Repository for Antibody Incompatible Transplantation Evidence
63 results (filtered)
  • Ko Y
  • Kim JY
  • Kim SH
  • Kim DH
  • Lim SJ
  • Shin S
  • Kim YH
  • Jung JH
  • Park SK
  • Kwon H
  • et al.
Ann Transplant. 2020 Oct 6;25:e927420 doi: 10.12659/AOT.927420.

BACKGROUND Patients receiving ABO-incompatible (ABOi) or human leukocyte antigen (HLA)-incompatible (HLAi) kidney transplantation (KT) require potent immunosuppression and are thus at a higher risk of infectious complications. We evaluated the clinical outcomes of KT stratified by ABO and HLA incompatibilities and identified the factors associated with the clinical outcomes. MATERIAL AND METHODS Recipients who underwent living-related KT between 2012 and 2017 were included and classified into 4 groups: ABO-compatible and HLA-compatible (ABOc/HLAc), HLA-incompatible (ABOc/HLAi), ABO-incompatible (ABOi/HLAc), and ABO-incompatible and HLA-incompatible (ABOi/HLAi). Cox proportional hazards regression analyses were carried out to evaluate the risk factors of acute rejection. Out of the 1732 patients who underwent KT, 1190, 131, 358, and 53 were in the ABOc/HLAc, ABOi/HLAc, ABOc/HLAi, and ABOi/HLAi groups, respectively. RESULTS The ABO/HLAi group showed the lowest 5-year graft survival rate (91.7%). Death-censored graft survival was not significantly different among the groups. The mortality rate from infections was significantly higher in the ABOi/HLAi group (7.5%) than the other groups. Antibody-mediated rejection-free graft survival was the lowest in the ABOi/HLAi group, with significant differences compared with the ABOi/HLAc group (P=0.02) and the ABOc/HLAi group (P=0.03). ABOi/HLAi (hazard ratio [HR], 2.63; 95% confidence interval [CI], 1.04-6.65; P<0.01) and combined infection (HR, 1.91; 95% CI, 1.45-2.51; P<0.01) were significant risk factors for acute rejection. CONCLUSIONS Patients with both ABO and HLA incompatibilities showed inferior rates of overall patient and graft survival due to infectious complications. Infection was a prominent risk factor of acute rejection following KT after adjusting for possible confounders including ABO and HLA incompatibility.

  • Tafulo S
  • Malheiro J
  • Dias L
  • Lobato L
  • Ramalhete L
  • Martinho A
  • Bolotinha C
  • Costa R
  • Ivo M
Transpl Immunol. 2020 Oct;62:101317 doi: 10.1016/j.trim.2020.101317.
BACKGROUND:

The inclusion of compatible pairs within kidney paired exchange programs has been described as a way to enhance these programs. Improved immunological matching for the recipient in compatible pair has been described to be a possible benefit.

METHODS:

The main purpose of our study was to determine if the introduction of compatible pairs in the Portuguese kidney paired exchange program would result in a better match for these patients, but also to assess if this strategy would increase the number of incompatible pairs with a possible match. We included 17 compatible pairs in kidney paired exchange pool of 35 pairs and performed an in-silico simulation determining HLA eplet mismatch load between the co-registered and matched pairs using HLA MatchMaker, version 3.0.

RESULTS:

Our study showed that the inclusion of fully HLA-A, -B, -DR mismatched compatible pairs within the national Portuguese KEP increased matched rate within ICP (0.71%) and improved HLA eplet matching within compatible pairs. 16 of 17 (94.12%) of the CP obtained one or more transplants possibilities and 13 (81.25%) would have been transplanted with significantly lower HLA class I and class II total and antibody-verified eplet mismatch load (83.9 ± 16.9 vs. 59.8 ± 12.2, P = .002 and 30.1 ± 5.5 vs. 21.2 ± 3.0, P = .003, respectively).

CONCLUSIONS:

This strategy is a viable alternative for compatible pairs seeking a better matched kidney and Portuguese KEP program should allow them this possibility.

  • Pandey P
  • Setya D
  • Sinha V
  • Bhatt A
  • Devra A
  • Pande A
  • Kumar P
  • Ranjan S
Ther Apher Dial. 2020 Oct;24(5):578-590 doi: 10.1111/1744-9987.13467.

