Desensitization Outcomes: Quantifying and Questioning
Article first published online: 9 JUN 2014
© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 14, Issue 7, pages 1475–1476, July 2014
How to Cite
Cole, E. and Tinckam, K. J. (2014), Desensitization Outcomes: Quantifying and Questioning. American Journal of Transplantation, 14: 1475–1476. doi: 10.1111/ajt.12789
- Issue published online: 20 JUN 2014
- Article first published online: 9 JUN 2014
- Manuscript Accepted: 16 APR 2014
- Manuscript Revised: 14 APR 2014
- Manuscript Received: 4 APR 2014
Lack of access to kidney transplantation is a critical issue for sensitized transplant candidates. Both living donor exchange (LDE) and desensitization with subsequent living donor transplantation, used separately or as part of a combined strategy, have significantly improved transplant options. However, studies have suggested that both acute and chronic antibody-mediated rejection are frequent problems in desensitized patients, leading to transplant glomerulopathy and significantly reduced graft survival as compared to patients without HLA donor-specific antibodies (DSAs) . In spite of this decrement in long-term graft survival, more recently, the Hopkins group demonstrated improved survival for desensitized patients when compared to those remaining on dialysis with or without subsequent transplantation . Desensitization has become a living donor transplant strategy employed at 50–70% of transplant centers in the United States. Regrettably, the use of this approach is threatened with the failure of the Center for Medicare and Medicaid studies to adjust for the anticipated reduction in graft survival when determining program-specific data. The resulting reports, which would target desensitizing centers, have the potential to reduce transplant access for sensitized patients in those very centers providing this enhanced treatment.
To assess the impact of center use of desensitization on the risk of being penalized for poor results, Orandi et al were able to assemble the largest cohort, by far, of HLA-incompatible living donor transplants following desensitization, offering the investigators and the transplant community an important opportunity to perform comparison studies . The study shows that graft and patient survival are significantly worse in recipients of either flow- or complement-dependent cytotoxicity crossmatch positive transplants and that centers performing such transplants would therefore risk regulatory discrimination. To preserve transplant opportunities for these patients, they suggest that the current risk-adjusted models be modified to include corrections for centers performing desensitization.
While the data support the conclusions, in our opinion, there are other major issues that remain outstanding. Although the previous study  suggested that the use of desensitization was associated with a significant benefit in patient survival as compared to dialysis, that study only included 211 desensitized, transplanted patients and the number at risk at 5 years was only 58. This current study has an impressive 535 patients with positive crossmatches with an additional 90 patients who are only DSA positive at risk at 5 years. Accordingly, an outcome comparison with patients on dialysis would permit even more impactful conclusions in confirming results of the previous single-center study and it is hoped that the authors will do such an analysis in the very near future.
It is clear that a randomized controlled trial to prove the survival benefit of incompatible living donor transplantation is not feasible, but it is nonetheless important that the methodology used to compare the groups be as robust as possible. The current study used risk factors available in the Scientific Registry of Transplant Recipients, whereas the previous study used patients who were matched more comprehensively based on panel reactive antibodies (PRA), age, blood group, number of previous transplants, proportion of years of renal replacement therapy with a functioning allograft, total number of years of renal replacement, race, sex and the presence or absence of diabetes. Other important data permitting a detailed comparison of patients with similar comorbidities might well be available from the individual centers and result in more meaningful analysis. While the methodology used by the authors to compare groups in both studies was reasonable, it might be helpful to apply different statistical tools, for example, propensity scores, to be sure that the answer is similar regardless of the method used for the comparison.
One of the most difficult problems in assessing results of incompatible living donor transplantation is comparing different groups of patients' antibody strength, especially between centers. The authors have used crossmatch results as a way of defining risk-groups of patients in both studies, which may be the best method available. However, as they acknowledge, the variability of both antibody testing definitions and crossmatch sensitivity between centers is substantial. Thus, patients might well fall into different risk-groups had they been tested at an alternate center. This is of some importance since there was no observed outcome difference when only DSA positive, crossmatch negative cases were considered, but this group may not be reproducibly defined in another cohort. To advance this field and for us to make the best decisions for our patients, improved inter-center accuracy and precision of DSA testing and crossmatching is a priority.
It is important to emphasize that living donor paired exchange does offer opportunities for sensitized patients to find donors to whom they have no DSA, with comparable outcomes to unsensitized patients , even in many recipients with higher cPRA. In the Canadian Blood Services Living Donor Paired Exchange National Registry, while 16% of the registered population had PRA between 80% and 96%, they accounted for 24% of those transplanted, the same proportion as 0% cPRA registrants with ABO-incompatible donors. On the other hand, those with cPRA of 97% or greater make up 32% of the Registry population but accounted for only 11% of transplants . Individual patient decisions must, therefore, take into account the likelihood of being matched in LDE, with a clear understanding of a given Registry's performance. As well, such Registries should use optimized matching schemes in order to give sensitized patients a better chance of matching. Ultimately, the choice between living donor paired exchange and/or desensitization must be individualized, considering patient preference, center expertise and alternative access options. For those centers offering desensitization to patients where that is the best option, analyses comparing survival to dialysis patients are urgently needed and would provide more conclusive data to support the importance of patient access and the need for appropriate adjustment by the Center for Medicare and Medicaid. Inflexible Center for Medicare and Medicaid analysis strategies may ultimately be counterproductive to clinical advances in this field and limiting to some of the most immunologically disadvantaged patients.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
- 5The Canadian kidney paired donation program: Impact of a national program to increase living donor transplantation. (submitted)., , , et al.