To Desensitize or Not to Desensitize: Conversation between 2 Nephrologists

[kickingandscreaming]

When Desensitization Makes Sense and When It Doesn't

Jeffrey S. Berns, MD; Deirdre L. Sawinski, MD
April 08, 2016


Jeffrey S. Berns, MD: Hello. This is Jeffrey Berns, editor-in-chief of Medscape Nephrology. I am here today to talk to you about a paper by Orandi and colleagues,[1] published in March 2016 in the New England Journal of Medicine and entitled "Survival Benefit With Kidney Transplants From HLA-Incompatible Live Donors." This article has generated a huge amount of interest in both the medical and lay press, including a front page article in the New York Times.[2]

I have come to learn, however, that although it sounds very attractive on the surface, there are some issues and concerns among the transplant community with this particular technique of making kidney transplants available for those who are on the wait list but are "sensitized." For any of you who are interested in learning more about the desensitization process, I refer you to a paper that will be published very shortly in the Clinical Journal of the American Society of Nephrology (CJASN) by Douglas Keith and Gayle Vranic.[3]

With me today is my colleague from the University of Pennsylvania, Dr Deirdre Sawinski, who is one of our transplant nephrologists. Deirdre, could you explain what this process involves and why it is important? Why should we be concerned about desensitization of potential kidney recipients of either living or deceased donor kidneys? What is involved in this particular technique?

Deirdre L. Sawinski, MD: Thank you, Dr Berns. I am happy to discuss this process. For a variety of reasons, sensitized patients are one of the largest growing groups on the kidney transplant wait list. Many patients have undergone previous transplants, which is probably the most important cause of sensitization. Blood transfusion and pregnancy can also lead to sensitization. These patients accumulate donor-specific or anti-HLA antibodies that are a barrier to finding a successful match.

The data clearly show that living donor transplantation is the best option, if at all possible. It is important to try to find a compatible living donor.

Dr Berns: These antibodies are important for people who are waiting for a deceased donor kidney as well as for those who have a potential living donor who has offered to donate a kidney but who is not compatible.

Dr Sawinski: Absolutely. Antibodies represent a barrier in transplantation regardless of whether the donor is alive or deceased. Unfortunately, the process of removing the antibodies is rather difficult. Antibodies are made by long-lived plasma cells that reside in the bone marrow, and those are highly resistant to induction and maintenance immunosuppression. The current standard of care for removing them involves using plasmapheresis or monoclonal antibodies that inhibit production of these other antibodies. Plasmapheresis removes the antibodies and replaces them with intravenous immunoglobulin, which is believed to reduce antibody production and also replace the lost antibodies. Rituximab is an anti–B-cell agent; in some clinical trials, other agents—such as bortezomib, which is a proteasome inhibitor used in treatment of multiple myeloma, or eculizumab, a terminal complement (TC-5) inhibitor—have been used to stop antibody production.
 Dr Berns: What are the risks of this to the patient?

Dr Sawinski: First, depending on how strong the antibodies are, as graded by the MFI, or mean fluorescent intensity, it may be more or less difficult to remove them. Second, success may depend on what the antibodies are directed against; whether it is a very common epitope or a very rare epitope may have more meaning in terms of the ability to find a compatible donor. Moreover, as you add to the overall immunosuppressive burden a patient experiences by doing this pretransplant desensitization, you increase the patient's risk for cancer down the line. Obviously, if a patient needs to be desensitized before receiving the transplant, the risk for rejection goes up and the allograft probably will not last as long.

Dr Berns: I also understand that if this is being used in someone who is waiting for a deceased donor, the patient needs to be at the very top of the list, otherwise the patient may go through this desensitization and later have it wear off, if you will.

Dr Sawinski: Absolutely. Because the antibodies are resistant to removal, antibody levels can fluctuate. Certainly, for those who are waiting for a deceased donor kidney, the desensitization effect can be transient. However, with the new kidney allocation system since December 2014, those patients who are most highly sensitized—those with a 98% or greater panel reactive antibody (PRA) score—get priority. This has increased transplant rates over the previous allocation system and has led many to question whether desensitization makes sense now. There is the immunosuppressive burden with desensitization; the cost associated with all of these medications, which may or may not be covered by insurance; the fact that success is not 100%; and the kidneys themselves do not last quite as long.

I would suggest a staged approach to this dilemma, whereby everyone is put on the list for a deceased donor. It is quite important that those who have a PRA score greater than 98% are active on the list at all times so that they can get that offer, that one-in-a-million chance of being matched with a compatible donor. If a patient has a living donor who is not compatible, I would advocate for the National Kidney Register, which permits living donor swaps, so you can trade your incompatible donor for another, compatible donor. That is the easiest option because then you do not have any added immunosuppressive burden, any added acute rejection risk, and the allograft should last longer. I would reserve desensitization as a last-ditch option for those for whom the first two options fail.

Dr Berns: So there is a role for desensitization, but you believe that with the new allocation system and the availability of kidney swaps, the role for desensitization is probably limited.

Dr Sawinski: Yes. I believe it is limited. I believe that living donor exchange and the new allocation system should be explored first. Desensitization should be reserved as a last resort for those who otherwise fail those two options.

Dr Berns: That should be the information that nephrologists can use to advise their patients: Talk to the transplant center about the likelihood of receiving a transplant without a swap, and short of that, find out what the opportunity is for a swap. Only if those options fail should you begin to explore the potential role for desensitization.

Dr Sawinski: I agree. The downsides to desensitization are significant, even if it works—and it does not always work. There are easier ways to facilitate this that will enable you to receive a kidney transplant with far fewer complications.

Dr Berns: Deirdre, thank you for spending some time with me today.

Dr Sawinski: My pleasure.

Dr Berns: This is Jeffrey Berns from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. Thank you for listening.
http://www.medscape.com/viewarticle/861367?src=wnl_edit_tpal&uac=220367EY#vp_1

[cassandra]

Thank you for the article KaS, i.s.o all this desensitization stuff more time and effort should be put into changing the organ donor law universally into the French system.

[okarol]

Thank you for posting this. This is exactly what we have been told. Jenna is 100% desensitized plus she has donor-specific antibodies.
The transplant team told her to hold off on desensitization and try paired donation (she is in 3 swaps with 3 donors now) and she has priority on the deceased donor list.
She has been wait listed since 2012, but has not had any hits yet. Numerous potential donors came forward after being on the news, but no match was found.
Hopefully she can stay healthy until her miracle comes along.