Frequent-relapsing, steroid-dependent minimal change disease: is rituximab the answer?

In patients with minimal change disease, development of steroid-dependency or frequent relapses pose difficult therapeutic problems. Prolonged administration of corticosteroids or the use of additional immunosuppressive therapy can result in significant toxicity. Recent data point to the use of rituximab as an important treatment option to induce long-term remission in patients with minimal change diseases who are either frequent relapsers or require significant immunosuppression to remain in remission. Minimal change disease (MCD) accounts for the majority of cases of idiopathic nephrotic syndrome (NS) in children and up to 20% of cases of idiopathic NS in white adults [1]. On kidney biopsy, MCD is characterized by widespread effacement of epithelial cell foot processes on electron microscopy, while glomeruli appear normal on light microscopy and immunoglobulin and complement deposition are absent on immunofluorescence. Most cases of MCD are idiopathic, although drugs (such as non-steroidal anti-inflammatory drugs), hematological malignancies (mainly Hodgkin lymphoma) and thymoma are well-recognized causes of secondary MCD. While most patients respond to corticosteroid therapy, up to 25% of treated patients have frequent relapses and up to 30% of patients become steroid dependent [2, 3]. In these patients, alternative therapies aimed at minimizing corticosteroid toxicity have been used, including alkylating agents, antimetabolites and calcineurin inhibitors. While these agents may be beneficial, some patients respond poorly or not all, and their use may be complicated by the development of serious adverse effects, e.g., infertility and malignancy with the use of cyclophosphamide. With calcineurin inhibitors, steroid dependency may be replaced by dependence on calcineurin inhibitors, requiring years of treatment and the associated risk of nephrotoxicity [3]. In some patients, these agents are used in combination, adding to the potential adverse effects. An additional problem is non-compliance, especially in young patients. As such, alternative therapies that can result in the induction of long-term remission with a favorable safety profile have been sought. Rituximab (RTX), a chimeric monoclonal antibody directed against the B-lymphocyte-restricted cell-surface protein CD20, has achieved great success in the treatment of a number of autoimmune conditions affecting the kidney, including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and membranous nephropathy [4]. The serendipitous findings that RTX treatment in two young patients—a 16-year-old patient with severe idiopathic thrombocytopenic purpura and steroid-dependent NS with multiple relapses [5] and a child with recurrent focal segmental glomerulosclerosis (FSGS) after undergoing kidney transplantation who developed a lymphoproliferative disease—resulted in remission of proteinuria [6] suggested that B cells may be involved in the pathogenesis of FSGS and NS. Considering that MCD can evolve into FSGS and both have podocyte injury and widespread foot process effacement as a common denominator, it is not surprising that a ‘leap of faith’ could be made in using RTX to treat MCD (Figure 1). Indeed, two case reports—one by Gilbert et al. [7] of a 15-year-old girl with high-dose steroid-dependent MCD and one by Francois et al. of a 22-year-old woman with multirelapsing MCD—showed that RTX was effective in inducing complete remission of NS. The case reported by François et al. [8] is illustrative, for the patient had a history of MCD since she was 6 years old, with multiple relapses requiring repeated courses of cyclophosphamide, prolonged cyclosporine exposure with the development of nephrotoxicity, and unresponsiveness to mycophenolate mofetil and to an anti-CD25 antibody (basiliximab). She was treated with RTX, 375 mg/m, weekly for 4 weeks, with retreatment at 1 year. Complete remission 3 weeks later persisted for up to 28 months despite the absence of maintenance immunosuppression. IN F O C U S