Imlifidase in Kidney Transplantation: Balancing Safety and Practicality With the Promise of Expanding Access

Despite global efforts to improve access to kidney transplantation for highly sensitized patients through allocation priority, paired exchanges, and acceptable mismatch protocols, these individuals still face major barriers to receiving a transplant. Imlifidase transiently eliminates circulating antibodies, including donor-specific antibodies (DSAs), enabling access to HLA-incompatible deceased donor kidneys for highly sensitized candidates.1 Imlifidase was conditionally approved by the European Medicines Agency in 20202; however, its use in clinical practice has been temperate due partly to a lack of guidelines for its use and integration within allocation systems. The latest in a growing series of initial European clinical recommendations,3,4 the accompanying Belgian consensus guidelines on imlifidase-enabled deceased donor kidney transplantation mark a significant step toward wider European adoption of this novel therapy.5 A principal challenge for imlifidase implementation has been determining eligibility criteria, which must balance equitable transplant access with the reality of organ scarcity. Belgium will permit imlifidase for patients with a calculated panel-reactive antibody ≥85% who have waited for 3 y in Eurotransplant’s Acceptable Mismatch Program (which itself requires 2 y of waiting time) or 4 y on the standard waitlist, thus targeting patients who have proven highly unlikely to receive a compatible kidney offer. Eurotransplant members have expressed concerns that imlifidase-enabled HLA-incompatible transplants may have worse long-term outcomes, leading to these more conservative wait-time requirements. However, it should be noted that current 3-y data from the phase II international imlifidase trial support patient and allograft survival that is consistent with what is expected for these complex patients.6 Desensitization and living donor incompatible transplantation affords a significant survival benefit compared with remaining on the waiting list;7 we would hypothesize the same survival benefit following incompatible deceased donor transplantation enabled by imlifidase. Some limitations to stringent eligibility criteria based on waiting times are notable. Such requirements greatly reduce the pool of eligible patients; indeed, only about 154 Eurotransplant Acceptable Mismatch Program patients would currently qualify.8 In contrast, the United Kingdom has set a calculated panel-reactive antibody threshold of ≥99%, identifying patients who are considered very difficult to match and only require 2 y of waiting time.3 This may capture a larger population of eligible patients for whom overall medical complexity associated with long wait times poses less risk, which will enable the clinical teams to focus on gaining familiarity with managing the unique immunological challenges of desensitization and antibody rebound. Having good outcomes among patients early in a group’s experience will lead to confidence and the expertise needed to take on the more challenging patients. Regarding the decision to use imlifidase, Belgian guidelines recommend that patients meet specific criteria, including having a cumulative neat DSA of ≥6000 median fluorescence intensity on single antigen bead testing, with at least 1 immunodominant DSA of ≥2000 median fluorescence intensity. Additionally, patients should have a predicted positive B-cell and/or T-cell flow cytometry crossmatch without a positive T-cell complement-dependent cytotoxicity crossmatch. Although laboratory thresholds for virtual crossmatches may vary, the combination of a positive virtual crossmatch and at least a moderate-strength DSA offers a reasonable framework. In our opinion, scenarios where crossing a low-strength DSA, in particular where flow cytometry is likely to be negative, would not warrant the use of imlifidase. Rather, this agent should be used in scenarios where some other form of desensitization would invariably have been done to make transplantation safe. If plasma exchange either before or immediately after transplantation had not been needed otherwise, then imlifidase is also not likely necessary. When planning for imlifidase desensitization, mastering time management subsequent to an accepted organ offer is crucial. Moving forward with imlifidase desensitization requires an initial positive crossmatch, time for patient counseling/consent, drug administration and onset of effect, and confirmation of a negative crossmatch. Because these steps may extend the cold ischemic time, pre-cross-clamp organ allocation can save critical hours. Close coordination with the histocompatibility laboratory is paramount and communication should begin well before imlifidase administration so that no preventable delays occur. The Belgian guidelines require a negative post–imlifidase physical crossmatch before proceeding to transplant. We have used virtual crossmatch testing at this step. Either is acceptable, and it is reasonable to favor whichever results are most efficient in the specific setting where the transplant takes place. We find a 2-h post–imlifidase Luminex screen to be very informative since HLA antibody of these highly sensitized patients has previously been well characterized. In most cases, we have proceeded to transplant based on the 2-h Luminex, saving valuable time. Even if DSA is still present, the change in antibody strength observed after 2 h gives an indication of whether we will likely be safe to proceed at 4 h or whether we should prepare for a second imlifidase dose.9 The Belgian guidelines do allow for repeat dosing, recognizing that imlifidase is a “one-and-done” therapy due to the potential for antidrug antibody development.3 We have subscribed to the notion that once the first dose is administered, all possible efforts, including repeat dosing, should be made to enable transplantation so that the opportunity for the patient is not lost. Patients desensitized with imlifidase require careful posttransplant management. The treatment and monitoring framework in the Belgian guidelines is well structured, drawing on experience from the phase II imlifidase trials. The guidelines recommend delayed antithymocyte induction combined with B-cell depletion (to prevent cleavage of therapeutic antibodies) and IVIG to minimize DSA rebound. Most antibody-mediated rejection (AMR) episodes in clinical trials occurred within the first 3 mo, with no AMR episodes observed after 6 mo.6 This high-risk window shapes a focused monitoring strategy, tapering in intensity. A low threshold for measuring and remeasuring DSA levels is advised, as is treating rising DSAs as presumed AMR in the setting of delayed graft function or worsening graft function, even if biopsy data are pending or equivocal. Early imlifidase studies demonstrated that while AMR was not uncommon, it was universally treatable and did not increase the risks of graft loss in 3-y follow-up.6 The Belgian guidelines include surveillance biopsies at 14 d, 3 mo, and 1 y posttransplant, which will provide valuable data, especially on chronic AMR. We would comment that early surveillance biopsies should be weighed against bleeding risks and may be unnecessary, especially in patients who do not have rebounding DSAs. Overall, the Belgian guidelines offer a comprehensive framework for implementing an imlifidsae desensitization program. Their proposed requirement for a 24/7 imlifidase core reference team will prove invaluable as those comprising this team will rapidly accrue the expertise to optimize system efficiency, make informed decisions about donor and recipient selection, make quick decisions as to when to proceed to transplantation versus redose, and understand how to proactively treat rebounding DSAs to prevent early AMR. This experience and the ensuing confidence will enable imlifidase to be used to its fullest potential to safely transplant patients who currently have no realistic pathway to receiving a compatible kidney.