Successful renal transplantation across HLA barrier in sensitized individuals has been on the rise during the past decade, primarily due to improved desensitization regimes. The aim of this study was to share outcome of desensitization in renal transplant recipients with donor-specific anti-HLA antibodies (DSA). This was a retrospective analysis of all HLA immunized individuals who were prospective renal transplant recipients. All such patients underwent preconditioning as per the institutional desensitization protocol. Complement-dependent cytoxicity-based crossmatch (CDC-XM), luminex-based crossmatch (LM-XM) and flowcytometry-based crossmatch (FC-XM) were done in all cases. If any of these tests turned out positive, single antigen bead assay (SAB) was performed. Desensitization for DSA was performed in 55 patients and all patients were followed-up for 1 year to assess graft function and patient outcome. CDC-XM being a less sensitive assay, could not detect incompatibility in 29 (52.73%) cases. After desensitization, even though SAB and LM-XM results revealed an MFI within acceptable range, FC-XM being an extremely sensitive assay, continued to give a positive result in eight (14.55%) cases. The mean ± SD number of pretransplant TPE were 3.44 ± 0.98 (2-11). Out of 55, there were 10 patients who were lost to follow up. Patient and graft survival of 45 patients at 1 year was found to be 100%. Preconditioning for renal transplants in the form of immunosuppression with TPE is an extremely useful auxiliary for transplantation in HLA sensitized renal transplant recipients.

  • Marlu R
  • Bennani HN
  • Seyve L
  • Malvezzi P
  • Janbon B
  • Noble J
  • Christophe M
  • Motte L
  • Imerzoukene F
  • Chevallier E
  • et al.
J Clin Apher. 2020 Sep;35(5):444-452 doi: 10.1002/jca.21825.
INTRODUCTION:

ABO- or HLA-incompatible kidney transplantation is possible thanks to pretransplant antibody-depletion achieved by extracorporeal-treatment modalities. These methods induce depletion of some plasma proteins and may also impact on proteins involved in hemostasis.

METHODS:

To determine the impact of one session of immunoadsorption (IA) alone or combined with membrane filtration (MF) on clotting factors and natural anticoagulants, we performed a prospective, observational study on 13 patients waiting for HLA-/ABO-incompatible kidney transplants. Plasma hemostasis parameters were measured before and immediately after a first session of IA alone in six patients and of IA + MF in seven patients.

RESULTS:

IA alone induced depletion of fibrinogen and factor XIII (FXIII) whereas IA + MF caused greater depletion of all high-molecular-weight hemostatic proteins (fibrinogen, FV, FVIII, FXI, FXIII, von-Willebrand factor [VWF]). After an IA session, median reductions were 30% for fibrinogen and 43% for FXIII compared to baseline values. After a session of IA + MF, median decreases were 70% for fibrinogen, 54% for FV, 56% for FVIII, 37% for FXI, 78% for FXIII, and 62% for VWF. Noticeably, levels of low-molecular-weight factors (<100 kDa) were far less decreased than high-molecular-weight proteins with IA + MF, except for protein S and the tissue factor pathway inhibitor, which are known to be partially physiologically bound to high-molecular-weight molecules.

CONCLUSIONS:

IA and IA + MF induced significant depletion of some proteins implicated in the hemostatic process; however, IA + MF resulted in stronger modifications to hemostasis parameters than IA alone. This may have potential clinical implications regarding bleeding risk, and particularly depletion of fibrinogen and FXIII.

  • Senev A
  • Coemans M
  • Lerut E
  • Van Sandt V
  • Kerkhofs J
  • Daniëls L
  • Driessche MV
  • Compernolle V
  • Sprangers B
  • Van Loon E
  • et al.
J Am Soc Nephrol. 2020 Sep;31(9):2193-2204 doi: 10.1681/ASN.2020010019.
BACKGROUND:

In kidney transplantation, evaluating mismatches of HLA eplets-small patches of surface-exposed amino acids of the HLA molecule-instead of antigen mismatches might offer a better approach to assessing donor-recipient HLA incompatibility and improve risk assessment and prediction of transplant outcomes.

METHODS:

To evaluate the effect of number of eplet mismatches (mismatch load) on de novo formation of donor-specific HLA antibodies (DSAs) and transplant outcomes, we conducted a cohort study that included consecutive adult kidney recipients transplanted at a single center from March 2004 to February 2013. We performed retrospective high-resolution genotyping of HLA loci of 926 transplant pairs and used the HLAMatchmaker computer algorithm to count HLA eplet mismatches.

RESULTS:

De novo DSAs occurred in 43 (4.6%) patients. Multivariable analysis showed a significant independent association between antibody-verified eplet mismatch load and de novo DSA occurrence and graft failure, mainly explained by DQ antibody-verified eplet effects. The association with DQ antibody-verified eplet mismatches was linear, without a safe threshold at which de novo DSA did not occur. Odds for T cell- or antibody-mediated rejection increased by 5% and 12%, respectively, per antibody-verified DQ eplet mismatch.

CONCLUSIONS:

Eplet mismatches in HLA-DQ confer substantial risk for de novo DSA formation, graft rejection, and graft failure after kidney transplantation. Mismatches in other loci seem to have less effect. The results suggest that antibody-verified HLA-DQ eplet mismatch load could be used to guide personalized post-transplant immunosuppression. Adoption of molecular matching for DQA1 and DQB1 alleles could also help to minimize de novo DSA formation and potentially improve transplant outcomes.

