Visual Abstract
Keywords: acute allograft rejection, immunology, kidney biopsy, kidney transplantation, rejection, renal biopsy, renal transplantation, antibody-mediated rejection, human leukocyte antigen
Abstract
Background and objectives
The histology of antibody-mediated rejection after kidney transplantation is observed frequently in the absence of detectable donor-specific anti-HLA antibodies. Although there is an active interest in the role of non-HLA antibodies in this phenotype, it remains unknown whether HLA mismatches play an antibody-independent role in this phenotype of microcirculation inflammation.
Design, setting, participants, & measurements
To study this, we used the tools HLAMatchmaker, three-dimensional electrostatic mismatch score, HLA solvent accessible amino acid mismatches, and mismatched donor HLA–derived T cell epitope targets to determine the degree of HLA molecular mismatches in 893 kidney transplant recipients with available biopsy follow-up. Multivariable Cox proportional hazards models were applied to quantify the cause-specific hazard ratios of the different types of HLA mismatch scores for developing antibody-mediated rejection or histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. In all survival analyses, the patients were censored at the time of the last biopsy.
Results
In total, 121 (14%) patients developed histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies, of which 44 (36%) patients had concomitant T cell–mediated rejection. In multivariable Cox analysis, all different calculations of the degree of HLA mismatch associated with developing histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies. This association was dependent neither on the presence of missing self (potentially related to natural killer cell activation) nor on the formation of de novo HLA antibodies. Also, glomerulitis and complement C4d deposition in peritubular capillaries associated with the degree of HLA mismatch in the absence of anti-HLA antibodies.
Conclusions
The histology of antibody-mediated rejection and its defining lesions are also observed in patients without circulating anti-HLA antibodies and relate to the degree of HLA mismatch.
Introduction
Donor-specific anti-human leukocyte antigen (HLA) antibodies (HLA-DSAs) play an essential role in the development of the histologic lesions defining antibody-mediated rejection, particularly microvascular inflammation with glomerulitis (g) as the hallmark histologic injury, and their presence is associated with a higher risk of kidney allograft failure (1,2). However, a significant percentage of the patients who develop histology of antibody-mediated rejection do not have circulating HLA-DSAs (3–6). This phenotype creates uncertainty and dilemmas in the patients' clinical management (7,8). Comparing the clinical presentation and transcriptional changes of patients with histology of antibody-mediated rejection in the presence versus in the absence of HLA-DSAs, we previously showed that histologic and transcriptional profiles are similar but that outcomes were significantly worse in the HLA-DSA–positive cases (5,9).
Part of these cases with histology of antibody-mediated rejection and absence of HLA-DSAs could be related to the presence of non-HLA antibodies (10,11). Large numbers of antibodies against different non-HLA targets have been identified and associated with kidney graft rejection and graft failure (3,12). However, the results were often not reproducible and conflicting (13–16). Recent evidence indicates the contribution of direct natural killer (NK) cell activation through missing self in the occurrence of microvascular inflammation in the absence of HLA-DSAs (17,18).
Advances in protein modeling have enabled investigation of HLA dissimilarity between donor and recipient at the molecular level. Different tools exist for conducting HLA molecular mismatch assessment by quantifying amino acid sequence and structural disparities between mismatched HLA molecules. HLA solvent accessible amino acid mismatches (HLA-EMMA), Cambridge HLA immunogenicity score, and HLAMatchmaker provide an assessment of potential B cell recognition of the mismatched donor HLA molecules (19–22). Other tools, like mismatched donor HLA–derived T cell epitope targets (PIRCHE-II), define potential donor HLA-derived T cell epitope targets (23–26).
Here, we hypothesized that HLA alloimmunity could also play a role in the histology of the antibody-mediated rejection phenotype in an antibody-independent fashion. We tested this hypothesis by evaluating the association between the different HLA molecular mismatch scores and the risk for histology of antibody-mediated rejection and its defining histologic lesions in the absence of anti-HLA antibodies.
Materials and Methods
Study Population
All consecutive adult recipients of a single-kidney transplant at the University Hospitals Leuven between March 1, 2004 and February 6, 2013 were eligible for this observational cohort study. All transplants were ABO compatible with negative complement-dependent cytotoxicity crossmatch. All clinical data were prospectively collected during routine clinical follow-up and stored systematically in electronic formats. This retrospective study was approved by the Ethics Committee of the University Hospitals Leuven (S64006).
Human Leukocyte Antigen Genotyping and Human Leukocyte Antigen Molecular Mismatch Analysis
All recipients (n=926) and donors (n=926) of this cohort with available DNA samples were genotyped retrospectively at high-resolution level for 11 HLA loci (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1) by next-generation sequencing as described recently (24).
The high-resolution HLA genotypes for all 11 loci were uploaded to HLAMatchmaker (v3.1), HLA-EMMA (v1.00), Cambridge HLA Immunogenicity algorithm, and PIRCHE-II (v3.1.148) software to calculate the HLA molecular mismatches. We obtained the following total HLA molecular mismatch scores: total and only antibody-verified eplet mismatches, total amino acid mismatches, three-dimensional electrostatic mismatch score (EMS-3D), HLA-EMMA, and PIRCHE-II (19,20,23).
Killer Cell Immunoglobulin-Like Receptor Genotyping, Haplotyping, and the Definition of Missing Self
The recipients were retrospectively genotyped for the presence of the 14 killer cell Ig-like receptor genes and two pseudogenes on the next-generation sequencing platform at Histogenetics (Ossining, NY). Missing self was defined as the absence of a corresponding donor HLA class 1 antigen in combination with a specific inhibitory killer cell Ig-like receptor gene in an educated recipient, and “high” missing self was defined as the co-occurrence of two or more missing self-types as described in detail recently (17).
Detection of Circulating Antihuman Leukocyte Antigen Antibodies and Assignment of Donor-Specific Antihuman Leukocyte Antigen Antibodies
Pre- and post-transplant anti-HLA antibodies were screened using a LIFECODES LifeScreen Deluxe kit (Immucor) at day 0 and 3 months after transplantation and yearly after transplantation or at the time of an indication biopsy. Antibody identification was done with the LIFECODES Single Antigen Bead kit (Immucor) when there was a positive or suspected false-negative screening result. All samples of the patients who developed histology of antibody-mediated rejection were retrospectively tested for the presence of anti-HLA antibodies using the more sensitive single-antigen bead kits. A possible presence of HLA-DSAs was suspected at background-corrected median fluorescence intensity value of ≥500. For the final assignment of HLA-DSAs, patients' sera reactivity was analyzed as described previously (27).
