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A Personal Approach to "Asymptomatic" Donor Specific Antibodies or Fodder for Academic Deliberations


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Daniel Kim, MD, FRCPC
University of Alberta
Edmonton, AB, Canada
Dk@ualberta.ca



The downside of proposing an approach to a contentious topic is that there will be no shortage of experts ready to point out the errors of my ways. Alternatively, by the time someone actually proves me wrong, my eloquent discourse will have been long buried in the electronic wasteland of past LINKS issues. So, comforted by assured future anonymity, I share my thoughts on the conundrum of clinically silent donor specific HLA antibodies (DSA).

Not long ago, I attempted this and quickly found myself staring at the face of someone utterly confused, yet too generous, or perhaps too afraid to stop me. With that in mind, I will narrow the scope of my discussion to DSAs in the post-transplant recipient, evading issues around pre-transplant DSAs, methodological nuances or non HLA antibodies.

It is safe to say that DSAs negatively impact the allograft (Smith JD et al, 2011). Unfortunately, significant disagreement still exists around how to manage them. To succinctly outline my approach, I will pragmatically attempt to distill the arguments into three main questions: 1) When are DSAs significant? 2) How do DSAs affect the allograft? and 3) How do you "treat" them?

Firstly, the presence of DSAs does not necessarily equate to "activity". Unfortunately, measuring their clinical relevance by using methods such as cytotoxicity crossmatch, complement fixation (e.g. C1q assay), IgG subtyping have yielded inconsistent results (Campbell P, 2013). As such, although I do sometimes use these assays, I continue to use Luminex Single Antigen Bead testing (SAB) thresholds in most cases, with a cut-off of 1500, at least until more data becomes available (Gandhi et al, 2011).

As to the second question, I will make a general distinction between the impact of MHC Class I and II antibodies. Again, the data is limited but Class I DSAs appear to be more often associated with acute rejection and Class II DSAs with chronic rejection/CAV (Smith JD et al 2011; Raess M et al, 2013; Topilsky et al, 2013). As such, I generally monitor accordingly, either for acute rejection, with an earlier biopsy and echocardiogram, or for CAV with coronary angiography and IVUS/OCT (Optical Coherence Tomography) if not recently performed. All this presuming again that there are no clinical grounds for other testing.

Lastly, I will start by stating that there is no real evidence to support any interventions in this scenario. Nevertheless, I believe that sound judgement based on understanding of transplant medicine and immunology, can guide reasonable clinical decisions. The main caveat here of course, is to avoid "treating ourselves" and our own uncertainties. My approach would be summarized as being aware of the issue, monitoring longitudinally and optimizing immunosuppression as appropriate.

As I experience "déjà vu" and cringe at the thought of numerous bewildered faces staring down at the page, I have taken the liberty of drawing a chart that might help illustrate my take on this issue.

Ultimately, as more evidence becomes available, I am sure to revise my approach. In the meantime, I hope this provides "fodder" for collegial discussions, maybe over numerous glasses of red wine. Cheers. ■

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Disclosure Statement: The author has no conflicts of interest to disclose.


References:

  1. Smith JD, Banner NR, Hamour IM, et al. De novo donor HLA-specific antibodies after heart transplantation are an independent predictor of poor patient survival. Am J Transplant 2011; 11:312 - 319.
  2. Campbell P. Clinical relevance of human leukocyte antigen antibodies in liver, heart, lung and intestine transplantation. Current Opinion in Organ Transplantation 2013; 18(4):463-469.
  3. Gandhi MJ, DeGoey SR, Bundy K et al. Effect of Pretransplant Human Leukocyte Antigen Antibodies Detected by Solid-Phase Assay on Heart Transplant Outcomes. Transplantation Proceedings 2011; 43(10): 3840 - 3846.
  4. Tambur AR, Leventhal J, Kaufman DB et al. Tailoring Antibody Testing and How to Use it in the Calculated Panel Reactive Antibody Era: The Northwestern University Experience. Transplantation. 2008;86(8):1052-1059.
  5. Raess M, Fröhlich G, Roos M, et al. Donor-specific anti-HLA antibodies detected by Luminex: predictive for short-term but not long-term survival after heart transplantation. Transplant International 2013; 26: 1097-1107.
  6. Topilsky Y, Gandhi MJ, Hasin T, et al. Donor Specific Antibodies to Class II Antigens Are Associated With Accelerated Cardiac Allograft Vasculopathy - A 3-D volumetric IVUS study. Transplantation. 2013; 95(2): 389-396



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