Difficult-to-treat idiopathic nephrotic syndrome: established drugs, open questions and future options.

The idiopathic nephrotic syndrome in childhood can be classified according to the International Study of Kidney Disease in Children (ISKDC) based on the response to steroids. Typically, steroid-sensitive nephrotic syndrome (SSNS) is characterised by minimal changes in disease (MCD) histology, whereas in steroid-resistant nephrotic syndrome (SRNS) focal segmental glomerulosclerosis (FSGS) is the most prevalent lesion. Patients with SSNS may develop frequent relapses and/or steroid dependency, which can be difficult to treat. New studies confirm the value of calcineurin inhibitors (CNIs) and mycophenolic acid in preventing relapses of SSNS. Rituximab also plays an important role, but many questions regarding initial dosing, repetitions of courses, and long-term side effects remain unclear. SRNS, especially when unresponsive to treatment, can lead to chronic kidney disease. In particular, treatment with CNIs has improved the prognosis and recent data indicate that treatment can even be discontinued in many patients with full remission. In CNI-unresponsive SRNS, rituximab is less effective than in SSNS and the role of other biologicals (such as ofatumumab, abatacept, and others) remains unclear. A significant proportion of children with FSGS have genetic causes and most patients do not respond to immunosuppression, although individual patients with partial and even complete response have been documented. Future studies should evaluate treatments leading to long-term remission without maintenance immunosuppression in SSNS; in both genetic and immune-mediated SRNS, novel options to decrease the number of treatment-unresponsive patients seem mandatory, as they are at a high risk of developing end-stage renal disease.