Kidney Allograft Biopsies and Histologic Scoring
We included all post-transplant kidney allograft biopsies performed in this cohort (n=3744). Timing and scoring of the biopsies were described in detail previously (5). The severity of the individual lesions was semiquantitatively scored according to the Banff categories, and the diagnosis of antibody-mediated rejection was established retrospectively (28). In biopsies with microvascular inflammation, de novo or recurrent glomerulonephritis was not considered as exclusion criteria for diagnosing histology of antibody-mediated rejection—a slight deviation from the Banff rules we had for the immunohistochemical complement C4d staining (mAb, dilution 1:500), which was performed on frozen tissue instead of on paraffin section. Also, we used the following semiquantitative scores for complement C4d deposition: C4d=0, no staining of peritubular capillaries (0%); C4d=1, minimal staining (>0%–<25%); C4d=2, focal staining (25%–75%); and C4d=3, diffuse staining (>75%). A cutoff value of C4d>1 was considered as positive. Antibody-mediated rejection was diagnosed by the presence of the three 2019 Banff criteria for acute active antibody-mediated rejection, not taking into account non-HLA antibodies or gene expression changes. For the biopsies meeting the first two Banff 2019 criteria for antibody-mediated rejection irrespective of the third Banff criterion, we used the terminology histology of antibody-mediated rejection (5).
Statistical Analyses
Patient and donor characteristics are described by means and SDs for continuous variables and frequencies and percentages for categorical variables. Pearson correlation was used to measure the strength of the relationship between the number of HLA amino acid mismatches and the number of the different HLA mismatches calculated by the different approaches. Multivariable Cox proportional hazards models were applied to quantify the cause-specific hazard ratios (HRs) of the different types of HLA mismatch scores for developing antibody-mediated rejection or developing histology of antibody-mediated rejection in the absence of HLA-DSAs. In all survival analyses, the patients were censored at the time of the last biopsy. To address confounding, we adjusted all models for donor and recipient age, donor type (living, brain death, or circulatory death), cold ischemia time, and repeat transplantation. The HLA molecular mismatch scores were included linearly into the models. Sensitivity multivariable Cox analyses were performed in the pretransplant HLA-DSA–negative patients and in patients without anti-HLA antibodies, and patients were additionally censored at the time of de novo HLA-DSA occurrence. All P values of 0.05 were considered to indicate statistical significance. We used SAS (v9.4; SAS Institute, Cary, NC) and GraphPad Prism software (v9.3; GraphPad Software, San Diego, CA) for the statistical analyses.
Results
Study Population and Demographic Characteristics
From 1000 consecutive single-kidney transplants performed at our hospital between March 2004 and February 2013, 74 transplant pairs with insufficient DNA samples for compete high-resolution HLA typing and 33 patients without biopsy follow-up were excluded. Finally, 893 transplant pairs with complete high-resolution HLA genotyping and allograft biopsy follow-up were included in this study (Supplemental Figure 1). Pretransplant anti-HLA antibodies were detected in 233 patients (26%), of which 95 (41%) patients had HLA-DSAs (Table 1). Median follow-up time was 8 (interquartile range, 5–11) years, and 43 (5%) patients developed de novo HLA-DSAs during the follow-up; 150 allografts failed during follow-up, and 217 patients died with a functioning graft. The different HLA mismatch scores are highly correlated (Figure 1, Table 1).
Table 1.
Demographic and clinical characteristics and follow-up data of the study population (n=893)
| Cohort Characteristics | Total, n=893 |
|---|---|
| Recipient demographics | |
| Men, n (%) | 538 (60) |
| Age, yr, mean ± SD | 54±13 |
| Repeat transplantation, n (%) | 126 (14) |
| Body mass index, kg/m2, mean ± SD | 25.3±4.5 |
| White ethnicity, n (%) | 878 (98) |
| Donor demographics | |
| Men, n (%) | 477 (53) |
| Age, yr, mean ± SD | 48±15 |
| Living donor, n (%) | 42 (5) |
| Donation after brain death, n (%) | 703 (79) |
| Donation after cardiac death, n (%) | 148 (17) |
| Cold ischemia time, h, mean ± SD | 14.4±5.5 |
| Transplant characteristics | |
| HLA-ABDRDQ antigen mismatches (0–8), mean ± SD | 3.4±1.6 |
| HLA allele mismatches (0–17), mean ± SD | 8.3±3.1 |
| HLA amino acids mismatches (0–183), mean ± SD | 56.0±32.7 |
| HLA-EMMA score (0–173), mean ± SD | 45.6±24.5 |
| EMS-3D mismatch score (0–4.29), mean ± SD | 1.8±0.7 |
| Eplet mismatches (0–76), mean ± SD | 28.4±13.4 |
| Abv eplet mismatches (0–38), mean ± SD | 14.2±6.7 |
| PIRCHE-II score (0–1216), median (IQR) | 310 (205–452) |
| Pretransplant anti-HLA antibodies, n (%) | 233 (26) |
| Pretransplant donor-specific HLA antibodies, n (%) | 95 (11) |
| Induction therapy, n (%) | 369 (41) |
| Basiliximab | 317/369 (86) |
| Immunosuppression regimen: TAC-MPA-CS, n (%) | 762 (85) |
| De novo donor-specific HLA antibodies, n (%) | 43 (5) |
| Median follow-up time post-transplant, yr (IQR) | 8.0 (5.2–10.5) |
| Median biopsy follow-up time post-transplant, yr (IQR) | 2.1 (2.0–5.0) |
HLA-EMMA, HLA solvent accessible amino acid mismatches; EMS-3D, three-dimensional electrostatic mismatch score; Abv, antibody verified; PIRCHE-II, mismatched donor HLA–derived T cell epitope targets; IQR, interquartile range; TAC, tacrolimus; MPA, mycophenolic acid; CS, corticosteroids.
Figure 1.
Positive correlation between the number of HLA amino acid mismatches and the number of the HLA mismatches calculated by the different approaches. The Pearson correlation coefficient is displayed for each different HLA mismatch approach. EMS-3D, three-dimensional electrostatic mismatch score; HLA, human leukocyte antigen; HLA-EMMA, HLA solvent accessible amino acid mismatches; MM, mismatch; PIRCHE-II, mismatched donor HLA–derived T cell epitope targets.
The Association between Human Leukocyte Antigen Mismatch and Antibody-Mediated Rejection Is Mediated by Donor-Specific Antihuman Leukocyte Antigen Antibodies
According to the three criteria of the Banff 2019 classification, antibody-mediated rejection occurred in 102 (11%) patients of our cohort during follow-up; 79 of these patients (77%) were diagnosed with antibody-mediated rejection due to the presence of HLA-DSAs, 64 had pretransplant HLA-DSAs, and 15 had de novo HLA-DSAs, whereas 23 (23%) had C4d deposition in the absence of HLA-DSAs as serologic evidence for antibody-mediated rejection. Forty-four (43%) of the patients with antibody-mediated rejection had concomitant T cell–mediated rejection, and seven (7%) had borderline changes. All HLA mismatch scores independently associated with the hazard of developing antibody-mediated rejection (Table 2). After additional adjusting for the presence of HLA-DSAs, none of the HLA mismatch scores remained associated with developing antibody-mediated rejection (Table 2). Of the 23 patients diagnosed with antibody-mediated rejection due to C4d deposition in the absence of HLA-DSAs, 16 (70%) also had concomitant T cell–mediated rejection or borderline changes, yet antibody-mediated rejection did not associate with HLA mismatch.
Table 2.
