C1q-binding Donor-specific anti-HLA Antibodies Research Articles

Association Between De Novo C1q-Binding Donor-Specific Anti-HLA Antibodies and Clinical Outcomes After Kidney Transplantation: A Meta-Analysis

Donor-specific antibodies (DSAs) are recognized as an important factor of kidney allograft loss as a subsequent event of antibody-mediated rejection (AMR). The clinical relevance of de novo DSAs (dnDSAs) after kidney transplant, particularly in their ability to bind C1q, has been widely investigated to various extents among studies. A recent study was performed to examine the association between C1q-binding dnDSAs and succeeding clinical events after kidney transplant. A meta-analysis of studies published before April 2021 was conducted from PubMed, Science Direct, and Cochrane databases. Publications on dnDSA after kidney transplant focusing on differentiation between C1q-binding and non-C1q-binding were included. The outcomes analyzed were AMR rate and allograft loss. Studies using preformed DSA were excluded. The pooled risk ratio and 95% confidence interval (CI) were analyzed using Mantzel-Haenzel method, and the I2 value was used to determine the heterogeneity of the studies. Data analysis was conducted using Review Manager 5.3. A total of 535 patients from 13 studies who developed dnDSA after kidney transplant were analyzed. Among these, 239 (44.7%) had C1q-binding and 296 (55.3%) had non-C1q-binding dnDSA. Acute AMR was found in 59.2% (97/164) of the C1q-binding group and in 28.8% (49/170) of the non-C1q-binding group (risk ratio [RR], 0.58 [95% CI, 0.39-0.85], P = .006, I2 = 58%). Chronic AMR was found in 50% (19/38) of the C1q-binding group and in 16.9% (11/65) of the non-C1q-binding group (RR, 0.39 [95% CI, 0.21-0.71], P = .002, I2 = 0%). Allograft loss was found in 62.2% (74/119) of the C1q-binding group and in 34.1% (60/176) of the non-C1q-binding group (RR, 0.57 [95% CI, 0.38-0.85], P = .006, I2 = 61%). This meta-analysis demonstrates that patients who developed C1q-binding dnDSA display an increased risk of AMR and allograft loss compared with those with non-C1q-binding dnDSA. Therefore, C1q-binding dnDSAs are associated with inferior outcomes after kidney transplant.

The clinical utility of preformed C1q-binding donor-specific anti-HLA antibodies in kidney transplantation

The clinical utility of preformed C1q-binding donor-specific anti-HLA antibodies in kidney transplantation

Identification of latent classes of CAV trajectories after heart transplantation and their determinants

Cardiac allograft vasculopathy (CAV) remains a major issue associated with increased mortality after heart transplantation (HTx). