Potential Use of Rituxan in Membranous Nephropathy

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Take-home points from Mayo Clinic’s Fernando Fervenza’s excellent Renal Grand Rounds this morning, in which he addresses the potential use of rituximab as a treatment for membranous nephropathy:

-the “rule of thirds” that we learn about membranous nephropathy (e.g., 1/3 of patients will spontaneously remit, 1/3 of patients will stay the same, and 1/3 of patients will progress to ESRD) is not entirely accurate in that patients with an extremely high degree of proteinuria (e.g., more than 8-10 grams per day) have a very high rate of progression of kidney disease.  This becomes critical in interpreting the results of clinical trials; you really have to look at the baseline proteinuria characteristics of the cohort.
-in non-randomized controlled trials, investigators are finding that dosing Rituxan either using a 1gm iv at D+1 and D+15 protocol OR using a 375 mg/m2 every 4 weeks for 4 doses total leads to at least a partial remission in between 60-75% of membranous nephropathy patients, a rate which is seemingly greater than one would expect for spontaneous remissions. One such paper by Fervenza et al is shown here.  
-a randomized, controlled trial comparing Rituxan to another therapy (e.g., Cytoxan-prednisone or a calcineurin inhibitor) would really be necessary to fully recommend using this strategy in the treatment of membranous nephropathy.  However, it is not clear where the money for performing such a trial would or should come from–industry or government.  
-it may be necessary to look at longer end-points to fully assess the effectiveness of Rituxan.  Since Rituxan targets pre-B cells but not plasma cells, you presumably have to wait until the plasma cells die off for it to have full effect.  Furthermore, monitoring proteinuria (the current standard for evaluating clinical response) is not perfect since it may reflect chronic podocyte damage (which may take months to years to fully heal, if it ever does) rather than immunologically-mediated proteinuria.  
-it looks as if levels of the antibodies against the phospholipase A2 receptor which explains a good chunk of patients with membranous nephropathy correlates generally well with patients who respond to Rituxan; that is, patients who successfully achieve a remission with Rituxan tend to show a complete disappearance of this antibody as assessed by Western blog.  Although this does not prove causality, it does point to a potential means of monitoring patients for a potential response.  

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