Multivariable hazard ratios for the occurrence of antibody-mediated rejection (meeting all three Banff 2019 criteria) according to the different HLA mismatch approaches (n=893)
| HLA Mismatch Approach | Events | Cox Models | |
|---|---|---|---|
| Hazard Ratio | 95% Confidence Interval | ||
| (1) Not adjusted for the presence of pretransplant HLA-DSAs | |||
| HLA-ABDRDQ antigen MM (per 1) | 102 | 1.27 | 1.11 to 1.45 |
| HLA allele MM (per 1) | 102 | 1.08 | 1.01 to 1.16 |
| HLA amino acids MM (per 10) | 102 | 1.11 | 1.04 to 1.17 |
| HLA-EMMA (per 10) | 102 | 1.11 | 1.03 to 1.21 |
| EMS-3D MM score (per 1) | 102 | 1.67 | 1.25 to 2.25 |
| HLA eplet MM (per 10) | 102 | 1.22 | 1.05 to 1.42 |
| HLA abv eplet MM (per 10) | 102 | 1.46 | 1.08 to 1.97 |
| PIRCHE-II score (per 100) | 102 | 1.14 | 1.03 to 1.26 |
| (2) Adjusted for the presence of pretransplant HLA-DSAs | |||
| HLA-ABDRDQ antigen MM (per 1) | 102 | 1.14 | 0.99 to 1.32 |
| HLA allele MM (per 1) | 102 | 1.03 | 0.96 to 1.11 |
| HLA amino acids MM (per 10) | 102 | 1.04 | 0.98 to 1.10 |
| HLA-EMMA (per 10) | 102 | 1.05 | 0.96 to 1.15 |
| EMS-3D MM score (per 1) | 102 | 1.22 | 0.90 to 1.66 |
| HLA eplet MM (per 10) | 102 | 1.13 | 0.96 to 1.32 |
| HLA abv eplet MM (per 10) | 102 | 1.20 | 0.89 to 1.62 |
| PIRCHE-II score (per 100) | 102 | 1.02 | 0.91 to 1.14 |
Each row represents a separate multivariable analysis. The Cox models are shown (1) not adjusted for the presence of pretransplant HLA-DSAs and (2) adjusted for the presence of pretransplant HLA-DSAs. All multivariable models were adjusted for donor and recipient age, donor type, cold ischemia time, and repeat transplantation. HLA, human leukocyte antigen; HLA-DSA, donor-specific anti-HLA antibody; MM, mismatch; HLA-EMMA, HLA solvent accessible amino acid mismatches; EMS-3D, three-dimensional electrostatic mismatch score; Abv, antibody verified; PIRCHE-II, mismatched donor HLA–derived T cell epitope targets.
Contribution of Human Leukocyte Antigen Mismatch to the Development of Histology of Antibody-Mediated Rejection in the Absence of Donor-Specific Antihuman Leukocyte Antigen Antibodies
Next, we restricted the multivariable analyses to patients without pretransplant HLA-DSAs and additionally censored patients at the time of de novo HLA-DSA occurrence. Of 798 pretransplant HLA-DSA–negative kidney transplant recipients with available biopsy follow-up, 121 (15%) developed histology of antibody-mediated rejection in the absence of de novo HLA-DSAs. Of them, 110 (91%) met these criteria by the presence of microcirculation inflammation >1: 90 had g≥1 and/or peritubular capilaritis (ptc) >0, and 20 had g=0 but ptc≥2. Only 11 patients were diagnosed with histology of antibody-mediated rejection by C4d positivity and intimal arteritis >0 (n=5) or g=1/ptc=1 in the absence of T cell–mediated rejection/borderline changes (n=4) or acute thrombotic microangiopathy (n=2). Forty-four (36%) of the patients with histology of antibody-mediated rejection had concomitant T cell–mediated rejection, and an additional 16 (13%) had borderline changes; this was not statistically different from the antibody-mediated rejection group. In multivariable analyses (Table 3), HLA antigen mismatches (HR, 1.29 per one; 95% confidence interval [95% CI], 1.14 to 1.45; P<0.001), HLA allele mismatches (HR, 1.09 per one; 95% CI, 1.03 to 1.16; P=0.003), HLA amino acid mismatches (HR, 1.10 per ten; 95% CI, 1.04 to 1.16; P<0.001), HLA-EMMA (HR, 1.11 per ten; 95% CI, 1.04 to 1.20; P=0.004), EMS-3D (HR, 1.69 per one; 95% CI, 1.31 to 2.18; P<0.001), eplet mismatches (HR, 1.23 per ten; 95% CI, 1.07 to 1.41; P=0.003), and PIRCHE-II (HR, 1.15 per 100; 95% CI, 1.05 to 1.26; P=0.002) were all associated with developing histology of antibody-mediated rejection in the absence of HLA-DSAs (Figure 2).
Table 3.
Multivariable hazard ratios for histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies (meeting the first two Banff 2019 criteria) according to the different HLA mismatch approaches censored for de novo donor-specific anti-HLA antibody occurrence
| HLA Mismatch Approach | Events | Cox Models | |
|---|---|---|---|
| Hazard Ratio | 95% Confidence Interval | ||
| (1) HLA-DSA–negative patients,a n=798 | |||
| HLA-ABDRDQ antigen MM (per 1) | 121 | 1.29 | 1.14 to 1.45 |
| HLA allele MM (per 1) | 121 | 1.09 | 1.03 to 1.16 |
| HLA amino acids MM (per 10) | 121 | 1.10 | 1.04 to 1.16 |
| HLA-EMMA (per 10) | 121 | 1.11 | 1.04 to 1.20 |
| EMS-3D MM score (per 1) | 121 | 1.69 | 1.31 to 2.18 |
| HLA eplet MM (per 10) | 121 | 1.23 | 1.07 to 1.41 |
| HLA abv eplet MM (per 10) | 121 | 1.57 | 1.19 to 2.07 |
| PIRCHE-II score (per 100) | 121 | 1.15 | 1.05 to 1.26 |
| (2) HLA antibody–negative patients,a n=660 | |||
| HLA-ABDRDQ antigen MM (per 1) | 102 | 1.30 | 1.14 to 1.48 |
| HLA allele MM (per 1) | 102 | 1.10 | 1.03 to 1.17 |
| HLA amino acids MM (per 10) | 102 | 1.11 | 1.05 to 1.18 |
| HLA-EMMA (per 10) | 102 | 1.14 | 1.05 to 1.24 |
| EMS-3D MM score (per 1) | 102 | 1.74 | 1.33 to 2.29 |
| HLA eplet MM (per 10) | 102 | 1.25 | 1.08 to 1.45 |
| HLA abv eplet MM (per 10) | 102 | 1.65 | 1.22 to 2.23 |
| PIRCHE-II score (per 100) | 102 | 1.27 | 1.06 to 1.28 |
Each row represents a separate multivariable analysis. The Cox models were performed (1) in the absence of HLA-DSAs (n=798) and (2) in the absence of HLA antibodies (n=660). All multivariable models were adjusted for donor and recipient age, donor type, cold ischemia time, and repeat transplantation. The multivariable Cox analyses in pretransplant HLA-DSA–negative patients were additionally adjusted for the presence of anti-HLA antibodies. HLA, human leukocyte antigen; HLA-DSA, donor-specific anti-HLA antibody; MM, mismatch; HLA-EMMA, HLA solvent accessible amino acid mismatches; EMS-3D, three-dimensional electrostatic mismatch score; Abv, antibody verified; PIRCHE-II, mismatched donor HLA–derived T cell epitope targets.
