Unfortunately the evidence is not strong enough to suggest that the use of rituximab will have any effect on chronic antibody mediated rejection after kidney transplantation. The reason for this is possibly two-fold. Firstlly, the ineffectiveness of Rituximab, on its own, in dealing with preformed antibody as well as memory plasma cells is its shortcoming. Secondly, to have reasonable evidence for the question posed, one must undertake a study of a randomized nature with enough power to arrive at suitable conclusion. Such a trial may never take place, again, for several reasons, the most important being the lack of belief n the transplant world that Rituximab on its own can deliver such an important end-point.

Furthermore, in a sensitised patient, there are so many more variables at play (antibody level, Class1, Class 2, cumulative MFI, rebound of antibody after transplantation) that it would be difficult to tease out whether the use of rituximab at the outset really made a difference in the long-term. going in for a renal transplant. 

The best evidence to date in improving long-term graft survival (mechanism however not known or proved) seems to be from the Miami Group that have demonstarted better long-term survival in The third arm of a 3 arm study (standard Il-2, One dose of donor bone marrow and 2 doses of donor bone marrow).

Thank you very much, Dr.Vaidya for your invaluable input! This is very nice explanation! As a nephrology fellow, I feel like we are currently doing much better at reduction in acute rejection rate, but long-term allograft function and transplant glomerulopathy are still something that need a long road to go. Thank you for your suggestion and additional reference for me to read more.

Best regards,

Wisit

Hi Wisit

I agree with Anil in that  the evidence is not strong enough to suggest that the use of rituximab will have any effect on chronic antibody mediated rejection after kidney transplantation.

Chronic ABMR is a more difficult condition to treat because irreversible tissue damage has occurred in the setting of severely compromised graft survival.A small-scale retrospective study of rituximab combined with standard maintenance immunosuppression (including prednisone, mycophenolate mofetil and calcineurin inhibitors) in 31 patients with chronic ABMR had encouraging results, with partial therapeutic response and an increase in median graft survival in the rituximab-treated group compared with the control group (685 days vs. 439 days, respectively). The outcomes within the rituximab group were dichotomous, with significantly different median survival time in responders compared with nonresponders and control patients, though there were no pathologic parameters that distinguished any subset of patients.

Clinical trials of rituximab for the treatment of chronic ABMR are ongoing or recruiting patients (NCT00476164 [RituxiCAN-C4] in the United Kingdom and NCT00307125 in the United States).

Also the papers below might be helpful.

http://www.medscape.com/viewarticle/820671_4

http://www.ncbi.nlm.nih.gov/pubmed/25121474

This is a very important subject to debate.  As Anil will expect (!) I have to play devil's advocate.  Anti-HLA antibody undoubtedly can damage grafts.  However, DSA does not inevitably damage grafts.  We should not forget this.  And T cells remain important. Furthermore, Rituximab does not access many of the B cells in secondary lymphoid tissues.  Finally, B cells are of course important antigen presenting cells, modification of B cell function and B cell population dynamics having significant effects on the phenotype of the immune response in general and specifically the phenotype of primed T cells and in turn the isotype of antibody produced.  Rituximab is a blunt tool with which to try to modify this complex process.

I am not arguing against using Rituximab.  I am just arguing that trying to predict it's effects from first principles is fraught with problems: there may be much more to it's actions than "kills antibody producing cells so must be good IF antibody causing damage".  If clinical trials prove it's worth great.  But we need these data.  Anil has described the problems with this.

I am also very keen that we do not presume that all chronic graft dysfunction in the presence of antibody is chronic antibody mediated rejection.  Some is some isn't.  We need to make sure we convict the correct villain or the crimes continue.  Our tools to interrogate these processes in patients remain very limited.

Hope this makes sense!

I agree with the other responses as well.   Once there is antibody present that attacks the transplanted organ, Rituximab may be too little, too late.   What we need to be able to do is anticipate B cell activation against the graft and give the drug when the CD20+ cells need to be depleted.  Clinically we have done this in situations where we identify a rejection that either has very early humoral component or a patient with cellular rejection that has a history of DSA against a previous transplant and therefore is at high risk for DSA development against there second transplant.   The theory is that the B cells that are proliferating have specificity against the graft and therefore are depleted before they can recruit further B cells or differentiate into plasma cells that make DSA

Thank you, Dr. Isho, Dr.Smith and Dr. Harland for you invaluable input! These are really good explanations and I have learned a lots!

Best regards,

Wisit