Treatment Studies of Nephrotic Syndrome Also Offer Insight into Pathogenesis
BudWiederman, MD, MA, Evidence eMended Editor, Grand Rounds
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.
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
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
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.