Desensitization of HLA-Incompatible Kidney Recipients Shows Longer-Term Benefit

Roehr, Bob

doi: 10.1097/01.NEP.0000405317.65868.d0

In HLA-sensitized transplant candidates, desensitization therapy followed by living-donor kidney transplantation led to longer survival than did waiting for a compatible organ. By eight years, the survival advantage had more than doubled, reported the study, which compared these sensitized patients with matched controls. The work was published in the New England Journal of Medicine (2011;365:318-326).

“This is really the first study with long-term follow-up to show that desensitization saves lives, compared with really the only other option that is available to these patients, which is to wait for a compatible transplant on the deceased donor list,” said lead author Robert A. Montgomery, MD, DPhil, Director of the Johns Hopkins Comprehensive Transplant Center.

Stanley C. Jordan, MD, Director of Nephrology at Cedars-Sinai Medical Center, expressed a similar perspective. “It is very gratifying to see the results that have been achieved. I think it is a great verification of this approach to dealing with people who otherwise would have no chance to get a kidney transplant.”

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Matched Controls

In the study, which was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and by the Charles T. Bauer Foundation, 211 HLA-sensitized patients were desensitized with plasmapheresis and low-dose intravenous immune globulin prior to living-donor renal transplantation, which took place sometime between February 2008 and December 2009. Induction therapy consisted of daclizumab or antithymocyte globulin.

Of the 211 patients, 66.8% were women, 78.2% were white, 13.7% were black, and 8.1% were of other racial or ethnic groups. The study population had been on renal-replacement therapy for a mean of 8.8 years prior to desensitization.

Each desensitized patient was closely matched to five patients on the United Network for Organ Sharing waiting list. Two comparator groups were created: dialysis only, and a mixed group of dialysis or HLA-compatible transplantation.

In the desensitized group, patient survival was 90.6% at one year, 85.7% at three years, and 80.6% at five and eight years. The dialysis-only group had survival rates of 91.1%, 67.2%, 51.5%, and 30.5%, at the same time points, while the dialysis-or-transplantation group had respective survival rates of 93.1%, 77.0%, 65.6%, and 49.1%. The difference was statistically significant.

The Kaplan-Meier plots of survival overlapped for the first year but then began to diverge. The desensitized group showed only modest decline in months 12 to 48 and no decline in months 48 to 96, though the number of patients reaching those time points was smaller (75 at Month 48; 14 at Month 96). The two control groups progressed on a steady downward slope throughout the entire study period. About half of the study participants were followed for only three years posttransplant.

“The thing that is comforting is that the controls have essentially a very similar death rate [during the first year] to the patients who are being treated,” Dr. Montgomery said. “So it seems like it has much more to do with the comorbidities than the operation or the desensitization itself.

“After the first year, the benefit that we all know from having a functioning transplant kicks in. These patients are holding on to their kidneys, and that is what is causing the flattening of the curve for the treated patients.”

The overall rate of minor reactions to plasmapheresis was 10%. Three patients (1.4%) experienced major events associated with plasmapheresis, including anaphylaxis with hypotension and airway edema. The rate of surgical-site bleeding that necessitated a return to the operating room was 5.2%, and some of the bleeding complications may have been associated with desensitization, as plasmapheresis depletes coagulation factors.

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‘Not from Central Casting’

“These patients that we've desensitized are not from central casting: most of them have been on dialysis for years; they have a lot of comorbidity,” Dr. Montgomery said, noting that more than half (54.5%) had one or more previous transplants, which “seems to be the strongest sensitizing event.”

The average calculated cytotoxic panel-reactive antibody level was 82%, and 32.7% of patients had a level of 98% or more. Still, nearly all were desensitized—211 of the original 215 patients, or about 98%.

Dr. Montgomery said he was surprised to see no correlation between initial antibody levels and long-term outcomes. He initially assumed that “people with lower levels of antibody would probably have a greater benefit, but that turned out not to be the case. Even the people with very high levels of antibody, who were very difficult to desensitize and required a lot of therapy, had just as good a survival benefit.”

The tightly matched controls are as important an aspect of the study as its duration, Dr. Montgomery said. Many previous studies compared outcomes of this hard-to-treat population “with a 24-year-old first-time transplant,” he said. “There is just no comparison.”

Though only 14% of the patients in the dialysis-or-transplantation control group actually received a transplant, “the interesting thing was it did move the curve up, even though the transplant rate was really low,” Dr. Montgomery said.

In terms of next steps, Dr. Montgomery plans to “look with greater granularity” at patients who died during the first year to try to establish their phenotype. “You are not really going to help those folks,” and you are putting the live donor at risk, he said. “I think we can tease some of that out in a post hoc analysis, but we haven't done it yet.”

Aji Djamali, MD, Head of the Division of Nephrology at the University of Wisconsin School of Medicine and Public Health, was enthusiastic about the importance of the study but had questions about induction.

“It was not clear from the study who got what kind of induction,” he said. “I assume that Thymoglobulin [antithymocyte globulin], which is a powerful decreasing agent, was used in those who were on the higher end of sensitization. It is important for centers to know because if used inappropriately it may be associated with worse outcomes.”

Dr. Djamali believes there are structural barriers to some centers offering desensitization services. “These patients need extremely close monitoring and follow-up. It is very challenging to provide and coordinate” all of the components needed for their care. He suggested that centers might find participating in paired-exchange programs to be a better short-term use of their resources.

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Risk of Poorer Outcomes

Dr. Jordan is unsure how this paper might influence the adoption of desensitization for transplantation. The need for supporting infrastructure, such as “a blood bank HLA laboratory that is very good, the surgeons, plasmapheresis groups, pathology to support this kind of program,” is likely to deter some centers from adding the procedure, he said.

There is also the risk of poorer outcomes, particularly during a learning-curve phase, which might be interpreted negatively in an era of greater public transparency and online reporting of outcomes. Dr. Jordan believes that some centers might want to start with “lower-risk patients, patients who are not hard-core sensitized. If you can modify a lower titer antibody against the donor, I think that's the place to start. And that's a lot.”

Balanced against the greater challenges of treating a sensitized patient is a certain pattern, Dr. Jordan has noticed: “The majority of these patients are so pleased to have the opportunity for a transplant that they are ultra-compliant with their medicines, which is not always true with some of the other patient groups. I think that is why they tend to do better, or at least it evens it out.”

© 2011 Lippincott Williams & Wilkins, Inc.