Over the previous decade, 2 important developments have significantly improved access to transplant for highly sensitized patients in the United States. First, a change to the kidney allocation system (KAS) in December 2014 prioritized organ offers for patients with high levels of anti-HLA sensitization. As a result, the median waiting time for highly sensitized patients with cPRA of 98%–100% has decreased from >19 years to 3.2 years.1 A similar concept in Europe focusing on organ allocation to sensitized patients based on acceptable mismatches has succeeed in transplanting >1000 patients with excellent long-term outcomes.2 Second is the increased use of national paired exchange programs such as the National Kidney Registry, which facilitated 399 transplants in 2016 up from 21 transplants in 2008,3 which are widely considered the best initial options for patients with either ABO or HLA-incompatible living donors.
As a result of these developments, enthusiasm (and need) for desensitization of highly sensitized patients has decreased in recent years. While published multicenter data suggest a survival advantage for patients undergoing desensitization followed by live donor transplantation compared with those waiting for a compatible organ offer,4 these data were collected before implementation of KAS, and patients in the control group were not necessarily enrolled in paired exchange programs. Desensitizing treatments are expensive, resource intensive, and place patients at risk for morbidity associated with potent immunosuppression. Furthermore, these treatments remove circulating antibody or temporarily inhibit antibody production without significant effect on immunologic memory. As such, there is a well-documented memory immune response following HLA-incompatible transplant, with postdesensitization antibody-mediated rejection (AMR) rates generally ranging from 25% to 50%.5
In this issue of Transplantation, Vo et al6 further characterize the postdesensitization immune response in a cohort of 90 highly sensitized patients undergoing desensitization with IVIG, rituximab, +/−PLEX/tocilizumab, stratified by donor-specific antibody (DSA) status at the time of and following transplant. They report high rates of AMR in patients with persistent pretransplant and posttransplant DSA (45%) and in patients who developed de novo DSA but were DSA negative at transplant (70%, n = 10 patients), compared with those with pretransplant DSA that disappeared (11%) or those with no DSA pretransplant or posttransplant (10%). Despite higher rates of AMR in the former 2 cohorts, all patients experienced similar graft survival with a median follow-up time of 2.9 years. In the overall cohort, de novo DSA was detected in 19% despite high immunosuppressive exposure, with a 25% chance of developing de novo DSA if DSA was negative at final cross-match. They conclude that highly sensitized patients may benefit from desensitization and that the success of these programs relies on aggressive posttransplant antibody monitoring to identify those patients at higher risk for rejection and graft loss.
The experience described by Vo et al consists largely of deceased donor transplant and differs from the aforementioned study by Orandi et al4 in which a survival advantage was attributed to desensitization before living-donor transplant. Desensitization to facilitate deceased donor transplant is arguably a more challenging hurdle due to the lack of predictable transplant events. Despite these challenges, in this study and others, Vo et al7 have reported favorable results both in achieving transplant as well as acceptable posttransplant outcomes in desensitized patients receiving deceased donor transplants.8 However, other centers have failed to replicate these encouraging results using similar strategies.9 Previous data from Vo et al describe comparable graft and patient survival between desensitized and nondesensitized patients with a mean 2- year follow-up,8 but this has not been a consistent finding with other regimens. For example, 5-year data from the Mayo Clinic show significantly worse patient and graft survival in those undergoing desensitization versus HLA-compatible transplant, as well as protocol biopsy-detected transplant glomerulopathy in 55% of desensitized versus 7% of HLA-compatible recipients.10 Despite aggressive posttransplant DSA monitoring in the current report by Vo et al, histologically identified AMR was detected in 29% of desensitized recipients. As demonstrated in other studies, this is associated with a significant risk of transplant glomerulopathy and subsequent graft failure,10 which would not necessarily be captured with the mean 2.9 years of follow-up available in the current report.
Given these data, the best option would be to avoid HLA-incompatible transplant whenever possible, although not necessarily at the expense of significantly prolonged dialysis exposure while awaiting a compatible offer. When living donors are available, paired exchange should be attempted in order to avoid the cost and risk associated with desensitizing therapy as well as the posttransplant immune response that will likely translate into poorer long-term graft survival.
While information is not available in the current study by Vo et al regarding how many receiving deceased donor transplants also had an incompatible live donor option, one can assume kidney paired exchange was not a feasible option for most of this cohort. With this in mind, the risk/benefit assessment of desensitization must be reconsidered. Changes in KAS have helped to increase rates of deceased donor transplant for some but not all highly sensitized patients.11 Thus, proceeding with desensitization for those highly sensitized patients without living donors, where paired exchange is not possible and expected wait time is considered unacceptable, may be a reasonable consideration. When considering this option, however, one should account for the published variability in both postdesensitization transplant rates as well as outcomes. These metrics are heavily influenced by many factors such as the specific desensitization regimen, the cross-match assay(s) utilized, and the level of cross-match reactivity that a given center considers “acceptable.” Centers with published experience in desensitization have gained expertise over time not only in the desensitization procedure itself but also in the careful selection of patients whose health status is such that desensitizing treatment is less likely to cause serious harm and whose anti-HLA antibody status is such that treatment is likely to accomplish the ultimate goal of increasing organ offers with an acceptable final cross-match.
Ultimately, if desensitization is considered for highly sensitized patients, expectations should be tempered, and the encouraging outcomes published here may not translate to other programs or to the longer term. Paired exchange options should be exhausted, and a realistic estimate of wait time taking into account priorities for high cPRA patients under KAS should be considered. With this in mind, the current study by Vo et al provides an important guide for clinicians to identify those patients at the highest risk of posttransplant immunologic injury following desensitization if one chooses this route and emphasizes the importance of careful antibody monitoring throughout the posttransplant period.
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