Repository for Antibody Incompatible Transplantation Evidence
343 results
  • Kälble F
  • Süsal C
  • Pego da Silva L
  • Speer C
  • Benning L
  • Nusshag C
  • Pham L
  • Tran H
  • Schaier M
  • Sommerer C
  • et al.
Front Med (Lausanne). 2021 Dec 17;8:781491 doi: 10.3389/fmed.2021.781491.

Due to the current organ shortage, living donor kidney transplantation is increasingly performed across HLA (human leukocyte antigen) or ABO antibody barriers. There is still uncertainty about the risk of antibody-mediated rejection (AMR) episodes, which may limit long-term graft survival. From March 2007 to December 2016, 58 sensitized living donor kidney transplant candidates were identified and 38 patients eventually included in the study: 36 patients (95%) had pre-transplant and pre-desensitization Luminex-detected donor-specific HLA antibodies (DSA), and 17/36 patients (47%) in addition had a positive crossmatch result. Two patients had no detectable DSA but a positive CDC B-cell crossmatch result. Patients were treated with pre- and post-transplant apheresis and powerful immunosuppression including the anti-CD20 antibody rituximab (N = 36) in combination with thymoglobulin (N = 20) or anti-IL2 receptor antibody (N = 18). The results of the 38 successfully desensitized and transplanted patients were retrospectively compared to the results of 76 matched standard-risk recipients. Desensitized patients showed patient and graft survival rates similar to that of standard-risk recipients (P = 0.55 and P = 0.16, respectively). There was a trend toward reduced death-censored graft survival in desensitized patients (P = 0.053) which, however, disappeared when the 34 patients who were transplanted after introduction of sensitive Luminex testing were analyzed (P = 0.43). The incidence of rejection episodes without borderline changes were in desensitized patients with 21% similar to the 18% in standard-risk patients (P = 0.74). Thirty-six patients had pre-transplant HLA class I and/or II DSA that were reduced by 85 and 81%, respectively, during pre-transplant desensitization (P < 0.001 for both). On day 360 after transplantation, 20 of 36 (56%) patients had lost their DSA. The overall AMR rate was 6% in these patients, but as high as 60% in 5 (14%) patients with persistent and de novo DSA during year 1; 2 (40%) of whom lost their graft due to AMR. Eleven (31%) patients with persistent DSA but without de novo DSA had an AMR rate of 18% without graft loss while one patient lost her graft without signs of AMR. Our desensitization protocol for pre-sensitized living donor kidney transplant recipients with DSA resulted in good graft outcomes with side effects and rejection rates similar to that of standard-risk recipients. Adequate patient selection prior to transplantation and frequent immunological monitoring thereafter is critical to minimize rejection episodes and subsequent graft loss.

  • Osickova K
  • Hruba P
  • Kabrtova K
  • Klema J
  • Maluskova J
  • Slavcev A
  • Slatinska J
  • Marada T
  • Böhmig GA
  • Viklicky O
Front Med (Lausanne). 2021 Dec 14;8:780636 doi: 10.3389/fmed.2021.780636.

Recipient sensitization is a major risk factor of antibody-mediated rejection (ABMR) and inferior graft survival. The predictive effect of solid-phase human leukocyte antigen antibody testing and flow cytometry crossmatch (FCXM) in the era of peritransplant desensitization remains poorly understood. This observational retrospective single-center study with 108 donor-specific antibody (DSA)-positive deceased donor kidney allograft recipients who had undergone peritransplant desensitization aimed to analyze variables affecting graft outcome. ABMR rates were highest among patients with positive pretransplant FCXM vs. FCXM-negative (76 vs. 18.7%, p < 0.001) and with donor-specific antibody mean fluorescence intensity (DSA MFI) > 5,000 vs. <5,000 (54.5 vs. 28%, p = 0.01) despite desensitization. In univariable Cox regression, FCXM positivity, retransplantation, recipient gender, immunodominant DSA MFI, DSA number, and peak panel reactive antibodies were found to be associated with ABMR occurrence. In multivariable Cox regression adjusted for desensitization treatment (AUC = 0.810), only FCXM positivity (HR = 4.6, p = 0.001) and DSA number (HR = 1.47, p = 0.039) remained significant. In conclusion, our data suggest that pretransplant FCXM and DSA number, but not DSA MFI, are independent predictors of ABMR in patients who received peritransplant desensitization.

  • Kjellman C
  • Maldonado AQ
  • Sjöholm K
  • Lonze BE
  • Montgomery RA
  • Runström A
  • Lorant T
  • Desai NM
  • Legendre C
  • Lundgren T
  • et al.
Am J Transplant. 2021 Dec;21(12):3907-3918 doi: 10.1111/ajt.16754.

