COMMENTARY

Rituximab for Nephrotic Syndrome in Kids: A Note of Caution

William T. Basco, Jr., MD, MS

Disclosures

February 24, 2020

First-line Therapy for Nephrotic Syndrome: A Comparison

Idiopathic nephrotic syndrome is the most common disorder of glomerular function in pediatrics.[1] Approximately 40% of children diagnosed with idiopathic nephrotic syndrome will have a relapsing course that often is associated with repeated stretches of corticosteroid administration or even corticosteroid dependency. For those children, calcineurin inhibitors, such as tacrolimus, are considered the first-line therapy in an attempt to limit the use of steroids. Beta-lymphocyte-depleting antibodies, such as rituximab, are considered second-line therapy for patients who have failed to go into remission.

A recent randomized clinical open-label trial[1] sought to evaluate the performance of rituximab as a first-line steroid-sparing regimen compared with tacrolimus in maintaining relapse-free survival in children with nephrotic syndrome. The study was conducted at a single large medical center in India. The children were aged 3 to 16 years, with steroid-dependent nephrotic syndrome. All children were naïve to steroid-sparing agents prior to enrollment, and all had undergone kidney biopsy to confirm the diagnosis.

The two treatment arms:

  • The tacrolimus group received daily tacrolimus therapy plus tapering alternate-day oral steroids for up to 12 months

  • The rituximab group received two to four infusions, 1 week apart, along with alternate-day steroids for 4 weeks (of note, in the end, all rituximab patients received two infusions)

Relapse was identified by home urine dipstick testing for protein; significant proteinuria was confirmed by laboratory testing. The main outcome of interest was 12-month, relapse-free survival. Secondary endpoints included the frequency of relapses and the time to first relapse, as well as the cumulative steroid exposure, expressed in mg/kg/year.

A Win for Rituximab

The study ultimately enrolled 120 children, with 60 in each group. There was a slight male predominance among the sample (53%), and the median age was 7.1 years. Approximately 70% of the children had minimal change disease on biopsy, while 30% had focal segmental glomerulosclerosis. The groups had equal historical steroid exposure/treatment before randomization.

Almost all measures favored rituximab. For example, the proportion of children experiencing no relapse was 89.8% among rituximab recipients and 63.8% among tacrolimus recipients. The cumulative steroid exposure was 86.3 mg/kg/yr in the tacrolimus group compared with 25.8 mg/kg/yr in the rituximab group.

From an adverse events standpoint, the only difference was the infection rate, which was 43.3% among the tacrolimus group compared with 21.7% among the rituximab group. There were more infusion reactions among the rituximab group, but none required hospitalization.

The study's conclusion was that rituximab, when compared with tacrolimus, was associated with a significant and clinically important reduction in risk for relapse among children with steroid-dependent nephrotic syndrome.

Viewpoint

Most of my clinical time is spent as a hospitalist and, along with nephrologists, I treat many of these children. I agree that this study showed very large clinical effects, with an 80% reduction in relapse risk, and cumulative steroid delivery or exposure that was less than one third of the tacrolimus group. These appear to be very meaningful differences in the primary outcomes. In addition, the secondary outcome of infection rate favored treatment with rituximab.

However, before this should become widespread practice, I imagine that nephrologists would want to see additional studies, completed in different genetic groups of patients, along with longer follow-up, as suggested by the study authors. Larger and longer trials will be needed to assess the counterbalancing risks for rare adverse outcomes from rituximab (eg, pulmonary fibrosis, myocarditis, ulcerative colitis). These findings, however, seem significant enough to compel further research. A full risk-benefit analysis will determine whether we should change our go-to medication for children with steroid-resistant/dependent nephrotic syndrome.

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