  • Babu A
  • Khovanova N
  • Shaw O
  • Griffin S
  • Briggs D
  • Krishnan NS
  • Fletcher S
  • Imray C
  • Seitz A
  • Baker R
  • et al.
Transpl Int. 2020 Sep;33(9):1128-1139 doi: 10.1111/tri.13663.

Anti-HLA-antibody characteristics aid to risk-stratify patients and improve long-term renal graft outcomes. Complement activation by donor-specific antibody (DSA) is an important characteristic that may determine renal allograft outcome. There is heterogeneity in graft outcomes within the moderate to high immunological risk cases (cross-match-positive). We explored the role of C3d-positive DSAs in sub-stratification of cross-match-positive cases and relate to the graft outcomes. We investigated 139 cross-match-positive living-donor renal transplant recipients from four transplant centres in the United Kingdom. C3d assay was performed on serum samples obtained at pretreatment (predesensitization) and Day 14 post-transplant. C3d-positive DSAs were found in 52 (37%) patients at pretreatment and in 37 (27%) patients at Day 14 post-transplant. Median follow-up of patients was 48 months (IQR 20.47-77.57). In the multivariable analysis, pretreatment C3d-positive DSA was independently associated with reduced overall graft survival, the hazard ratio of 3.29 (95% CI 1.37-7.86). The relative risk of death-censored five-year graft failure was 2.83 (95% CI 1.56-5.13). Patients with both pretreatment and Day 14 C3d-positive DSAs had the worst five-year graft survival at 45.5% compared with 87.2% in both pretreatment and Day 14 C3d-negative DSA patients with the relative risk of death-censored five-year graft failure was 4.26 (95% CI 1.79, 10.09). In this multicentre study, we have demonstrated for the first time the utility of C3d analysis as a distinctive biomarker to sub-stratify the risk of poor graft outcome in cross-match-positive living-donor renal transplantation.

  • Sakamoto S
  • Iwasaki K
  • Tomosugi T
  • Niemann M
  • Spierings E
  • Miwa Y
  • Horimi K
  • Takeda A
  • Goto N
  • Narumi S
  • et al.
Front Immunol. 2020 Aug 27;11:2000 doi: 10.3389/fimmu.2020.02000.

Risk prediction of de novo donor specific antibody (DSA) would be very important for long term graft outcome after organ transplantation. The purpose of this study was to elucidate the association of eplet mismatches and predicted indirectly recognizable HLA epitopes (PIRCHE) scores with de novo DSA production. Our retrospective cohort study enrolled 691 living donor kidney transplantations. HLA-A, B, DRB and DQB eplet mismatches and PIRCHE scores (4 digit of HLA-A, B, DR, and DQ) were determined by HLA matchmaker (ver 2.1) and PIRCHE-II Matching Service, respectively. Weak correlation between eplet mismatches and PIRCHE scores was identified, although both measurements were associated with classical HLA mismatches. Class II (DRB+DQB) eplet mismatches were significantly correlated with the incidence of de novo class II (DR/DQ) DSA production [8/235 (3.4%) in eplet mismatch ≤ 13 vs. 92/456 (20.2%) in eplet mismatch ≥ 14, p < 0.001]. PIRCHE scores were also significantly correlated with de novo class II DSA production [26/318 (8.2%) in PIRCHE ≤ 175 vs. 74/373 (19.8%) in PIRCHE ≥ 176, p < 0.001]. Patients with low levels of both class II eplet mismatches and PIRCHE scores developed de novo class II DSA only in 4/179 (2.2%). Analysis of T cell and B cell epitopes can provide a beneficial information on the design of individualized immunosuppression regimens for prevention of de novo DSA production after kidney transplantation.

  • Kramer CSM
  • Koster J
  • Haasnoot GW
  • Roelen DL
  • Claas FHJ
  • Heidt S
HLA. 2020 Jul;96(1):43-51 doi: 10.1111/tan.13883.

In renal transplantation, polymorphic amino acids on mismatched donor HLA molecules can lead to the induction of de novo donor-specific antibodies (DSA), which are associated with inferior graft survival. To ultimately prevent de novo DSA formation without unnecessarily precluding transplants it is essential to define which polymorphic amino acid mismatches can actually induce an antibody response. To facilitate this, we developed a user-friendly software program that establishes HLA class I and class II compatibility between donor and recipient on the amino acid level. HLA epitope mismatch algorithm (HLA-EMMA) is a software program that compares simultaneously the HLA class I and class II amino acid sequences of the donor with the HLA amino acid sequences of the recipient and determines the polymorphic solvent accessible amino acid mismatches that are likely to be accessible to B cell receptors. Analysis can be performed for a large number of donor-recipient pairs at once. As proof of principle, a previously described study cohort of 191 lymphocyte immunotherapy recipients was analysed with HLA-EMMA and showed a higher frequency of DSA formation with higher number of solvent accessible amino acids mismatches. Overall, HLA-EMMA can be used to analyse compatibility on amino acid level between donor and recipient HLA class I and class II simultaneously for large cohorts to ultimately determine the most immunogenic amino acid mismatches.