Assessed at the time of transplantation.
Figure 2.
Associations between HLA mismatches and histology of antibody-mediated rejection in the absence of HLA-DSAs. The figure depicts the histology of antibody-mediated rejection-free survival analysis in patients without HLA-DSAs stratified according to tertiles of HLA mismatch scores and censored for de novo HLA-DSA occurrence (n=798). (A) HLA-ABDRDQ antigen mismatches (0–2, 3–4, and 5–8). (B) HLA allele mismatches (0–6, 7–9, and 10–17). (C) HLA amino acids mismatches (0–38, 39–69, and 70–183). (D) HLA-EMMA score (0–32, 33–55, and 56–125). (E) EMS-3D score (0–1.46, 1.47–2.03, and 2.03–4.29). (F) HLA eplet mismatches (0–21, 22–34, and 35–76). (G) HLA antibody-verified eplet mismatches (0–11, 12–16, and 17–38). (H) PIRCHE-II score (0–245, 248–392, and 393–1216). ABMRh, histology of antibody-mediated rejection (meeting the first two Banff 2019 criteria).
Sensitivity analysis restricted to patients without detectable anti-HLA antibodies (n=660), thus further excluding patients with non–HLA-DSAs, confirmed that all different HLA mismatch scores were independently associated with histology of antibody-mediated rejection in the absence of anti-HLA-antibodies (Table 3). Subsequent multivariable models, censored additionally for cases with histology of antibody-mediated rejection in the absence of HLA-DSAs but with C4d deposition (classified as antibody-mediated rejection according to Banff 2019), showed the same associations, confirming that HLA mismatch was associated with histology of antibody-mediated rejection in the absence of any serologic (HLA-DSAs) or histologic (C4d deposition in peritubular capillaries) evidence of antibody involvement (Supplemental Table 1). The subgroup of patients with histology of antibody-mediated rejection with g (g>0) was also associated with HLA mismatches in the absence of anti-HLA antibodies and C4d deposition. The association between HLA mismatch and histology of antibody-mediated rejection in the absence of HLA-DSAs was not dependent on missing self (Supplemental Table 2).
Additionally, we investigated the relative contribution of the individual HLA mismatch scores for each HLA molecule to the development of histology of antibody-mediated rejection in the absence of HLA-DSAs by inclusion of the individual EMS-3D score for each HLA molecule in the multivariable analysis censored at the time of de novo HLA-DSA occurrence. First, we included the individual EMS-3D scores for one HLA molecule in the multivariable Cox model (Supplemental Table 3). The EMS-3D scores for HLA-A, HLA-C, and HLA-DQA1B1 independently associated with the occurrence of histology of antibody-mediated rejection in patients without HLA-DSAs and anti-HLA antibodies. Next, we included all EMS-3D scores in one multivariable Cox model (Table 4), which suggested that the EMS-3D score for the HLA-DQA1B1 molecule (HR, 1.15 per 0.1; 95% CI, 1.04 to 1.27; P=0.007) has a larger effect on the associations between the HLA mismatch scores and the risk of histology of antibody-mediated rejection in the absence of HLA-DSAs and anti-HLA antibodies (n=660).
Table 4.
Multivariable hazard ratios for histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies (meeting the first two Banff 2019 criteria) according to the different three-dimensional electrostatic mismatch scores for each HLA molecule censored for de novo donor-specific anti-HLA antibody occurrence
| HLA Three-Dimensional Electrostatic Mismatch Score | Events | Cox Models | |
|---|---|---|---|
| Hazard Ratio | 95% Confidence Interval | ||
| (1) HLA-DSA–negative patients,a n=798, per 0.1 | |||
| EMS-3D score for HLA-A | 121 | 1.08 | 0.99 to 1.18 |
| EMS-3D score for HLA-B | 121 | 1.02 | 0.91 to 1.14 |
| EMS-3D score for HLA-C | 121 | 1.07 | 0.98 to 1.17 |
| EMS-3D score for HLA-DRB1 | 121 | 0.92 | 0.77 to 1.21 |
| EMS-3D score for HLA-DRB345 | 121 | 0.95 | 0.82 to 1.11 |
| EMS-3D score for HLA-DQA1B1 | 121 | 1.15 | 1.04 to 1.27 |
| EMS-3D score for HLA-DPBA1B1 | 121 | 1.07 | 0.94 to 1.21 |
| (2) HLA antibody–negative patients,a n=660, per 0.1 | |||
| EMS-3D score for HLA-A | 102 | 1.07 | 0.98 to 1.17 |
| EMS-3D score for HLA-B | 102 | 1.00 | 0.89 to 1.14 |
| EMS-3D score for HLA-C | 102 | 1.10 | 0.99 to 1.21 |
| EMS-3D score for HLA-DRB1 | 102 | 0.98 | 0.80 to 1.20 |
| EMS-3D score for HLA-DRB345 | 102 | 0.95 | 0.81 to 1.12 |
| EMS-3D score for HLA-DQA1B1 | 102 | 1.13 | 1.01 to 1.26 |
| EMS-3D score for HLA-DPBA1B1 | 102 | 1.09 | 0.95 to 1.25 |
The first multivariable model was performed (1) in the absence of HLA-DSAs (n=798), and the second multivariable model was performed (2) in the absence of HLA antibodies (n=660). Both multivariable models were adjusted for donor and recipient age, donor type, cold ischemia time, and repeat transplantation. The first multivariable Cox model in pretransplant HLA-DSA–negative patients was additionally adjusted for the presence of anti-HLA antibodies. HLA, human leukocyte antigen; HLA-DSA, donor-specific anti-HLA antibody; EMS-3D, three-dimensional electrostatic mismatch score.
Assessed at the time of transplantation.
Associations of Human Leukocyte Antigen Mismatch and Individual Histopathologic Banff Lesions in the Absence of Antihuman Leukocyte Antigen Antibodies
Finally, we investigated the associations of the degree of HLA mismatch and the occurrence of the individual Banff lesions in this cohort of patients without pretransplant anti-HLA antibodies and censored for de novo HLA-DSA occurrence (n=660) (Supplemental Table 4). The occurrences of g, endarteritis, ptc, and C4d deposition in peritubular capillaries were independently associated with the different HLA mismatch scores (Figure 3). Also, tubulitis and interstitial inflammation, lesions defining T cell–mediated rejection or borderline changes, were associated with the different HLA mismatch scores (Supplemental Table 4). We therefore investigated the presence of concomitant T cell–mediated rejection in anti-HLA antibody-negative patients with histology of antibody-mediated rejection; 34% (34 of 101) of patients with histology of antibody-mediated rejection in the absence of anti-HLA antibodies had concomitant T cell–mediated rejection on the same biopsy. Concomitant T cell–mediated rejection was present in 20%, 45%, and 20% of biopsies with g>0, ptc>1, and C4d>0, respectively.
Figure 3.
