Study Questions Rituximab’s Benefit for Children with Hard-To-Treat Idiopathic Nephrotic Syndrome

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The drug rituximab recently emerged as a potential treatment for the childhood kidney disorder known as idiopathic nephrotic syndrome (INS). This anti-CD20 monoclonal antibody has been used successfully to treat immune disorders such as lymphoma and arthritis, but it does not appear to benefit children who have INS that is resistant to standard treatments. That was the conclusion of a recent study by Magnasco et al. in the Journal of the American Society of Nephrology.

Rituximab for INS

Although the cause of INS in children is not fully known, it is believed to be an immune disorder. The disease mechanisms are poorly understood, with the exception of the most severe cases that are caused by molecular defects in genes that encode functionally important glomerular epithelial-cell (podocyte) proteins. Cases not associated with these gene mutations are thought to be due to an immunological dysfunction leading to a circulating factor that modifies the permeability of the glomerular filtration barrier.

Idiopathic nephrotic syndrome is a continuum of clinical disorders characterized by severe proteinuria, hypoalbuminemia, dyslipidemia, and hypercoagulability. There are three histological variants of primary INS: minimal-change nephrotic syndrome, focal segmental glomerulosclerosis, and membranous nephropathy.

With an estimated incidence of two to seven cases per 100,000 children and a prevalence of nearly 16 cases per 100,000, the syndrome causes considerable hardships including fatigue, decreased appetite, weight gain, facial swelling, abdominal swelling or pain, foamy urine, edema, and food intolerances or allergies. Relapses may occur throughout childhood, but once a child reaches puberty the disease typically stays in remission. Although the long-term outcome of the disease is favorable, the treatments’ adverse effects can negatively impact the quality of life of children and their families.

Gian Marco Ghiggeri, MD, of the IRCCS Giannina Gaslini Children Hospital in Genoa, Italy, and his colleagues recently reported that rituximab can successfully reduce proteinuria in children with idiopathic nephrotic syndrome that responds to standard treatments consisting of steroids and calcineurin inhibitors (such as cyclosporin). Therefore, rituximab may allow these patients to discontinue these potentially toxic medications.

Rituximab could help these children by interacting with regulatory elements of the cytoskeleton, and therefore directly modifying the podocyte structure. The drug also affects regulatory elements of B cells positive for CD20 that are implicated in innate immunity and affect Th17 cells. Rituximab also appears to reduce monocyte expression of soluble urokinase-type plasminogen activator receptor, which plays a direct pathogenetic role in focal segmental glomerulosclerosis.

Hard-to-Treat Cases

Up to 80 percent of children with INS respond to steroids, with complete remission usually occurring within 30 days. The remaining cases can be particularly difficult to treat and can lead to end stage renal disease. To test the potential of this agent in children with INS that is unresponsive to standard treatments, Ghiggeri and his team conducted the first open-label randomized controlled trial of rituximab in 31 children with INS that was refractory to steroids and calcineurin inhibitors. All the children, who ranged in age from 2 to 16 years, continued taking steroids and calcineurin inhibitors at the same doses as before they enrolled. Half of the patients also received two doses of rituximab (375 mg/m2 intravenously) as add-on therapy.

After 3 months of treatment, rituximab did not reduce proteinuria (change, –12 percent [95 percent confidence interval, –73 percent to 110 percent] p = 0.77). Additional adjustment for previous remission and interaction terms (treatment by baseline proteinuria and treatment by previous remission) did not change the results. According to the authors, these data do not support the addition of rituximab to prednisone and calcineurin inhibitors in children with resistant idiopathic nephrotic syndrome.

By identifying which patients benefit from rituximab and which do not, “our work represents a step forward on the road to treating nephrotic syndrome in children and it helps define the potentiality and limits of new therapies based on humanized antibodies for the disease,” said Ghiggeri.

Previous studies investigating the use of rituximab in patients with persistent resistance to the classic combination of steroids and calcineurin inhibitors include a short series from 2009 that showed no effect in six of eight patients and a partial response in the remaining two patients after four or six treatments (Fernandez-Fresnedo G, et al. Clin J Am Soc Nephrol 2009; 4:1317–1323). Another study based on questionnaires sent to members of the International Pediatric Nephrology Association found that 44 percent of patients with steroid-resistant nephrotic syndrome had a good initial response to rituximab (Prytula A, et al. Pediatr Nephrol 2010; 25:461–468). Also, a 2010 study reported complete or partial remission in 16 of 33 patients with steroid-resistant nephrotic syndrome who were otherwise refractory to all proven therapies (Gulati A, et al. Clin J Am Soc Nephrol 2010; 5:2207–2212).

“Within the last decade several case reports with positive effects of rituximab in different forms of pediatric nephrotic syndrome were published, but randomized trials were lacking. Despite the negative outcome of the study by Magnasco et al., it is very important as it is the first prospective randomized trial on the effect of rituximab in pediatric steroid-resistant nephrotic syndrome,” said Kerstin Benz, who was not involved with the study and is a nephrologist at the University of Erlangen-Nürnberg, in Germany.The results suggest that researchers and clinicians need a much better understanding of INS to develop effective therapies against hard-to-treat cases. A total of 12 renal genes involved in resistant forms of the disease have been characterized to date, and the list will likely grow. Future molecular analyses will enable researchers to conduct a more comprehensive analysis of all genes potentially involved in the syndrome and to characterize patient populations in whom new therapies may be successful.

Disclosures: The study was supported by the Renal Child Foundation (Genoa, Italy) and La Fondazione La Nuova Speranza (Milan, Italy).

The article “Rituximab in Children with Resistant Idiopathic Nephrotic Syndrome,” appeared online at in May 2012, doi: 10.1681/ASN.2011080775.