Steroid-Sparing Agents for Nephrotic Syndrome in Children

Steroid-sparing agents for nephrotic syndrome are the medicines used to keep a child in remission while reducing or stopping steroids: levamisole (an immune-modulating drug), mycophenolate mofetil (MMF, an immunosuppressant), cyclophosphamide (an immunosuppressant also used in chemotherapy), the calcineurin inhibitors ciclosporin and tacrolimus, and rituximab. The choice between them depends above all on the child's steroid threshold, the lowest steroid dose that holds remission.

Dr. Shraddha Lohia, then Consultant, Paediatric Nephrology at Fortis Memorial Research Institute, Gurgaon, India, set out the sequence she uses, the monitoring each drug needs, and the points at which a kidney biopsy or genetic test changes the plan. This article follows that sequence. For the definitions of frequent relapses, steroid dependence and steroid resistance, see diagnosis and classification of nephrotic syndrome; for the overview of the whole condition, see the complete guide to difficult nephrotic syndrome.

Why steroid-sparing agents matter

The case for these drugs is the child's development. Dr. Lohia's argument is straightforward: once a child can be taken off steroids, growth stays on track, and immunisation becomes easier, since vaccine responses are blunted in a child on immunosuppression. For children with frequent relapses or steroid dependence, she brings the steroid dose down to the bare minimum. The steroid toxicity article sets out the side effects these drugs help avoid.

The first decision: is a biopsy needed before treatment?

KDIGO (Kidney Disease: Improving Global Outcomes) separates children by age. In a child under 12 who responds well, there is no need for an immediate kidney biopsy: treat orally and observe. In a child older than 12, a kidney biopsy is recommended. The same applies to congenital nephrotic syndrome. In Dr. Lohia's summary, any child younger than one year or older than 12 years should have a biopsy to identify the cause. A child under 12 who fails to respond moves into the "special situations" pathway, where biopsy and genetic testing are considered.

Choosing a steroid-sparing agent by steroid threshold

Dr. Lohia chooses the next drug according to the steroid dose on which the child relapses, expressed per kilogram of body weight.

• Threshold below 0.5 mg/kg. Steroids followed by levamisole.
• Threshold above 0.5 mg/kg. Skip levamisole and go directly to MMF.

Her practice sequence, in full, is: steroids; then levamisole or MMF according to the threshold; then cyclophosphamide, provided the child is older than five and younger than 11; then a kidney biopsy and a calcineurin inhibitor (ciclosporin or tacrolimus); and finally rituximab for the most difficult children. Before any of these, a frequently relapsing child may be held on low-dose alternate-day prednisolone for 6 to 12 months.

Levamisole for nephrotic syndrome

Levamisole is Dr. Lohia's first steroid-sparing agent for children with a low steroid threshold. It is cheap relative to MMF and the other drugs, and has the fewest side effects. In her experience, Indian and African children respond surprisingly well to it, and a European randomised trial has also confirmed its benefit. That combination of low cost, few side effects and a good response makes it a practical first choice where budgets are tight.

Mycophenolate mofetil (MMF)

MMF is somewhat more expensive and needs monitoring: Dr. Lohia checks blood tests every three months for abnormalities, including liver toxicity. Once the child is established on MMF, the steroid dose can be tapered. MMF is typically continued for two to three years.

Cyclophosphamide

If MMF does not hold the child in remission, the next step is cyclophosphamide, given as a single 12-week course. It is not repeated.

The reason is gonadal toxicity. Dr. Lohia avoids cyclophosphamide in children younger than about four or five years and in adolescents, using it in the window between about five and 11 years. Outside that window, the child moves to the next rung.

Calcineurin inhibitors: ciclosporin and tacrolimus

Calcineurin inhibitors (CNIs) suppress the immune response by blocking calcineurin, an enzyme that activates T cells. Dr. Lohia sets three rules for their use.

1. Biopsy first. A kidney biopsy is done before a CNI is started, to establish the underlying histology.
2. Counsel the parents. CNIs are a double-edged sword: they benefit the child, but they can also damage the kidneys. Families should hear this before treatment begins.
3. Repeat the biopsy at three years. Given that risk to the kidneys, three years of CNI treatment is the landmark at which Dr. Lohia repeats the biopsy.

Tacrolimus has a practical advantage over ciclosporin: its cosmetic side effects are much less marked. Its drawback, in her account, is that glucose tolerance can be impaired, which needs watching.