Associations of HLA mismatches and individual histopathologic Banff lesions in the absence of anti-HLA antibodies. Forest plots with multivariable hazard ratios evaluating the relationship of HLA mismatches with the development of the individual antibody-mediated rejection lesions in anti-HLA antibody–negative patients (n=660). Each multivariable Cox analysis was adjusted for donor and recipient age, donor type, cold ischemia time, and repeat transplantation. 95% CI, 95% confidence interval; abv, antibody verified; aHR, adjusted hazard ratio.
Discussion
We demonstrated that the degree of HLA mismatch, assessed by a range of HLA mismatching approaches, is associated with the occurrence of the histology of antibody-mediated rejection in patients without serologic evidence of circulating anti-HLA antibodies. Individual lesions of histology of antibody-mediated rejection, like g, ptc, and C4d deposition, in peritubular capillaries also associated independently with the degree of HLA mismatch between donor and recipient in the absence of any detectable anti-HLA antibodies. Although this study confirmed that HLA-DSAs associated with histology of antibody-mediated rejection, our findings indicate that the lesions defining histology of antibody-mediated rejection are not specific to antibody involvement and can be caused by immune activation through donor-recipient HLA mismatch independent of anti-HLA antibodies.
To our knowledge, this is the first study to demonstrate that the degree of HLA mismatch, as assessed with a wide range of older but also recently developed molecular HLA matching tools, is independently associated with histology of antibody-mediated rejection also in the absence of HLA-DSAs and anti-HLA antibodies. Histology of antibody-mediated rejection in the absence of HLA-DSAs is a frequently encountered (3–6,17) but ill-explained phenotype, currently not considered in the Banff 2019 classification (28). This heterogeneous phenotype has been associated recently with non-HLA antibodies yet also fully antibody-independent processes, such as NK cell activation related to missing self (10,17). Our finding, that HLA mismatching independently associates with this phenotype as it does for T cell–mediated rejection (26), illustrates that histology of antibody-mediated rejection and its defining lesions are less specific for antibody involvement.
Recently, it was demonstrated that high missing self and NK cell activation might cause microvascular rejection in the absence of HLA antibodies (17). The current study also shows for the first time that HLA mismatches confer a risk for histology of antibody-mediated rejection independent of missing self (potentially related to NK cell activation) and independent of HLA antibodies. This suggests that antibody-independent NK cell activation mediated by the missing self is just one of the ways in which HLA mismatch on the HLA-directed allorecognition pathway may lead to this histologic phenotype. As one third of the cases with this phenotype had concomitant T cell–mediated rejection, our study suggests a possible involvement of the primary T cell activation in this phenotype in antibody- and complement-independent processes. Such relation to T cell activation and microvascular inflammation (both g and peritubular capillary congestion) has been demonstrated in preclinical studies and relates to the fact that T cells can recognize all antigens, including HLA (class 2) antigens expressed by endothelium (29–31). However, as we report on a clinical cohort study, causality cannot be proven. The real activating and effector mechanisms of how HLA mismatches, through adaptive or innate immunity, cause microvascular rejection in the absence of circulating HLA antibodies and remain essentially unknown.
The finding that the genetic donor-recipient mismatch is independently associated with histology of antibody-mediated rejection in the absence of HLA-DSAs indicates that this phenotype truly represents kidney transplant rejection defined as immune responses instigated by mismatched alloantigens, in this case mismatched HLA antigens. However, the fact that we had this association in the absence of anti-HLA antibodies challenges the idea that histology of antibody-mediated rejection and its defining lesions g, ptc, and C4d deposition in peritubular capillaries are specific for antibody-mediated allograft rejection. Therefore, the distinction between antibody-mediated rejection and T cell–mediated rejection Banff phenotypes is not robust and becomes even more challenging than it already was because of the description of the nonspecificity of intimal arteritis (32) and the co-occurrence of antibody-mediated rejection and T cell–mediated rejection in “mixed rejections.” Instead of focusing on the artificial dichotomy between antibody-mediated rejection and T cell–mediated rejection from the histologic presentation, for clinical purposes and treatment decisions, more focus on the actual infiltrating cell types and on the identification of the underlying pathophysiologic process, such as HLA or non-HLA antibodies, missing self, and HLA mismatches, could become highly valuable (33).
Further to our previously described association between HLA mismatch and antibody-mediated rejection (24,34–36), our results show that this association is mediated by the presence of HLA-DSAs without additional independent effects of the degree of HLA mismatch per se. Although Banff 2019 also classifies HLA-DSA–negative, C4d-positive histology of antibody-mediated rejection as canonical antibody-mediated rejection, our study did not show a relation with the degree of HLA mismatch. Non-HLA auto- or alloantibodies could play a role in this unexplained complement activation in some of these patients, although we cannot confirm this hypothesis in this cohort. To reassure that we did not miss any circulating HLA-DSAs using only the screening kit, we have retrospectively tested samples of patients with histology of antibody-mediated rejection with single-antigen bead identification kits and confirmed the absence of HLA-DSAs in these patients; however, some antibodies against rare DPB1 alleles or DQA1/DQB1 combination epitopes not covered in the SAB assay could have been missed. Importantly, we recently showed that patients with this phenotype also have different graft outcomes compared with antibody-mediated rejection with detectable HLA-DSAs (5). All of this together indicates that Banff 2019 C4d+ antibody-mediated rejection in the absence of HLA-DSAs cases cannot simply be equated to cases with antibody-mediated rejection with detectable HLA-DSAs. Thus, this microvascular rejection phenotype in the absence of HLA-DSAs likely represents a heterogeneous group of patients. Multiple causal factors likely play a role, including immunogenic HLA mismatches, T and NK cell activation, AKI, recurrent disease, non-HLA antibodies, and even some missed HLA-DSAs, and subgroups of these patients are at risk for inferior graft outcomes.
The association between HLA disparity and histology of antibody-mediated rejection was independent of the way of calculating the donor-recipient HLA molecular mismatch. We used all currently available tools to quantify the HLA dissimilarity between donor and recipient at the HLA molecular level and described strong correlation between all tools. Although all of these tools primarily aim at predicting de novo HLA-DSA occurrence, we clearly demonstrated that the underlying driver for the development of histology of antibody-mediated rejection is the HLA dissimilarity between donors and recipients.
This study has some limitations. The single-center nature of our study and the study population, mainly White participants with continued access to immunosuppression therapy and mainly deceased donors, may limit the generalizability of these findings to other different populations without external validation. For the diagnosis of antibody-mediated rejection, we used histology as a gold standard without molecular gene expression analysis and relied entirely on the diagnostic criteria of the most recent Banff classification. Future updates of the diagnostic criteria for antibody-mediated rejection (perhaps including mandatory molecular analyses in the gold standard definition) could affect the interpretation of our data. We did not investigate associations with other graft outcomes in this study as we were only interested in the contribution of HLA mismatch and the occurrence of histology of antibody-mediated rejection in the absence of HLA-DSAs. Also, we did not assess any non-HLA mismatches, as linkage disequilibrium may exist with the degree of HLA mismatches. Finally, some HLA-DSAs might have been missed as the currently available assays do not have 100% sensitivity. However, if many of the patients without HLA-DSAs but with histology of antibody-mediated rejection have undetected clinically relevant HLA-DSAs, we would expect to see an association between this group and worse graft outcome, which was not the case in our cohort as published earlier (5). Further work is needed to validate our findings in a different population and to elucidate the HLA antibody–independent immune processes instigating microcirculation inflammation and C4d deposition. However, such a cohort for external validation should have sufficient granular data on both sides, complete high-resolution HLA typing, complete anti-HLA antibody follow-up, and detailed biopsy follow-up data.