Imlifidase is a cysteine proteinase which specifically cleaves IgG, inhibiting Fc-mediated effector function within hours of administration. Imlifidase converts a positive crossmatch to a potential donor (T cell, B cell, or both), to negative, enabling transplantation to occur between previously HLA incompatible donor-recipient pairs. To date, 39 crossmatch positive patients received imlifidase prior to a kidney transplant in four single-arm, open-label, phase 2 studies. At 3 years, for patients who were AMR+ compared to AMR-, death-censored allograft survival was 93% vs 77%, patient survival was 85% vs 94%, and mean eGFR was 49 ml/min/1.73 m2 vs 61 ml/min/1.73 m2 , respectively. The incidence of AMR was 38% with most episodes occurring within the first month post-transplantation. Sub-analysis of patients deemed highly sensitized with cPRA ≥ 99.9%, and unlikely to be transplanted who received crossmatch-positive, deceased donor transplants had similar rates of patient survival, graft survival, and eGFR but a higher rate of AMR. These data demonstrate that outcomes and safety up to 3 years in recipients of imlifidase-enabled allografts is comparable to outcomes in other highly sensitized patients undergoing HLA-incompatible transplantation. Thus, imlifidase is a potent option to facilitate transplantation among patients who have a significant immunologic barrier to successful kidney transplantation. Clinical Trial: ClinicalTrials.gov (NCT02790437), EudraCT Number: 2016-002064-13.

  • Tang C
  • Unterrainer C
  • Fink A
  • Cinca S
  • Ruhenstroth A
  • Scherer S
  • Morath C
  • Zeier M
  • Mehrabi A
  • Süsal C
  • et al.
HLA. 2021 Nov;98(5):423-430 doi: 10.1111/tan.14422.

HLA matching and avoidance of unacceptable mismatches are important aspects in the selection of donors for solid organ transplantation. The impact of HLA-DPB1 incompatibility on the outcomes of kidney transplantation is not fully understood. We investigated a potential effect of mismatching for HLA-DPB1 at allele, eplet, or Terasaki epitope (TerEp) level on the formation of de novo donor-specific antibodies (dnDSA) and also asked whether polymorphisms associated with HLA-DPB1 expression level may influence dnDSA induction. Furthermore, we analyzed the correlation between graft survival and HLA-DPB1 mismatches defined by different approaches. A cohort of 366 patients who received a kidney transplant at the Heidelberg University Hospital, Germany, with availability of pre- and post-transplant HLA antibody results by single antigen testing as well as of donor and recipient HLA-DPB1 high-resolution typing were analyzed retrospectively. Susceptibility to increased HLA-DPB1 expression was predicted by the linked dimorphism rs9277534 A/G of the HLA-DPB1 gene. Neither HLA-DPB1 mismatches at allele, eplet or TerEp level nor exposure to donor's high HLA-DPB1 expression were significantly associated with the risk of developing dnDSA against HLA-DPB1. However, HLA-DPB1 eplet and TerEp mismatches had a significant negative impact on graft survival (p < 0.001 and p = 0.003, respectively). Matching for HLA-DPB1 at epitope instead of allele level appears to have potential to improve graft survival in kidney transplantation.

  • Ishida H
  • Unagami K
  • Omoto K
  • Kanzawa T
  • Tanabe K
Exp Clin Transplant. 2021 Oct;19(10):1032-1040 doi: 10.6002/ect.2021.0234.
OBJECTIVES:

Antibody-mediated rejection in patients with positive crossmatches can be severe and result in sudden onset of oliguria, leading to graft loss. In an attempt to prevent posttransplant oliguria, we adopted a preoperative desensitization protocol involving the use of high-dose intravenous immunoglobulin/plasmapheresis and the anti-CD20 antibody, rituximab, in 41 transplant recipients with positive crossmatch test results.

MATERIALS AND METHODS:

We retrospectively examined the clinical courses of the 41 kidney transplant recipients, paying special attention to renal graft function, urine volume, and changes in the titers of donor-specific antibodies.

RESULTS:

Four grafts were lost during an average of 4.5-year follow-up. Average graft function was excellent, with a serum creatinine level of 1.3 ± 0.4 mg/dL. Sufficient urine output, with no oliguria or anuria, was achieved postoperatively in 40 of the 41 patients. However, among the 34 patients who underwent graft biopsies, the biopsies revealed acute antibody-mediated rejection in 21 patients (62%), and chronic antibodymediated rejection in 10 patients (30%).

CONCLUSIONS:

The high-dose intravenous immunoglobulin treatment included in our desensitization protocol was shown to be safe and effective for achieving successful transplant outcomes and allowed the avoidance of more aggressive B-cell-targeted treatments, such as C5 inhibitors and/or proteosome inhibitors, for preventing posttransplant oliguria and anuria.