Rituximab for difficult nephrotic syndrome

Rituximab is a monoclonal antibody given by intravenous infusion that depletes B cells. Dr. Lohia places it at the top of the ladder for difficult-to-treat children, and finds that it makes management of difficult nephrotic syndrome much easier.

It also solves a problem that has nothing to do with biology. Some families struggle to give tablets twice a day: the doses clash with school, some young children cannot swallow tablets, and some drugs have no liquid formulation. For these children, infusions replace the daily tablets, and rituximab becomes a very good option on practical grounds alone.

Two of Dr. Lohia's cases illustrate both reasons.

• A steroid-dependent girl had been on steroids for about five years and had visible steroid toxicity when she was referred. Cyclophosphamide came first, then tacrolimus for two years, on which she did well. When twice-daily dosing became too hard to manage around school, her parents asked for an injectable option. Two doses of rituximab followed, and she has been in remission since.
• A child first affected at one and a half years had received so much treatment that it was unclear whether the disease was steroid dependent or frequently relapsing. He arrived with anasarca and was given albumin with diuretics. Once that episode was treated he was started on a CNI and, because he had not fully improved on it, was given rituximab as well. He is now very well controlled.

Steroid-resistant nephrotic syndrome

Steroid-resistant nephrotic syndrome (SRNS) is, in Dr. Lohia's words, an entirely different entity. The KDIGO framework she presented divides it into several groups, each with its own implications.

• Confirmation period. If a child has reached only partial remission after four weeks of daily steroids, KDIGO allows a further period of up to two weeks to confirm resistance, during which intravenous methylprednisolone pulses may be given. Dr. Lohia begins counselling parents for a kidney biopsy at four weeks, so that the result is ready by the end of week six.
• Late responders. Children who respond between four and six weeks are steroid sensitive, but late.
• CNI-responsive and CNI-resistant SRNS. Whether a child responds to a calcineurin inhibitor is decided only after six months of treatment, not earlier and not later.
• Multidrug-resistant SRNS. A child who has not responded to two different steroid-sparing drugs.
• Secondary SRNS. A child who initially responded well to steroids but later stops responding.

The six-month rule for CNI response has a practical caveat. One of Dr. Lohia's patients, a nine-year-old girl with severe anasarca and a very low albumin who needed repeated albumin infusions, showed no response to tacrolimus after two months. Formally she was not yet CNI resistant. But giving albumin and tacrolimus in parallel had become very difficult for the family, so Dr. Lohia moved to rituximab, and the child went into remission.

When to do a kidney biopsy in nephrotic syndrome

Dr. Lohia's indications for kidney biopsy in nephrotic syndrome:

• Age older than 12 years or younger than one year at onset.
• Steroid-resistant nephrotic syndrome.
• Steroid-sensitive disease that needs a CNI (a pre-CNI biopsy).
• Marked microscopic or macroscopic haematuria.
• Systemic features, in which case complement levels (C3 and C4) and antinuclear antibodies (ANA) are also checked to exclude vasculitis.
• Kidney failure that is not explained by hypovolaemia (low circulating blood volume).

When to do genetic testing in nephrotic syndrome

Genetic testing identifies inherited forms of nephrotic syndrome, which usually do not respond to immunosuppression. Dr. Lohia recommends it for:

• Steroid-resistant nephrotic syndrome.
• Congenital nephrotic syndrome.
• Syndromic presentations with abnormal physical features.
• A family history of nephrotic syndrome or of kidney transplantation, which points towards familial focal segmental glomerulosclerosis (FSGS) or inherited steroid resistance.

Dr. Lohia also described newer treatments under study. None is yet part of her practice, but they may become options in future.

Amyloidosis in children

Asked about amyloidosis during the session, Dr. Lohia noted that it is very rare in children and is generally seen in adults. A kidney biopsy establishes the diagnosis, and management is directed at controlling the underlying inflammatory disease, together with supportive care.

Running the ladder outside a specialist centre

Much of this ladder can be run by a local paediatrician with specialist support. Dr. Lohia's example is the child who has completed a year of levamisole and needs to move to MMF: once the plan is agreed, the medicine can be arranged, the local doctor briefed on what to look for in the three-monthly blood tests, and the results shared for review. Where a drug is unavailable locally, she offered to have it arranged through the distributor. The full discussion is on the Live Discussion page.