In conclusion, we demonstrated that donor-recipient HLA mismatch is at least partially involved in developing the histologic presentation of antibody-mediated rejection and its defining lesions in an HLA antibody–independent process, regardless of the way of calculating the donor-recipient HLA disparity. This indicates that the lesions considered suggestive of antibody activity are not specific for antibody involvement detectable by the current single-antigen bead Luminex assays. The often concomitant presence of tubulointerstitial inflammation, a hallmark of T cell–mediated rejection, suggests that this microvascular inflammation can potentially be explained by primary T cell activation as an initiating process. Instead of focusing on the artificial dichotomy between antibody-mediated and T cell–mediated rejection from the histologic presentation, these data highlight the need to clearly differentiate the Banff histologic picture from the identified underlying pathophysiology and a need for clinicopathologic reclassification of kidney transplant rejection biopsies.
Disclosures
F. Claas reports consultancy agreements with GenDx and Immucor and serving in an advisory or leadership role for Eurotransplant, Matchis, and Pregmune. M.-P. Emonds reports employment with Red Cross Flanders and serving on the Eurotransplant Tissue Typing Advisory Committee. V. Kosmoliaptsis reports patents or royalties with the University of Cambridge. D. Kuypers reports consultancy agreements with Astellas Company, CSL Behring, GSK, HANSA, Sangamo-Tx, Takeda, and UCB; research funding from Astellas Inc.; honoraria from Astellas, CSL Behring, GSK, HANSA, Takeda, and UCB; serving as an associate editor for Transplantation; serving as an editorial board member for Current Clinical Pharmacology, Therapeutic Drug Monitoring, and Transplantation Reviews; and speakers bureau for Astellas and HIKMA. M. Naesens reports research funding from CareDx. M. Naesens is the inventor on two patents related to the Fonds Wetenschappelijk Onderzoek-SBO (Strategisch Basis Onderzoek) application. The first patent is EP19152365.3: mRNA-based biomarkers for antibody-mediated transplant rejection. This biomarker was licensed in September 2020 to CareDx, a precision medicine solutions company focused on solutions for transplant patients. The second patent is PCT/EP2018/097044: Biomarkers for typing allograft recipients (the patent application was submitted December 2018). B. Sprangers reports serving as an expert ad hoc for the European Medicines Agency. E. Van Loon reports research funding from a Research Foundation Flanders fellowship grant. All remaining authors have nothing to disclose.
Funding
This project is funded by Research Foundation–Flanders (Fonds Wetenschappelijk Onderzoek [FWO]) and Flanders Innovation & Entrepreneurship Agency (VLAIO) with a TBM (ToegepastBiomedisch onderzoek met een primairMaatschappelijke finaliteit) project grant IWT.150199, awarded to M. Naesens. J. Callemeyn is supported by FWO fellowship grant 1196119N. H.C. Copley acknowledges funding from Medical Research Council with Clinical Research Training fellowship MR/S006745/1. V. Kosmoliaptsis acknowledges funding from National Institute for Health and Care Research fellowship PDF-2016-09-065. M. Naesens is a senior clinical investigator under FWO grant 1844019N and is also funded by Katholieke Universiteit Leuven grant C32/17/049 (a C3 internal grant). B. Sprangers is a senior clinical investigator under FWO grant 1842919N.
Supplementary Material
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
Author Contributions
M. Naesens and A. Senev conceptualized the study; J. Callemeyn, M. Coemans, M.-P. Emonds, D. Kuypers, E. Lerut, M. Naesens, A. Senev, E. Van Loon, and V. Van Sandt were responsible for data curation; H.C. Copley, V. Kosmoliaptsis, and A. Senev were responsible for formal analysis; M. Naesens and A. Senev wrote the original draft; and J. Callemeyn, F. Claas, M. Coemans, H.C. Copley, M.-P. Emonds, P. Koshy, V. Kosmoliaptsis, D. Kuypers, E. Lerut, M. Naesens, A. Senev, B. Sprangers, A. Van Craenenbroeck, E. Van Loon, and V. Van Sandt reviewed and edited the manuscript.
Data Sharing Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Supplemental Material
This article contains the following supplemental material online at https://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.00570122/-/DCSupplemental.
Supplemental Table 1. Multivariable analysis hazard ratios for histology of antibody-mediated rejection (meeting the first two Banff 2019 criteria) according to the different HLA mismatch approaches censored for the occurrence of de novo HLA-DSAs and for HLA-DSA–negative C4d+ antibody-mediated rejection.
Supplemental Table 2. Multivariable hazard ratios for HLA-DSA–negative histology of antibody-mediated rejection (meeting the first two Banff 2019 criteria) according to the different HLA mismatch approaches censored for de novo HLA-DSA occurrence and additionally adjusted for missing self.
Supplemental Table 3. Multivariable hazard ratios for HLA-DSA–negative histology of antibody-mediated rejection (meeting the first two Banff 2019 criteria) according to the individual EMS-3D score for each HLA molecule censored for de novo HLA-DSA occurrence.
Supplemental Table 4. Multivariable hazard ratios for individual Banff histopathologic lesions in the pretransplant HLA antibody–negative patients censored for de novo HLA-DSA occurrence (n=660).
Supplemental Table 5. Multivariable hazard ratios for histology of antibody-mediated rejection in the absence of HLA-DSAs according to the different HLA mismatch approaches censored for de novo HLA-DSA occurrence and including patient death with a functioning graft as a competing event (N=798).
Supplemental Table 6. STROBE checklist.
Supplemental Figure 1. Patient enrollment and study design.