  • Basu A
  • Prieto M
  • Kosberg C
  • Mai ML
  • Khamash HA
  • Jadlowiec CC
  • Issa NS
  • Dean PG
  • Lorenz EC
  • Stegall MD
  • et al.
Transplantation. 2020 Jun;104(6):1229-1238 doi: 10.1097/TP.0000000000002947.
BACKGROUND:

We examined the 10-year experience of Mayo Clinic's kidney paired donation (KPD).We aimed to determine the benefits for the recipients of enrolled ABO/HLA compatible pairs and determine the factors associated with prolonged KPD waiting time.

METHODS:

We performed a retrospective study of 332 kidney transplants facilitated by the Mayo 3-site KPD program from September 2007 to June 2018.

RESULTS:

The median (interquartile range) time from KPD entry to transplantation was 89 days (42-187 days). The factors independently associated with receiving a transplant >3 months after KPD entry included recipient blood type O and calculated panel reactive antibodies ≥98%. Fifty-four ABO/HLA compatible pairs participated in KPD for the following reasons: cytomegalovirus mismatch (18.5% [10/54]), Epstein-Barr virus (EBV) mismatch (EBV) (9.3% [5/54]), age/size mismatch (51.9% [28/54]), or altruistic reasons (20.3% [11/54]). Cytomegalovirus and EBV mismatch were avoided in 90% (9/10) and 100% (5/5) of cases. Recipients who entered KPD for age/size mismatch and altruistic reasons received kidneys from donors with lower Living Kidney Donor Profile Index scores than their actual donor (median [interquartile range] 31.5 [12.3-47]; P < 0.001 and 26 (-1 to 46); P = 0.01 points lower, respectively). Median time to transplant from KPD entry for compatible pair recipients was 70 days (41-163 days), and 44.4% (24/54) of these transplants were preemptive. All chains/swaps incorporating compatible pairs included ABO/HLA incompatible pairs.

CONCLUSIONS:

KPD should be considered for all living donor/recipient pairs because the recipients of these pairs can derive personal benefit from KPD while increasing the donor pool for difficult to match pairs.

  • Sapir-Pichhadze R
  • Zhang X
  • Ferradji A
  • Madbouly A
  • Tinckam KJ
  • Gebel HM
  • Blum D
  • Marrari M
  • Kim SJ
  • Fingerson S
  • et al.
Kidney Int. 2020 Apr;97(4):778-785 doi: 10.1016/j.kint.2019.10.028.

To optimize strategies that mitigate the risk of graft loss associated with HLA incompatibility, we evaluated whether sequence defined HLA targets (eplets) that result in donor-specific antibodies are associated with transplant outcomes. To define this, we fit multivariable Cox proportional hazard models in a cohort of 118 382 United States first kidney transplant recipients to assess risk of death-censored graft failure by increments of ten antibody-verified eplet mismatches. To verify robustness of our findings, we conducted sensitivity analysis in this United States cohort and assessed the role of antibody-verified eplet mismatches as autonomous predictors of transplant glomerulopathy in an independent Canadian cohort. Antibody-verified eplet mismatches were found to be independent predictors of death-censored graft failure with hazard ratios of 1.231 [95% confidence interval 1.195, 1. 268], 1.268 [1.231, 1.305] and 1.411 [1.331, 1.495] for Class I (HLA-A, B, and C), -DRB1 and -DQB1 loci, respectively. To address linkage disequilibrium between HLA-DRB1 and -DQB1, we fit models in a subcohort without HLA-DQB1 eplet mismatches and found hazard ratios for death-censored graft failure of 1.384 [1.293, 1.480] for each additional antibody-verified HLA-DRB1 eplet mismatch. In a subcohort without HLA-DRB1 mismatches, the hazard ratio was 1.384 [1.072, 1.791] for each additional HLA-DQB1 mismatch. In the Canadian cohort, antibody-verified eplet mismatches were independent predictors of transplant glomerulopathy with hazard ratios of 5.511 [1.442, 21.080] for HLA-DRB1 and 3.640 [1.574, 8.416] for -DRB1/3/4/5. Thus, donor-recipient matching for specific HLA eplets appears to be a feasible and clinically justifiable strategy to mitigate risk of graft loss.