinction. Complete remission is urine protein negative or trace on three or more consecutive days. Partial remission is a fall in proteinuria that does not reach that level, typically still showing on the dipstick. Relapse is a return to the nephrotic range, 3+ on three consecutive days. The dipstick scale (negative, trace, 1+, 2+, 3+, 4+) is what makes these categories easy to apply at the bedside, and it is the reading Dr. Lohia asks doctors and parents to track.

Classifying nephrotic syndrome: four cases

Dr. Lohia taught the definitions through cases, each of which turns on one judgement.

A relapse after a first episode. A four-year-old presented with anasarca (generalised swelling of the whole body) and oliguria (low urine output), was confirmed to have nephrotic syndrome and started on steroids. At the two-week review he was in remission. After completing six weeks plus six weeks of treatment, he returned six months later with a cough, a cold and periorbital swelling. This is a relapse, and the trigger is the respiratory infection.

An infrequent relapser. A two-year-old boy presented with his first episode of anasarca and oliguria, without hypertension or haematuria. Urine protein was 4+, the UPCR was in the nephrotic range and the urine sediment was normal. He received 2 mg/kg of prednisolone daily followed by 1.5 mg/kg on alternate days for six weeks, twelve weeks in all, and stayed well for twelve months before relapsing. With fewer than two relapses in six months and fewer than three in twelve, he is an infrequent relapser with a good steroid response.

A frequent relapser. A two-year-old had four relapses in the year after his first episode. That makes him frequently relapsing.

A steroid-dependent child. A two-year-old weighing 10 kg relapsed and was treated with 2 mg/kg daily, followed by 15 mg on alternate days for four weeks, with the dose then tapered. He was in remission by week two, moved into partial remission as the dose came down, and was in full relapse by week eight on 10 mg. Dividing the relapse dose by his weight gives a steroid requirement of about 1 mg/kg: he is steroid dependent, with a high threshold. That threshold, as the steroid-sparing agents article explains, determines which drug comes next.

Initial investigations for nephrotic syndrome

Dr. Lohia's essential workup is designed to work in resource-limited settings. Each test answers a specific question.

1. Urinalysis and complete blood count. Nephrotic syndrome is usually triggered by an infection. The first task is to make sure no infection is still active before steroids begin.
2. Kidney function and serum sodium. A child who arrives with anasarca can have acute kidney injury and hyponatraemia.
3. Total protein and serum albumin. These tell the doctor whether the child is likely to need an albumin infusion. Albumin is expensive, and given without the right indication much of it is simply lost in the urine.
4. Total cholesterol, if the doctor follows the older definition.
5. Chest X-ray and tuberculin test. Tuberculosis must be excluded before long courses of steroids. Dr. Lohia shared the Indian guideline here because the infectious disease burden in India and Africa is similar.

Further tests are added when the child does not respond or when the history raises a concern. Raised liver enzymes or a history of jaundice, for example, call for hepatitis B and hepatitis C testing. Collectively, the workup rules out tuberculosis, active infection and atypical features that would point away from idiopathic disease.

Nephrotic syndrome vs malnutrition

Nephrotic syndrome and malnutrition are completely different conditions, in Dr. Lohia's view, and clinical acumen separates them. Where malnutrition is common, a swollen child with a low albumin may have either:

• In oedematous malnutrition (kwashiorkor), swelling starts in the feet and lower legs and reaches the face only in the most severe grade, usually with skin and hair changes and wasting; the pot belly reflects weak abdominal muscles.
• Serum albumin can be very low in both conditions, so albumin alone does not separate them. The decisive test is the urine: only nephrotic syndrome produces nephrotic-range proteinuria.
• In nephrotic syndrome, the albumin is low and the oedema follows a characteristic sequence that parents describe clearly: first around the eyes, then the face, then the hands and legs, then from the abdomen down to the genitals, until the child has some difficulty walking and breathing.

Oedema in nephrotic syndrome: when to give diuretics and albumin

Diuretics and albumin infusion should be used only when indicated, and Dr. Lohia insists it is a clinical decision, not one driven by laboratory values. Her indications are respiratory distress, genital swelling and anasarca. She described three groups of children.

Minimal oedema early in a relapse. A child who comes in immediately after relapsing with only slight periorbital swelling will respond to steroids and does not need a diuretic. Dr. Lohia treats the cause of the relapse first, such as an infection. If there is no clear cause, she starts prednisolone at 2 mg/kg and reviews the child every third day to see whether a diuretic is needed or remission is coming.

Spreading oedema despite steroids. A child seen 7 to 10 days into a relapse who has not responded to initial management, and whose facial oedema is spreading despite 2 mg/kg of steroids, needs oral diuretics. On 2 mg/kg for about 10 to 14 days such a child will go into remission, but the swelling is causing discomfort in the meantime.

Resistant oedema. A child with anasarca, a lower albumin and no response to oral diuretics needs albumin infusion with diuretics. These children can be recognised clinically: the abdomen is so distended that it causes respiratory embarrassment, or there is genital oedema. Their serum albumin is typically around 1.5 g/dL, and they respond very well to albumin with diuretics.

She starts diuretics in children who are struggling with their swelling partly to protect them from infection: oedema fluid is, in her words, a perfect culture medium, and she does not want a secondary bacterial infection on top of the relapse.

Abdominal pain, ascites and pleural effusion in nephrotic syndrome

Abdominal pain in a child with nephrotic syndrome has several causes, and Dr. Lohia lists four:

• Spontaneous bacterial peritonitis. Treat with antibiotics, generally a third-generation cephalosporin, whichever is available. Many of these children harbour subclinical infection even without overt signs. Children with peritonitis receive antibiotics, diuretics and albumin infusion.
• Stretching of the liver capsule.
• Rapid abdominal distension. Children are not used to a large abdomen. Dr. Lohia compares the change to going from not pregnant to five, seven or even nine months pregnant. The result is pain as well as discomfort: walking and play become very difficult, and younger children who cannot tell discomfort from pain simply become irritable.
• Intestinal wall oedema. The bowel is swollen as well as the skin, which causes diarrhoea and further pain.

Draining ascites by tap is generally avoided: the puncture site tends to leak, infection follows, and the child can go on to develop sepsis. A small diagnostic tap is still used when peritonitis is suspected, to culture the fluid.

Pleural effusion follows the same mechanism as the rest of the oedema. Low albumin lets fluid leave the blood vessels and collect in dependent spaces (third spacing), and in Dr. Lohia's experience the right side is affected more often than the left.

Questions from doctors on several of these points, including the full discussion of diuretic and albumin indications, are on the Live Discussion page.