Wednesday, April 7, 2010

Preventing Chronic Rejection: Can it B?


For the past 5 years, alloantibody measurement has become a standard of practice in recipients of kidney transplants experiencing worsening allograft function. This week, I admitted a patient who had a rising creatinine and on biopsy mild-moderate interstitial infiltration. No peritubular C4d stain or tubulitis. Transplant glomerulopathy (TG) was seen in 2 out of 10 glomeruli, but C4d stain was negative as well. She had received a deceased kidney transplant 3 years prior and Luminex assay showed that she has now positive donor specific alloantibodies.


Looking at the Banff criteria for humoral rejection, she would be classified as borderline rejection. Even though she had positive alloantibodies, the absence of complement fragment deposition on biopsy excludes this case from the current humoral rejection category.


The finding of rising antibody titers and negative complement deposition is being increasingly recognized and has become a gray zone in transplantation. Some pathologists are starting to call it: smoldering antibody mediated rejection, since it does seem that antibodies are been deposited in the glomeruli capillary leading to the TG. Moreover, TG is a poor prognostic marker. Lastly, the presence of alloantibodies predicts worse allograft outcome and in the presence of C4d positive biopsies, requires therapeutic action: Plasmapheresis + IVIg + pulse dose steroids.


Current immunossupressive regimens used in transplantation target mainly T cells, therefore the rational for targeting B cells seems reasonable, especially since B cells are the origin of plasma cells. There are now 4 clinical trials addressing multiple questions about the benefit of rituximab posttransp. If you are considering giving to one of your patients, please check if he/she would be eligible to one of these trials. That is the only way we can help our community to address the risk/benefit questions of this approach. Other B cell-oriented therapies are also coming in the market soon, like inhibitors of B cell cytokines (BAFF and APRIL) and complement inhibitors.


What about my patient? She received the full course Plasmapheresis + IVIg + pulse dose steroids, despite her borderline classification. We decided not give her rituximab at this time since there was only mild evidence of antibody injury, considering a rebiopsy later to readdress it.


Finally, the preemptive use of rituximab prior to the development of AMR will also become an important question, with a recent trial in cynomolgus monkeys showing capability of decreasing alloantibody production and chronic rejection when combined with calcineurin inhibitors. New era of preemptive B cell targeting? Too early to tell...


2 comments:

Rene C Bakker, The Netherlands said...

I am not aware of any studies that show a beneficial result of treating CHR patients with IVIG, plasmapheresis and high dose steroids. Is this opinion based or evidence based? Which surrogate marker should be used in such cases? DSA titer? But is this a validated tool? I guess there also risks at using such therapies, are these taken into account?

Leonardo V Riella said...

Great questions Rene! As you know, chronic rejection is multifactorial. If evidence of humoral rejection is present in the absence of significant chronicity, aggressive treatment is warranted. Our management in the grey zone area of + DSA + transplant glomerulopathy but - C4d is opinion based. Risks should be included in the decision process as usual. The level of DSA titers have not been standardized, so for now we rely on the conversion from negative to positive as the most important feature. Upcoming studies including the CTOT trial ongoing in our lab are trying to clarify remaining questions. Thanks for your comments again.