  • Noble J
  • Metzger A
  • Daligault M
  • Chevallier E
  • Bugnazet M
  • Bardy B
  • Naciri Bennani H
  • Terrier N
  • Fiard G
  • Franquet Q
  • et al.
Kidney Int Rep. 2021 Aug 2;6(10):2629-2638 doi: 10.1016/j.ekir.2021.07.024.
INTRODUCTION:

In the setting of kidney transplantation (KT), we assessed the efficacy of desensitization and compared the survival of desensitized patients (HLA-incompatible KT) with similarly sensitized patients receiving HLA-compatible KT or sensitized patients still on a waiting list after adjusting for the usually unaccounted immortal time bias.

METHODS:

All patients in a French KT center on the waiting list between August 1994 and December 2019 with a high level of sensitization (panel-reactive antibodies [PRAs] ≥80%) were included. The primary outcome was all-cause mortality. A time-varying covariate Cox survival model was used to account for the immortal time bias. A landmark analysis was used as a sensitivity analysis.

RESULTS:

During the study period, 326 patients with high PRAs were followed, among which 147 (45%) remained on the waiting list at the time of last follow-up and 179 benefited from a KT. Thirty-six patients were desensitized, of which 30 received a kidney transplant, including eight deceased kidney donors. There were no differences in mortality rates between desensitized KT patients, nondesensitized KT patients, and waitlisted patients after adjusting for immortal time bias (hazard ratio [HR] = 0.48, P = 0.22). Death-censored graft survival was similar between desensitized and nondesensitized KT patients (HR = 0.92, P = 0.88 adjusting for donor age >65 years, donor status, and time on the waiting list). Mean estimated glomerular filtration rate at 1 year post-KT was similar for desensitized KT patients (53.3 ± 21 vs. 53.6 ± 21 ml/min per 1.73 m2 for nondesensitized patients; P = 0.95).

CONCLUSIONS:

HLA-desensitization was effective for highly sensitized patients and gave access to KT without detrimental effects on patient or graft survival rates.

  • Jordan SC
  • Legendre C
  • Desai NM
  • Lorant T
  • Bengtsson M
  • Lonze BE
  • Vo AA
  • Runström A
  • Laxmyr L
  • Sjöholm K
  • et al.
Transplantation. 2021 Aug 1;105(8):1808-1817 doi: 10.1097/TP.0000000000003496.
BACKGROUND:

Highly HLA sensitized patients have limited access to life-saving kidney transplantation because of a paucity of immunologically suitable donors. Imlifidase is a cysteine protease that cleaves IgG leading to a rapid decrease in antibody level and inhibition of IgG-mediated injury. This study investigates the efficacy and safety of imlifidase in converting a positive crossmatch test to negative, allowing highly sensitized patients to be transplanted with a living or deceased donor kidney.

METHODS:

This open-label, single-arm, phase 2 trial conducted at 5 transplant centers, evaluated the ability of imlifidase to create a negative crossmatch test within 24 h. Secondary endpoints included postimlifidase donor-specific antibody levels compared with predose levels, renal function, and pharmacokinetic/pharmacodynamic profiles. Safety endpoints included adverse events and immunogenicity profile.

RESULTS:

Of the transplanted patients, 89.5% demonstrated conversion of baseline positive crossmatch to negative within 24 h after imlifidase treatment. Donor-specific antibodies most often rebounded 3-14 d postimlifidase dose, with substantial interpatient variability. Patient survival was 100% with graft survival of 88.9% at 6 mo. With this, 38.9% had early biopsy proven antibody-mediated rejection with onset 2-19 d posttransplantation. Serum IgG levels began to normalize after ~3-7 d posttransplantation. Antidrug antibody levels were consistent with previous studies. Seven adverse events in 6 patients were classified as possibly or probably related to treatment and were mild-moderate in severity.

CONCLUSIONS:

Imlifidase was well tolerated, converted positive crossmatches to negative, and enabled patients with a median calculated panel-reactive antibody of 99.83% to undergo kidney transplantation resulting in good kidney function and graft survival at 6 mo.

  • Krishnan N
  • Abimbola A
  • Machan N
  • Daga S
  • Gopalakrishnan K
  • Lam F
  • Tan L
  • Kashi H
  • Imray C
  • Zehnder D
  • et al.
Transplant Direct. 2021 Jul 19;7(8):e732 doi: 10.1097/TXD.0000000000001183.
BACKGROUND:

HLA incompatible renal transplantation still remains one of best therapeutic options for a subgroup of patients who are highly sensitized and difficult to match but not much is known about its long-term graft and patient survival.

