Difficult Nephrotic Syndrome in Children

Difficult nephrotic syndrome in children is the minority of childhood nephrotic syndrome that does not settle with a single course of steroids: children who relapse frequently, who become steroid dependent, or who do not respond to steroids at all. Most children respond well to steroids, but more than half of those followed for a year go on to frequent relapses or steroid dependence, and a small group stops responding.

Dr. Shraddha Lohia, then Consultant, Paediatric Nephrology at Fortis Memorial Research Institute, Gurgaon, India, built her masterclass for paediatricians and general practitioners across Africa around this problem. Her aim was practical: to help doctors diagnose and classify each episode correctly, treat relapses and complications, provide supportive care, and recognise the point at which a child needs a paediatric nephrologist. This guide sets out her framework. Three companion articles go deeper into diagnosis, classification and oedema management, steroid-sparing agents, biopsy and genetic testing, and steroid toxicity, diet and long-term monitoring.

What is difficult nephrotic syndrome in children?

Nephrotic syndrome becomes difficult when a child relapses frequently, becomes steroid dependent or stops responding to steroids. Nephrotic syndrome itself is a kidney disorder in which the glomeruli, the kidney's filters, leak large amounts of protein into the urine. Dr. Lohia defines it by three features: nephrotic-range proteinuria, low serum albumin and oedema. Raised cholesterol, once part of the definition, has been taken out of the current guideline, so a child can be diagnosed with or without it.

In a child between roughly 2 and 12 years of age, the disease is usually idiopathic, most often the minimal change pattern (in which the kidney looks almost normal under a light microscope), and it typically responds well to steroids. Outside that window the picture changes. A child under one year raises the possibility of congenital nephrotic syndrome, and a child older than 12 is more likely to have a secondary cause such as systemic lupus erythematosus (SLE). Steroid-sensitive nephrotic syndrome is common, and doctors in general paediatric practice see far more of it than specialists do. That is why Dr. Lohia concentrated on the children who fall outside the easy pattern.

The working classification she uses divides children first by their response to steroids:

• Steroid sensitive, which includes three courses: infrequently relapsing, frequently relapsing and steroid dependent.
• Steroid resistant, which she treats as an entirely different entity with its own investigations and treatment.

The precise definitions of remission, relapse, frequent relapses, dependence and resistance, and how to apply them to real cases, are covered in the diagnosis and classification article.

Relapse rates in childhood nephrotic syndrome

Only 7% of children with steroid-sensitive nephrotic syndrome stayed free of relapse over a year of follow-up, and more than half relapsed frequently or became steroid dependent. Dr. Lohia presented data from a study of children with steroid-sensitive disease followed for one year. The distribution is the single most useful fact for setting expectations with families:

Her shorthand for parents is roughly "30, 30, 30": about a third relapse infrequently, about a quarter to a third relapse frequently, and about a third become steroid dependent. Only a small fraction never relapse at all. Families who expect a single course of treatment to end the illness are, in most cases, going to be disappointed, and the counselling has to reflect that from the first visit.

The timing of steroid response matters just as much. By Dr. Lohia's figures, 93% of children are in remission by the fourth week of daily steroids, and 97% by the end of the sixth week. The children in the 4% gap between those two points are, in her experience, the ones who prove very difficult to treat: they tend to become steroid dependent or steroid resistant.

Steroid dose for nephrotic syndrome: first episode and relapse

The backbone of treatment is oral prednisolone, and Dr. Lohia follows the paediatric schedule she described as standard under the KDIGO (Kidney Disease: Improving Global Outcomes) guideline.

First episode. Prednisolone 2 mg/kg daily for 6 weeks, followed by 1.5 mg/kg on alternate days for a further 6 weeks: twelve weeks of treatment in total.

Relapse. Treat any triggering infection first. Then give 2 mg/kg daily until the child is in remission, followed by 1.5 mg/kg on alternate days for 4 weeks.

Infrequent relapsers. These children can simply be observed between episodes. Dr. Lohia's priority is to complete any pending vaccinations once the steroid course is over, because every infection avoided is a relapse avoided.

Frequent relapsers. The first line is a low-dose maintenance course of prednisolone on alternate days, continued for 6 to 12 months depending on how the child responds. If the dose needed to keep the child in remission is too high, or the child keeps relapsing, the next step is a steroid-sparing agent.

Infection deserves particular emphasis. Nephrotic syndrome is generally triggered by an infection, and Dr. Lohia's rule is to make sure no infection is persisting before steroids start; otherwise, in her words, the course goes "downhill". A cough and cold followed by periorbital swelling (puffiness around the eyes) a few months after a first episode is the classic presentation of a relapse.

When steroids are not enough: the steroid-sparing ladder

Steroids are used heavily for three reasons, in Dr. Lohia's analysis: they are readily available, they are cheap, and in many settings there are neither alternative medicines nor a specialist to guide their use. The cost of that reliance falls on the child, through hypertension, obesity, impaired glucose tolerance, cataracts, bone disease, short stature and behavioural change.

