Management of Nephrotic Syndrome in Childhood

Summary

Nephrotic syndrome is defined as proteinuria sufficiently severe to result in hypoalbuminaemia, oedema and hyperlipidaemia. The early modern history of this illness was characterised by the serendipitous development of renal biopsy technique at approximately the same time as the use of corticosteroids for nephrotic syndrome. The coincidence of these events set the stage for evaluating therapeutic response to corticosteroids and cytotoxic agents in relation to renal histology and ultimate clinical outcome.

The International Study of Kidney Disease in Children (ISKDC) was initiated in the 1960s as a multicentre study examining these relationships in children. Over the next decade this study, as well as contributions from other investigators, helped define optimum therapy for these children. It was determined that a child with nephrotic syndrome under the age of 6 years, who did not present with hypertension, azotaemia, hypocomplementaemia or signs of systemic illness, had an approximately 85% chance of responding to corticosteroid therapy. If only those children who had minimal change histology on biopsy were considered, 94% responded. The original regimen which is still used today, was 60 mg/m² bsa/day prednisone administered on a 3 times per day dosage schedule for 4 weeks, followed by an additional 4 weeks of therapy at a dose of 40 mg/m² bsa given as a single oral dose every other day.

Of those who respond roughly one-third will have no relapses, while almost half will have frequent relapses (⩾ 2 in 6 months) and the rest will have infrequent relapses. Patients in relapse are treated as at presentation but are usually converted to the 40 mg/m² bsa dose when the urine has been free of protein for 3 days, and are then tapered off or maintained on this dose for several weeks, depending on the individual’s history of relapses and incidence of side effects from corticosteroids.

For those children who are suffering frequent relapses and severe corticosteroid side effects (e.g. growth failure, morbid obesity, aseptic necrosis of bone), cytotoxic agents were identified as providing long term remission. After inducing remission with conventional corticosteroid dosages, cyclophosphamide is administered at a dose of 2 mg/kg/day given as a single dose for 8 weeks. This regimen was shown to lead to approximately 70% of patients being in remission 2 years after completion of this course of therapy. Chlorambucil given at a dose of 0.2 mg/kg/day as a single oral dose has been equally efficacious. A subgroup of the frequently relapsing patients, termed steroid-dependent (defined as relapsing while tapering prednisone or very shortly after discontinuing prednisone) are less likely to benefit from cytotoxic therapy, with only 30% being in remission 2 years after therapy is completed. In addition, children with histological lesions other than minimal change (e.g. focal segmental glomerulosclerosis) are less likely to respond to corticosteroids or cytotoxic agents.

Two other agents have been used for treatment of nephrotic syndrome. In steroid-dependent or -resistant children oral cyclosporin 7 mg/kg/day kept serum trough concentrations between 100 and 200 μg/L. Many of these patients relapsed when therapy was discontinued. Chlormethine (nitrogen mustard) has also been effective in producing long relapse-free intervals when used at a dose of 0.1 mg/kg/day, given as a single intravenous dose for 4 days.

The risks of these medications are discussed, focusing on leucopenia, infertility and risk of subsequent malignancy. At the dosages noted above, leucopenia is not required for the therapeutic effect and does not usually prevent the completion of therapy, infertility is rare, and at present the question of increased risk of malignancy due to the use of cytotoxic agents remains unanswered.