Pushing the envelope across HLA boundaries: HLA-incompatible renal transplants

By Martina M. McGrath, MD
July 6, 2016

The deceased-donor renal transplant waiting list continues to expand inexorably, and currently, up to 15% of wait-listed patients are awaiting their second or subsequent kidneys. With this changing demographic, the challenge of transplanting patients with increasing levels of HLA sensitization becomes ever more prevalent.

The study by Orandi et al, published in NEJM in March 2016, has given us an important insight in managing these patients. Using a rigorous matching technique, they queried the benefit of undergoing HLA incompatible live-donor transplantation versus remaining on the wait list or receiving a deceased-donor kidney, or remaining on the wait list. The first control was chosen as this is the alternative for most patients who cannot find a compatible live donor. The second control represents those for whom a deceased donor cannot be found due to sensitization barriers.

HLA incompatible transplantation occurs in a situation where the recipient has pre-formed anti-HLA antibodies against donor HLA antigens (donor specific antibodies). In this study, patients were stratified using a clinically relevant approach taking into account the presence of donor specific anti-HLA antibody detected only on Luminex single antigen screen, its presence with a positive flow crossmatch or its presence with a positive cytotoxic crossmatch. Each of these conditions is associated with increasing antibody ‘strength’ and increasing risk of antibody-mediated rejection. All patients underwent some form of desensitization protocol along with post-transplant immunosuppression; the specifics of these therapies were not dictated in the study protocol and no details were provided in the paper.  Complications such as opportunistic infections, rejection episodes and rates of graft failure were also not included.

The investigators found that across all subgroups, highly significant survival benefits were seen up to 8-years follow up. At 5 years, the survival was 86% in the transplanted group, versus 74.4% for those remaining on the wait list or receiving a deceased-donor kidney, and 59.2% for those who remained on the wait list. At 8 years, the difference had further increased to 76.5% vs 62.9% and 43.9%. Put in another way, the risk of death was decreased by a factor of 3.49 by undergoing incompatible live donation versus remaining on the wait list or receiving a deceased-donor kidney; and by a factor of 6.48 compared with remaining on the wait list.

To date, there has been some uncertainty as to whether carrying out these transplants was truly of benefit to these patients, particularly given their high risk of antibody mediated rejection, anticipated shortened graft survival as a result and the need for intensive immunosuppression to mitigate the rejection risk, along with all its associated complications.  These factors, along with regulatory pressures to achieve good outcomes, have given some centers pause in considering these transplants.

These compelling data can give encouragement to transplant professionals that, despite considerable challenges in caring for such patients post-transplantation, there is still a marked survival benefit to receiving a kidney, even in the setting of positive immunological screening tests.

transplant survival graph

Orandi BJ et al. N Engl J Med 2016;374:940-950

Headshot of Dr. McGrath

 

Dr. Martina McGrath is an instructor in medicine at Harvard Medical School, and a member of the Renal Division, Department of Medicine, at Brigham and Women’s Hospital, both in Boston.

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