METHODS:

One hundred thirty-four HLA incompatible renal transplantation patients from 2003 to 2018 with a median follow of 6.93 y were analyzed retrospectively to estimate patient and graft survivals. Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes.

RESULTS:

The overall patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort. The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low at 83%, 64%, and 40% at 1, 5, and 10 y, respectively, compared with other groups (Bead/CDC, P = 0.007; CDC/Flow, P = 0.001; and microbead assay/flow cytometry crossmatch, P = 0.837), although those with a low CDC titer (<1 in 2) have comparable outcomes to the CDC negative group. Female patients in general fared worse in both patient and graft survival outcomes in each of the 3 groups based on pretreatment crossmatch, although this did not reach statistical significance. Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y when compared with no rejection (P < 0.001). Rejection that occurred or continued to occur after the first 2 wk of transplantation caused a significant reduction in graft survivals (P < 0.001), whereas good outcomes were seen in those with a single early rejection episode.

CONCLUSIONS:

One-, 5-, and 10-y HLA incompatible graft and patient survival is comparable to deceased donor transplantation and can be further improved by excluding high-CDC titer cases. Antibody-positive female patients show worse long-term survival. Resolution of early rejection is associated with good long-term graft survival.

  • Koo TY
  • Lee JH
  • Min SI
  • Lee Y
  • Kim MS
  • Ha J
  • Kim SI
  • Ahn C
  • Kim YS
  • Kim J
  • et al.
Kidney Int. 2021 Jul;100(1):206-214 doi: 10.1016/j.kint.2021.01.027.

HLA-incompatible living donor kidney transplantation (LDKT) is one of efforts to increase kidney transplantation opportunity for sensitized patients with kidney failure. However, there are conflicting reports for outcomes of HLA-incompatible kidney transplantation compared to patients who wait for HLA-compatible deceased donor kidney transplantation (DDKT) in the United States and United Kingdom. Waiting for an HLA-compatible DDKT is relatively disadvantageous in Korea, because the average waiting time is more than five years. To study this further, we compared outcomes of HLA-incompatible LDKT with those who wait for HLA-compatible DDKT in Korea. One hundred eighty nine patients underwent HLA-incompatible LDKT after desensitization between 2006 and 2018 in two Korean hospitals (42 with a positive complement-dependent cytotoxicity cross-match, 89 with a positive flow cytometric cross-match, and 58 with a positive donor-specific antibody with negative cross-match). The distribution of matched variables was comparable between the HLA-incompatible LDKT group and the matched control groups (waiting-list-only group; and the waiting-list-or-HLA-compatible-DDKT groups; 930 patients each). The HLA-incompatible LDKT group showed a significantly better patient survival rate compared to the waiting-list-only group and the waiting-list-or-HLA-compatible-DDKT groups. Furthermore, the HLA-incompatible LDKT group showed a significant survival benefit as compared with the matched groups at all strength of donor-specific antibodies. Thus, HLA-incompatible LDKT could have a survival benefit as compared with patients who were waitlisted for HLA-compatible DDKT or received HLA-compatible DDKT in Korea. This suggests that HLA-incompatible LDKT as a good option for sensitized patients with kidney failure in countries with prolonged waiting times for DDKT.

  • Kwofie L
  • Anderson R
  • Steel H
  • Meyer Wa P
Afr Health Sci. 2021 Jun;21(2):735-742 doi: 10.4314/ahs.v21i2.32.
BACKGROUND:

Anti-human leukocyte antigen antibodies (anti-HLA) play a crucial role in graft. Detection of anti-HLA, both pre- and post-transplant is a crucial investigation in clinical organ transplantation.

OBJECTIVES:

Three methodologies for the detection of lymphocytotoxic antibodies were compared to establish which of these is best suited to optimise pre-transplant donor-recipient matching.

METHODS:

Serum samples from 15 renal transplant patients were tested for the presence of anti-HLA by i) cytotoxic-dependent cross-match (CDCXM), ii) flow cytometric cross-match (FCXM) and iii) Luminex-based donor specific antibody cross-match (DSAXM) method, Confirmatory tests for the presence of preformed HLA antibodies were tested using Luminex methodology.

RESULTS:

Two (13%) of the 15 patients had positive HLA Class I antibodies (Ab) using all 3 methods. An additional 2 HLA Class I Ab were identified with FCXM/CDCXM. DSAXM identified 1 HLA Class I positive, not indicated by CDCXM/FCXM.High HLA Class II positivity (40%), identified by CDCXM, while DSAXM and FCXM identified two and one patients, respectively. CDCXM produced 4 false-positive results confirmed by lymphocyte single antigen (LSA) assay.

CONCLUSIONS:

The DSAXM method appears to add value in pre-transplantation screening to identify pre-sensitised patients that may not reject the donor graft due to the absence of donor-specific antibodies.