References
- 1.Loupy A, Lefaucheur C: Antibody-mediated rejection of solid-organ allografts. N Engl J Med 379: 1150–1160, 2018. 10.1056/nejmra1802677 [DOI] [PubMed] [Google Scholar]
- 2.Loupy A, Hill GS, Jordan SC: The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol 8: 348–357, 2012. 10.1038/nrneph.2012.81 [DOI] [PubMed] [Google Scholar]
- 3.Delville M, Lamarthée B, Pagie S, See SB, Rabant M, Burger C, Gatault P, Giral M, Thaunat O, Arzouk N, Hertig A, Hazzan M, Matignon M, Mariat C, Caillard S, Kamar N, Sayegh J, Westeel P-F, Garrouste C, Ladrière M, Vuiblet V, Rivalan J, Merville P, Bertrand D, Le Moine A, Huyen J-PD, Cesbron A, Cagnard N, Alibeu O, Satchell SC, Legendre C, Zorn E, Taupin J-L, Charreau B, Anglicheau D: Early acute microvascular kidney transplant rejection in the absence of anti-HLA antibodies is associated with preformed IgG antibodies against diverse glomerular endothelial cell antigens. J Am Soc Nephrol 30: 692–709, 2019. 10.1681/ASN.2018080868 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Parajuli S, Redfield RR, Garg N, Aziz F, Mohamed M, Astor BC, Zhong W, Djamali A, Mandelbrot DA: Clinical significance of microvascular inflammation in the absence of anti-HLA DSA in kidney transplantation. Transplantation 103: 1468–1476, 2019. 10.1097/TP.0000000000002487 [DOI] [PubMed] [Google Scholar]
- 5.Senev A, Coemans M, Lerut E, Van Sandt V, Daniëls L, Kuypers D, Sprangers B, Emonds MP, Naesens M: Histological picture of antibody-mediated rejection without donor-specific anti-HLA antibodies: Clinical presentation and implications for outcome. Am J Transplant 19: 763–780, 2019. 10.1111/ajt.15074 [DOI] [PubMed] [Google Scholar]
- 6.Sis B, Jhangri GS, Riopel J, Chang J, de Freitas DG, Hidalgo L, Mengel M, Matas A, Halloran PF: A new diagnostic algorithm for antibody-mediated microcirculation inflammation in kidney transplants. Am J Transplant 12: 1168–1179, 2012. 10.1111/j.1600-6143.2011.03931.x [DOI] [PubMed] [Google Scholar]
- 7.Haas M: The revised (2013) Banff classification for antibody-mediated rejection of renal allografts: Update, difficulties, and future considerations. Am J Transplant 16: 1352–1357, 2016. 10.1111/ajt.13661 [DOI] [PubMed] [Google Scholar]
- 8.Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, Nankivell BJ, Halloran PF, Colvin RB, Akalin E, Alachkar N, Bagnasco S, Bouatou Y, Becker JU, Cornell LD, Duong van Huyen JP, Gibson IW, Kraus ES, Mannon RB, Naesens M, Nickeleit V, Nickerson P, Segev DL, Singh HK, Stegall M, Randhawa P, Racusen L, Solez K, Mengel M: The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant 18: 293–307, 2018. 10.1111/ajt.14625 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Callemeyn J, Lerut E, de Loor H, Arijs I, Thaunat O, Koenig A, Meas-Yedid V, Olivo-Marin JC, Halloran P, Chang J, Thorrez L, Kuypers D, Sprangers B, Van Lommel L, Schuit F, Essig M, Gwinner W, Anglicheau D, Marquet P, Naesens M: Transcriptional changes in kidney allografts with histology of antibody-mediated rejection without anti-HLA donor-specific antibodies. J Am Soc Nephrol 31: 2168–2183, 2020. 10.1681/ASN.2020030306 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Lefaucheur C, Viglietti D, Bouatou Y, Philippe A, Pievani D, Aubert O, Duong Van Huyen JP, Taupin JL, Glotz D, Legendre C, Loupy A, Halloran PF, Dragun D: Non-HLA agonistic anti-angiotensin II type 1 receptor antibodies induce a distinctive phenotype of antibody-mediated rejection in kidney transplant recipients. Kidney Int 96: 189–201, 2019. 10.1016/j.kint.2019.01.030 [DOI] [PubMed] [Google Scholar]
- 11.Reindl-Schwaighofer R, Heinzel A, Kainz A, van Setten J, Jelencsics K, Hu K, Loza BL, Kammer M, Heinze G, Hruba P, Koňaříková A, Viklicky O, Boehmig GA, Eskandary F, Fischer G, Claas F, Tan JC, Albert TJ, Patel J, Keating B, Oberbauer R; iGeneTRAiN consortium : Contribution of non-HLA incompatibility between donor and recipient to kidney allograft survival: Genome-wide analysis in a prospective cohort. Lancet 393: 910–917, 2019. 10.1016/S0140-6736(18)32473-5 [DOI] [PubMed] [Google Scholar]
- 12.Dragun D, Catar R, Philippe A: Non-HLA antibodies against endothelial targets bridging allo- and autoimmunity. Kidney Int 90: 280–288, 2016. 10.1016/j.kint.2016.03.019 [DOI] [PubMed] [Google Scholar]
- 13.Senev A, Otten HG, Kamburova EG, Callemeyn J, Lerut E, Van Sandt V, Kuypers D, Emonds MP, Naesens M: Antibodies against ARHGDIB and ARHGDIB gene expression associate with kidney allograft outcome. Transplantation 104: 1462–1471, 2020. 10.1097/TP.0000000000003005 [DOI] [PubMed] [Google Scholar]
- 14.Kamburova EG, Gruijters ML, Kardol-Hoefnagel T, Wisse BW, Joosten I, Allebes WA, van der Meer A, Hilbrands LB, Baas MC, Spierings E, Hack CE, van Reekum FE, van Zuilen AD, Verhaar MC, Bots ML, Drop ACAD, Plaisier L, Melchers RCA, Seelen MAJ, Sanders JS, Hepkema BG, Lambeck AJA, Bungener LB, Roozendaal C, Tilanus MGJ, Voorter CE, Wieten L, van Duijnhoven EM, Gelens MACJ, Christiaans MHL, van Ittersum FJ, Nurmohamed SA, Lardy NM, Swelsen W, van der Pant KAMI, van der Weerd NC, Ten Berge IJM, Hoitsma A, van der Boog PJM, de Fijter JW, Betjes MGH, Heidt S, Roelen DL, Claas FH, Bemelman FJ, Otten HG: Antibodies against ARHGDIB are associated with long-term kidney graft loss. Am J Transplant 19: 3335–3344, 2019. 10.1111/ajt.15493 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Deltombe C, Gillaizeau F, Anglicheau D, Morelon E, Trébern-Launay K, Le Borgne F, Rimbert M, Guérif P, Malard-Castagnet S, Foucher Y, Giral M: Is pre-transplant sensitization against angiotensin II type 1 receptor still a risk factor of graft and patient outcome in kidney transplantation in the anti-HLA Luminex era? A retrospective study. Transpl Int 30: 1150–1160, 2017. 10.1111/tri.13009 [DOI] [PubMed] [Google Scholar]
- 16.Reindl-Schwaighofer R, Heinzel A, Gualdoni GA, Mesnard L, Claas FHJ, Oberbauer R: Novel insights into non-HLA alloimmunity in kidney transplantation. Transpl Int 33: 5–17, 2020. 10.1111/tri.13546 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Koenig A, Chen CC, Marçais A, Barba T, Mathias V, Sicard A, Rabeyrin M, Racapé M, Duong-Van-Huyen JP, Bruneval P, Loupy A, Dussurgey S, Ducreux S, Meas-Yedid V, Olivo-Marin JC, Paidassi H, Guillemain R, Taupin JL, Callemeyn J, Morelon E, Nicoletti A, Charreau B, Dubois V, Naesens M, Walzer T, Defrance T, Thaunat O: Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants. Nat Commun 10: 5350, 2019. 10.1038/s41467-019-13113-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Callemeyn J, Lamarthée B, Koenig A, Koshy P, Thaunat O, Naesens M: Allorecognition and the spectrum of kidney transplant rejection. Kidney Int 101: 692–710, 2022. 10.1016/j.kint.2021.11.029 [DOI] [PubMed] [Google Scholar]
