This is a retrospective observational study of a randomized controlled trial. Sound confusing? It's really not, and although it's a small study it does offer some fresh insight into pathogenesis and treatment of complicated nephrotic syndrome.
Source: Kamei K, Ishikura K, Sako M, et al. Long-term outcome of childhood-onset complicated nephrotic syndrome after a multicenter, double-blind, randomized, placebo-controlled trial of rituximab. Pediatr Nephrol. 2017;32(11):2071-2078; doi:10.1007/s00467-017-3718-0. See AAP Grand Rounds commentary by Dr. Pamela Singer (subscription required).
It's not hard to imagine how a randomized controlled trial (RCT) morphed into an observational study. In this report on rituximab use for complicated (frequently relapsing or steroid-dependent) nephrotic syndrome, the initial study was a randomized, placebo-controlled trial of rituximab in 52 (mostly) children with these conditions. Results of a preplanned interim analysis showed superiority of rituximab over placebo in lowering relapses over a 12 month period. After this RCT was completed, patients originally receiving placebo were offered entry into a second study on the pharmacokinetics of rituximab, which allowed for observation of 2 cohorts going forward (or backward, if you will!): group A did not need additional rituximab or immunosuppressive agents during the observation period, and group B did require such treatments. This is a somewhat complicated analysis because the use of treatments after the RCT ended was determined by the individual treating physicians.
When the statistical smoke cleared, the authors point out a number of interesting conclusions. First, although rituximab does appear to have benefit in these complicated nephrotic syndrome circumstances, most patients receiving this agent will still experience more relapses down the road. However, the subgroup of patients who were doing well enough to enable discontinuation of steroids and immunosuppressives at the time of rituximab use seemed to be more likely to achieve long-term remission of their disease, compared to patients who needed to remain on steroids and/or immunosuppressives. This could mean that immunosuppressives in this "mild" group could be withheld after rituximab treatment.
Also, based on observations of B-cell depletion and recovery after rituximab, the authors speculate that the role of B cells in the pathogenesis of nephrotic syndrome might be indirect, involving some mechanism of the interaction between T and B cells. This could point the way to future treatment development and clinical trials.
One final note on the reporting of the article itself. Figure 3 in the study is an excellent example of graphical display of a lot of information in a form that conveys a great deal of understanding of the data. Sadly, I can't link directly to it due to copyright protections, but readers who have access to that journal should take a look. For all of you, please look at Charles Joseph Minard's map of Napoleon's 1812 Russia campaign, thought to be one of the best graphical displays of complex information in history. (I have a framed print hanging in my office, staring at me every day!) After all, Evidence-Based Medicine is nothing if we can't explain it to our patients in terms that they can use to make healthcare choices.
