Clinical Outcomes and Donor-specific Antibody Rebound 5 y After Kidney Transplant Enabled by Imlifidase Desensitization

Abstract

Background: Imlifidase is an IgG-cleaving endopeptidase conditionally approved in Europe for desensitization of highly sensitized patients before kidney transplantation. We present 5-y outcomes and donor-specific antibody (DSA) levels for clinical trial participants from a single site who received imlifidase for desensitization before incompatible transplantation (NCT02790437).

Methods: Imlifidase was administered up to 24 h before living or deceased donor kidney transplantation. DSAs were monitored before transplantation, at days 7 and 28, and at 5 y posttransplant.

Results: At 5 y, 7 of 8 participants were alive. One of these 7 had suboptimal graft function secondary to donor-derived disease but remained dialysis independent. Three participants had antibody-mediated rejection (AMR), which occurred in the first 30 d in all cases and was successfully treated. No new episodes of suspected or biopsy-proven AMR occurred after 30 d posttransplant. Seven participants had DSA rebound. DSAs commonly persisted 5 y posttransplant, although they were generally lower strength compared with pre-imlifidase. Dilution studies of sensitized serum enabled the identification of lower AMR risk phenotypes for persisting DSAs. Severe and/or opportunistic infections were not observed at greater than expected frequency.

Conclusions: Five-year outcomes of imlifidase-enabled incompatible transplants are overall favorable. DSA rebound is common, but antibody strength lessens in the long term, and longitudinally persisting DSAs did not lead to premature graft failure.

Graphical abstract

FIGURE 1.

Aggregate DSA levels stratified by HLA class. A, The distribution of all class I DSA MFIs over time (left) and the distribution of only the immunodominant class I DSAs (right) over time. Box upper and lower bounds are at the third and first quartiles, with the median value annotated and the line bounding the range of values. Baseline and year 5 were compared using a paired t test. B, The distribution of all class II DSA MFIs over time (left) and the distribution of only the immunodominant class II DSAs (right) over time, with the same schema. DSA, donor-specific antibody; MFI, mean fluorescence intensity.

FIGURE 2.

Aggregates of dilutional titrations for DSA strength. Sera were serially diluted up to 1:128 concentration and separately run on Luminex single-antigen beads. DSAs were identified on the basis of patient and donor HLA typing. A, HLA class I DSA titrations. B, HLA class II DSA titrations. In both cases, the upper panel shows the average MFI when all DSAs were included, whereas the lower panel shows the average MFI in each serial dilution restricted only to the immunodominant DSA to mitigate the disproportionate impact of participants with multiple DSAs. DSA, donor-specific antibody; MFI, mean fluorescence intensity.

FIGURE 3.

Donor-specific antibody titrations for repeat HLA mismatches. A, DSA titrations for the 3 cases of confirmed repeat HLA mismatches. B, A comparison between participants 7 and 8, who produced the same DSAs against a common epitope on DQ5 and DQ6 with comparable baseline strength. DSAs of participant 7 was a case of repeat HLA mismatch, whereas DSAs of participant 8 was not. DSA, donor-specific antibody; MFI, mean fluorescence intensity.

FIGURE 4.

Total IgG levels pre- and posttransplant. Total IgG levels were monitored as part of the original study protocol and then as part of routine clinical care. Pretransplant and the latest total IgG level through the 5 y of follow-up were compared using a paired t test.

FIGURE 5.

Aggregate third-party antibody levels stratified by HLA class. A, The distribution of all class I third-party MFIs over time (left) and stratified by baseline weak third-party antibodies (middle; pretransplant MFI <8000 in 1:16 dilution) or baseline strong third-party antibodies (right; pretransplant MFI >8000 in 1:16 dilution). Box upper and lower bounds are at the third and first quartiles, with the median value annotated and the line bounding the range of values. Baseline and year 5 were compared using a paired t test. B, The distribution of all class II third-party MFIs over time (left) and stratified by baseline weak third-party antibodies (middle; pretransplant MFI <8000 in 1:16 dilution) or baseline strong third-party antibodies (right; pretransplant MFI >8000 in 1:16 dilution), with the same schema. DSA, donor-specific antibody; MFI, mean fluorescence intensity.