Second-line options for refractory steroid-sensitive and -resistant nephrotic syndrome.

Although initially, many children with idiopathic nephrotic syndrome respond to steroid therapy, a repeated course for patients with relapses often causes significant steroid toxicity. Patients with frequent relapses or steroid dependency thus require alternative treatment, and so far, cyclophosphamide or levamisole have been regarded as first-choice options, although the latter is no longer available in many countries. Data are accumulating that mycophenolic acid may be an alternative for these patients. Calcineurin inhibitors (cyclosporine A or tacrolimus) are usually effective and are often used after cytotoxic treatment, but long-term treatment is necessary, raising concerns regarding the accumulation of side effects. Still, some patients show a tendency to relapse even on this maintenance regimen and some even have a refractory course that creates a medical dilemma. For this situation, recent data have demonstrated an effect of monoclonal antibodies directed to B cells - rituximab, a drug that may also prove to be a therapeutic option in less complicated cases. Patients that do not respond to initial steroid treatment need genetic testing and a renal biopsy, since focal segmental glomerulosclerosis may be present. Treatment options include pulse methylprednisolone, often in addition to calcineurin inhibitors (mainly cyclosporine but also, recently, tacrolimus). Cyctotoxic treatment, especially intravenous cyclophosphamide, has been found to be effective in steroid-resistant nephrotic syndrome by some studies but is inferior to calcineurin inhibitors. In addition, mycophenolic acid and rituximab have been used in children with primary focal segmental glomerulosclerosis; however, response seems to be inferior in comparison with patients with steroid-sensitive nephrotic syndrome. Taken together, idiopathic nephrotic syndrome, including steroid-sensitive as well as steroid-resistant patients, is a potentially serious disorder. Although much progress has been made in recent years and a wide arsenal of immunological interventions is available, some patients have a treatment refractory course. Prospective studies or at least standardization of treatment for complicated cases is urgently needed.