The introduction of corticosteroids more than 50 years ago dramatically improved the prognosis of children with nephrotic syndrome. Corticosteroids remain the standard initial treatment for children with this disease, but a considerable proportion of patients do not respond and are therefore at risk of progressing to end-stage renal disease. Because of this risk, new therapeutic strategies are needed for steroid-resistant nephrotic syndrome. These strategies have historically focused on identifying effective alternative immunosuppressive agents, such as ciclosporin and tacrolimus, yet evidence now indicates that nephrotic syndrome results from podocyte dysfunction. Even conventional immunosuppressive agents, such as glucocorticoids and ciclosporin, directly affect podocyte structure and function, challenging the ‘immune theory’ of the pathogenesis of childhood nephrotic syndrome in which disease is caused by T cells. This Review summarizes the currently available treatments for childhood nephrotic syndrome, and discusses selected novel pathways in podocytes that could be targeted for the development of next-generation treatments for children with this syndrome.
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van Husen M, Kemper MJ. New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome. Pediatr Nephrol. 2011 Jun;26(6):881-92.
Although many children with idiopathic nephrotic syndrome (INS) respond initially to steroid therapy, repeated courses for patients with relapses often cause significant steroid toxicity. Patients with frequent relapses who develop steroid dependency thus require alternative treatment. The first such options have been considered to be cyclophosphamide or levamisole, although the latter is no longer available in many countries. There is also an increasing body of data indicating that mycophenolic acid (MPA) may be an alternative for these patients. Calcineurin inhibitors (cyclosporine A or tacrolimus) are usually effective and often used after cytotoxic treatment, but long-term treatment with these agents is necessary, raising concerns of a possible accumulation of side effects. Some patients show a tendency to relapse even on such maintenance regimens, and some even have a refractory course that creates a medical dilemma. For this situation, recent data indicate that monoclonal antibodies directed to B-cells (e.g. rituximab) may have some effect and that such drugs may also prove to be a therapeutic option in less complicated cases. Patients that do not respond to steroid treatment need genetic testing and a renal biopsy since focal segmental glomerulosclerosis (FSGS) may be present. Treatment options include pulse methylprednisolone, often in addition to calcineurin inhibitors, mainly in the form of cyclosporine, but tacrolimus has also come into recent favor. Some studies have found cytotoxic treatment, especially intravenous cyclophosphamide, to be effective in steroid resistant nephrotic syndrome, but it seems to be inferior to calcineurin inhibitors. MPA and rituximab have also been used in children with primary FSGS, but the response seems to be inferior to that in patients with steroid sensitive nephrotic syndrome. Taken together, INS in both steroid-sensitive and steroid-resistant patients is a potentially complicated disorder, and despite a wide arsenal of immunological interventions, some patients have a treatment refractory course. Prospective studies or at least standardized treatment for complicated cases is urgently needed.
Manrique-Rodríguez S, Fernandez-Llamazares CM, Sanjurjo-Saez M. Pharmacotherapeutic review and update of idiopathic nephrotic syndrome in children. Pharm World Sci. 2010 Jun;32(3):314-21.
The treatment algorithm established in our hospital is consistent with the evidence available. Prednisone constitutes the first line treatment with evidence level Ia. When corticosteroids do not achieve remission, there are other therapeutic options that are not clearly positioned yet and further studies that provide more information on their comparative efficacy and safety are needed. These alternative therapeutic options are cyclosporine, mycophenolate mofetil, levamisol, cyclophosphamide and methylprednisolone, as independent strategies or as part of “Mendoza Protocol”, tacrolimus and rituximab. Their sequence of introduction in the therapeutic scheme of NS is classified as evidence level IV and grade D recommendation.
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Gipson DS, Massengill SF, Yao L, Nagaraj S, Smoyer WE, Mahan JD, Wigfall D,
Miles P, Powell L, Lin JJ, Trachtman H, Greenbaum LA. Management of childhood
onset nephrotic syndrome. Pediatrics. 2009 Aug;124(2):747-57.
The therapeutic approach to childhood nephrotic syndrome is based on a series of studies that began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children in 1967. The characteristics of children presenting with nephrotic syndrome have changed over recent decades with greater frequency of the challenging condition focal segmental glomerulosclerosis and a greater prevalence of obesity and diabetes mellitus, which may be resistant to glucocorticoids in the former and exacerbated by long-term glucocorticoid therapy in the latter 2 conditions. The Children’s Nephrotic Syndrome Consensus Conference was formed to systematically review the published literature and generate a children’s primary nephrotic syndrome guideline for use in educational, therapeutic, and research venues.
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