Her answer is a structured ladder of steroid-sparing agents, chosen according to how much steroid the child needs to stay in remission:

1. Prednisolone, with levamisole when the steroid threshold is low.
2. Mycophenolate mofetil (MMF) when the threshold is higher or levamisole fails.
3. Cyclophosphamide, as a single course in children of the right age.
4. Calcineurin inhibitors (ciclosporin or tacrolimus), after a kidney biopsy.
5. Rituximab for the most difficult children.

The order, the monitoring each drug needs, the place of kidney biopsy and genetic testing, and the definitions that govern steroid-resistant disease are covered in the article on steroid-sparing agents, biopsy and genetic testing. The full list of steroid side effects, and how to monitor growth, blood pressure, eyes and bone, is in the article on steroid toxicity, diet and long-term monitoring.

Difficult cases in practice: steroid overuse and rituximab

Prolonged steroid treatment without a plan to taper can leave a child more exposed to infection and relapse, as one of Dr. Lohia's cases shows. The child, first affected at four and a half years of age, was treated locally with steroids continuously for about five months and then developed pneumonia: prolonged steroid exposure had left her immunity severely depleted. Because infection in turn triggers relapse, such a child can enter a cycle of infection, relapse and more steroids.

At the other end of the spectrum, Dr. Lohia showed children whose disease had seemed intractable until they reached the top of the ladder. A girl referred after about five years of continuous steroids, with marked steroid toxicity, and a nine-year-old with severe anasarca (generalised swelling of the whole body) who needed repeated albumin infusions, both went into remission on rituximab. Their full treatment histories, and what they teach about timing, are set out in the steroid-sparing agents article. For difficult nephrotic syndrome, Dr. Lohia's experience is that rituximab can make management far simpler.

Counselling parents of a child with nephrotic syndrome

Dr. Lohia regards counselling as part of the treatment. A child with a kidney disease carries a heavy stigma in many families, who often equate any kidney problem with kidney failure. They need repeated reassurance across what is a long journey. She frames the conversation around four questions.

Why does my child have this disease? Between about 2 and 12 years of age, nephrotic syndrome is idiopathic: it has no identifiable external cause. Under one year it is usually congenital, and over 12 it is more often secondary to another disease.

How long will the relapses continue? Nobody can predict this precisely, and Dr. Lohia tells families so. It depends on the child's response to treatment and on the maturity of the kidneys. Some children grow out of relapses by 12, some by 18, and some later.

What can we do to prevent relapses? Complete the routine vaccination schedule and add pneumococcal and influenza vaccines. Practise hand washing, avoid crowded places and wear a mask: fewer infections mean fewer relapses. Before any planned surgery or dental extraction, the family should ask the surgeon or dentist to speak to the nephrologist, so that a stress dose of steroid can be given if needed.

How will we know the child is unwell? Dr. Lohia asks parents to test the urine daily with a dipstick when the seasons change and through the winter. Proteinuria sometimes appears before an infection and sometimes after it. Swelling, a child who seems "off", who sleeps more or who passes less urine are all signals to act.

Treating nephrotic syndrome locally with specialist support

Many children with difficult nephrotic syndrome do not need to travel. Dr. Lohia's view is that working with the local doctor is the best model: it costs the family less, the child does not have to travel to India to buy medicines or see her, and the child is treated by a doctor who can follow them up.

Two practical barriers came up in the session. The first is access to medicines: where levamisole, MMF, tacrolimus or rituximab are not available, Dr. Lohia offered to have them arranged through the distributor and couriered at a reasonable rate, noting that medicines and healthcare in India are relatively inexpensive by international standards. The second is continuity. Some families call her because their child is swelling and they cannot reach a doctor; others come back from a consultation with medicines but no letter explaining what happened. A shared plan solves both. Once the treating doctor and the nephrologist agree, for example, that a year of levamisole is complete and it is time to move to MMF, the medicine can be arranged in advance, the local doctor briefed on what to watch for in the blood work, and the reports shared for review whenever the doctor wants a second opinion.

Questions from doctors in South Sudan, Nigeria and elsewhere, including how to separate nephrotic syndrome from malnutrition and when to use albumin and diuretics, are collected in the Live Discussion from this masterclass. More on kidney disease in adults and children is gathered under nephrology.

When to refer a child with nephrotic syndrome to a paediatric nephrologist

Dr. Lohia's framework points to six clear triggers for referral to a paediatric nephrologist:

• No remission after four weeks of daily steroids, which is when she begins counselling parents about a kidney biopsy.
• A child younger than one year or older than 12 at onset.
• Frequent relapses or steroid dependence that need a steroid-sparing agent, particularly once a calcineurin inhibitor is being considered.
• Significant blood in the urine, systemic features, or kidney dysfunction not explained by low circulating volume.
• A family history of nephrotic syndrome or kidney transplantation, which points towards genetic disease.
• Visible steroid toxicity: short stature, obesity, cataracts, hypertension or striae.

Dr. Shraddha Lohia is currently Principal Consultant – Paediatric Nephrology at Max Hospital, Vaishali, India.