Editorial

Desensitization Outcomes: Quantifying andQuestioning

E. Cole* and K. J. Tinckam

Renal Transplant Programme, University Health Network/University of Toronto, Toronto, ON, Canada�Corresponding author: Edward Cole,edward.cole@uhn.ca

Received 24 January 2014, revised 14 April 2014 andaccepted for publication 16 April 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 anti-

bodies (DSAs) (1). In spite of this decrement in long-term

graft survival, more recently, the Hopkins group demon-

strated improved survival for desensitized patients

when compared to those remaining on dialysis with or

without subsequent transplantation (2). 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 andMedicaid 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 desensitiza-

tion, offering the investigators and the transplant commu-

nity an important opportunity to perform comparison

studies (3). 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-adjustedmodels bemodified 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 (2) 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 yearswas 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,whichmay be the bestmethod available. However,

as they acknowledge, the variability of both antibody testing

American Journal of Transplantation 2014; 14: 1475–1476Wiley Periodicals Inc.

�C Copyright 2014 The American Society of Transplantationand the American Society of Transplant Surgeons

doi: 10.1111/ajt.12789

1475

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 towhom they have noDSA,with comparable

outcomes to unsensitized patients (4), 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 trans-

planted, 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 (5).

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 individual-

ized, 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.

Disclosure

The authors of this manuscript have no conflicts of interest

to disclose as described by the American Journal of

Transplantation.

References

1. Bentall A, Cornell LD, Gloor JM, et al. Five year outcomes in living

donor kidney transplants with a positive crossmatch. Am J

Transplant 2013; 13: 76–85.

2. Montgomery RA, Lonze BE, King KE, et al. Desensitization in HLA-

incompatible kidney recipients and survival. N Engl JMed 2011; 365:

318–326.

3. Orandi BJ, Garonzik-Wang JM,Massie AB, et al. Quantifying the risk

of incompatible kidney transplantation: A multicenter study. Am J

Transplant 2014; 14: 1573–1580.

4. Bray RA, Nolan JD, Larsen C, et al. Transplanting the highly

sensitized patient: The Emory algorithm. Am J Transplant 2006; 6:

2307–2315.

5. Cole EH, Nickerson P, Campbell P, et al. The Canadian kidney paired

donation program: Impact of a national program to increase living

donor transplantation. (submitted).

Cole and Tinckam

1476 American Journal of Transplantation 2014; 14: 1475–1476