- 19.Kramer CSM, Koster J, Haasnoot GW, Roelen DL, Claas FHJ, Heidt S: HLA-EMMA: A user-friendly tool to analyse HLA class I and class II compatibility on the amino acid level. HLA 96: 43–51, 2020. 10.1111/tan.13883 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Kosmoliaptsis V, Sharples LD, Chaudhry AN, Halsall DJ, Bradley JA, Taylor CJ: Predicting HLA class II alloantigen immunogenicity from the number and physiochemical properties of amino acid polymorphisms. Transplantation 91: 183–190, 2011. 10.1097/TP.0b013e3181ffff99 [DOI] [PubMed] [Google Scholar]
- 21.Duquesnoy RJ, Marrari M, Tambur AR, Mulder A, Sousa LC, da Silva AS, do Monte SJ: First report on the antibody verification of HLA-DR, HLA-DQ and HLA-DP epitopes recorded in the HLA epitope registry. Hum Immunol 75: 1097–1103, 2014. 10.1016/j.humimm.2014.09.012 [DOI] [PubMed] [Google Scholar]
- 22.Mallon DH, Kling C, Robb M, Ellinghaus E, Bradley JA, Taylor CJ, Kabelitz D, Kosmoliaptsis V: Predicting humoral alloimmunity from differences in donor and recipient HLA surface electrostatic potential. J Immunol 201: 3780–3792, 2018. 10.4049/jimmunol.1800683 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Lachmann N, Niemann M, Reinke P, Budde K, Schmidt D, Halleck F, Pruß A, Schönemann C, Spierings E, Staeck O: Donor-recipient matching based on predicted indirectly recognizable HLA epitopes independently predicts the incidence of de novo donor-specific HLA antibodies following renal transplantation. Am J Transplant 17: 3076–3086, 2017. 10.1111/ajt.14393 [DOI] [PubMed] [Google Scholar]
- 24.Senev A, Coemans M, Lerut E, Van Sandt V, Kerkhofs J, Daniëls L, Driessche MV, Compernolle V, Sprangers B, Van Loon E, Callemeyn J, Claas F, Tambur AR, Verbeke G, Kuypers D, Emonds MP, Naesens M: Eplet mismatch load and de novo occurrence of donor-specific anti-HLA antibodies, rejection, and graft failure after kidney transplantation: An observational cohort study. J Am Soc Nephrol 31: 2193–2204, 2020. 10.1681/ASN.2020010019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Wiebe C, Kosmoliaptsis V, Pochinco D, Gibson IW, Ho J, Birk PE, Goldberg A, Karpinski M, Shaw J, Rush DN, Nickerson PW: HLA-DR/DQ molecular mismatch: A prognostic biomarker for primary alloimmunity. Am J Transplant 19: 1708–1719, 2019. 10.1111/ajt.15177 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Wiebe C, Rush DN, Gibson IW, Pochinco D, Birk PE, Goldberg A, Blydt-Hansen T, Karpinski M, Shaw J, Ho J, Nickerson PW: Evidence for the alloimmune basis and prognostic significance of borderline T cell-mediated rejection. Am J Transplant 20: 2499–2508, 2020. 10.1111/ajt.15860 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Senev A, Emonds MP, Van Sandt V, Lerut E, Coemans M, Sprangers B, Kuypers D, Naesens M: Clinical importance of extended second field high-resolution HLA genotyping for kidney transplantation. Am J Transplant 20: 3367–3378, 2020. 10.1111/ajt.15938 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell LD, Clahsen-van Groningen MC, Demetris AJ, Dragun D, Duong van Huyen JP, Farris AB, Fogo AB, Gibson IW, Glotz D, Gueguen J, Kikic Z, Kozakowski N, Kraus E, Lefaucheur C, Liapis H, Mannon RB, Montgomery RA, Nankivell BJ, Nickeleit V, Nickerson P, Rabant M, Racusen L, Randhawa P, Robin B, Rosales IA, Sapir-Pichhadze R, Schinstock CA, Seron D, Singh HK, Smith RN, Stegall MD, Zeevi A, Solez K, Colvin RB, Mengel M: The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant 20: 2318–2331, 2020. 10.1111/ajt.15898 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Halloran PF, Urmson J, Ramassar V, Melk A, Zhu LF, Halloran BP, Bleackley RC: Lesions of T-cell-mediated kidney allograft rejection in mice do not require perforin or granzymes A and B. Am J Transplant 4: 705–712, 2004. 10.1111/j.1600-6143.2004.00421.x [DOI] [PubMed] [Google Scholar]
- 30.Afrouzian M, Ramassar V, Urmson J, Zhu LF, Halloran PF: Transcription factor IRF-1 in kidney transplants mediates resistance to graft necrosis during rejection. J Am Soc Nephrol 13: 1199–1209, 2002. 10.1097/01.ASN.0000013302.11876.A5 [DOI] [PubMed] [Google Scholar]
- 31.Jabs WJ, Sedlmeyer A, Ramassar V, Hidalgo LG, Urmson J, Afrouzian M, Zhu LF, Halloran PF: Heterogeneity in the evolution and mechanisms of the lesions of kidney allograft rejection in mice. Am J Transplant 3: 1501–1509, 2003. 10.1046/j.1600-6135.2003.00269.x [DOI] [PubMed] [Google Scholar]
- 32.Lefaucheur C, Loupy A, Vernerey D, Duong-Van-Huyen JP, Suberbielle C, Anglicheau D, Vérine J, Beuscart T, Nochy D, Bruneval P, Charron D, Delahousse M, Empana JP, Hill GS, Glotz D, Legendre C, Jouven X: Antibody-mediated vascular rejection of kidney allografts: A population-based study. Lancet 381: 313–319, 2013. 10.1016/S0140-6736(12)61265-3 [DOI] [PubMed] [Google Scholar]
- 33.Calvani J, Terada M, Lesaffre C, Eloudzeri M, Lamarthée B, Burger C, Tinel C, Anglicheau D, Vermorel A, Couzi L, Loupy A, Duong Van Huyen JP, Bruneval P, Rabant M: In situ multiplex immunofluorescence analysis of the inflammatory burden in kidney allograft rejection: A new tool to characterize the alloimmune response. Am J Transplant 20: 942–953, 2020. 10.1111/ajt.15699 [DOI] [PubMed] [Google Scholar]
- 34.Wissing KM, Fomegné G, Broeders N, Ghisdal L, Hoang AD, Mikhalski D, Donckier V, Vereerstraeten P, Abramowicz D: HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with anti-interleukin-2 receptor antibodies. Transplantation 85: 411–416, 2008. 10.1097/TP.0b013e31816349b5 [DOI] [PubMed] [Google Scholar]
- 35.Davis S, Cooper JE: Acute antibody-mediated rejection in kidney transplant recipients. Transplant Rev (Orlando) 31: 47–54, 2017. 10.1016/j.trre.2016.10.004 [DOI] [PubMed] [Google Scholar]
- 36.Lim WH, Chapman JR, Coates PT, Lewis JR, Russ GR, Watson N, Holdsworth R, Wong G: HLA-DQ mismatches and rejection in kidney transplant recipients. Clin J Am Soc Nephrol 11: 875–883, 2016. 10.2215/CJN.11641115 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.