Anti-HLA Class II Antibodies Are the Most Resistant to Desensitization in Crossmatch-positive Living-donor Kidney Transplantations: A Patient Series

Abstract

Background: In HLA-incompatible kidney transplantation, the efficacy of desensitization in terms of anti-HLA antibody kinetics is not well characterized. We present an overview of the course of anti-HLA antibodies throughout plasma exchange (PE) desensitization in a series of crossmatch-positive patients.

Methods: All consecutive candidates in the Dutch HLA-incompatible kidney transplantation program between November 2012 and January 2022 were included. The eligibility criteria were a positive crossmatch with a living kidney donor and no options for compatible transplantation. Desensitization consisted of 5-10 PE with low-dose IVIg.

Results: A total of 16 patient-donor pairs were included. Patients had median virtual panel-reactive antibody of 99.58%. Cumulative donor-specific anti-HLA antibody (cumDSA) mean fluorescence intensity (MFI) was 31 399 median, and immunodominant DSA (iDSA) MFI was 18 677 for class I and 21 893 for class II. Median anti-HLA antibody MFI response to desensitization was worse in class II as compared with class I (P < 0.001), particularly for HLA-DQ. Class I cumDSA MFI decreased 68% after 4 PE versus 53% in class II. The decrease between the fifth and the 10th PE sessions was modest with 21% in class I versus 9% in class II. Antibody-mediated rejection occurred in 85% of patients, with the iDSA directed to the same mismatched HLA as before desensitization, except for 3 patients, of whom 2 had vigorous rebound of antibodies to repeated mismatches (RMMs). Rebound was highest (86%) in RMM-DSA with prior grafts removed (transplantectomy n = 7), lower (39%) in non-RMM-DSA (n = 30), and lowest (11%) for RMM-DSA with in situ grafts (n = 5; P = 0.018 for RMM-DSA transplantectomy versus RMM-DSA graft in situ). With a median follow-up of 59 mo, 1 patient had died resulting in a death-censored graft survival of 73%.

Conclusions: Patients with class II DSA, and particularly those directed against HLA-DQ locus, were difficult to desensitize.

Graphical abstract

FIGURE 1.

Class I and class II MFI response to desensitization. The response to desensitization as detected by Luminex single-antigen bead assay is depicted for the total of anti-HLA antibodies (A)–(E) as well for DSA (F)–(J). Patients were divided into 3 groups according to desensitization outcome: 5 PE and transplanted (group 1, n = 9); 10 PE and transplanted (group 2, n = 4); and 10 PE and not transplanted (group 3, n = 3). Predesensitization, only 1 of 9 patients had CDC-XM positivity in group 1, whereas all patients in groups 2 and 3 were CDC-XM positive. After desensitization, all patients in groups 1 and 2 had negative CDC-XM and hence were transplanted, whereas in group 3 CDC-XM remained positive precluding transplantation. Red lines indicate median values. Mann-Whitney U test was used to compare differences between groups. A P value of <0.05 was considered significant. In the analysis of groups 1, 2 and 3 combined, median anti-HLA antibody MFI response to desensitization was worse in class II as compared to class I (P < 0.001). Analyses on DSA followed the same trend; however, no statistical significance was reached (P = 0.05). CDC-XM, complement-dependent cytotoxicity crossmatch; DSA, donor-specific antibody; MFI, mean fluorescence intensity.

FIGURE 2.

Changes in cumDSA and iDSA MFI values for classes I and II before and after desensitization. Patients were divided into three groups according to desensitization outcomes: 5 PE and transplanted (group 1, n = 9); 10 PE and transplanted (group 2, n = 4); and 10 PE and not transplanted (group 3, n = 3). Predesensitization, only 1 of 9 patients had CDC-XM positivity in group 1, whereas all patients in groups 2 and 3 were CDC-XM positive. After desensitization, all patients in groups 1 and 2 had negative CDC-XM and hence were transplanted, whereas in group 3 CDC-XM remained positive precluding transplantation. The decrease in MFI of cumDSA was higher for class I (A) than for class II (B), in line with the higher decrease of the immunodominant DSA in class I (C) than for class II (D). cumDSA, cumulative DSA; DSA, donor-specific antibody; iDSA, immunodominant DSA; MFI, mean fluorescence intensity; PE, plasma exchange; tx, transplantation.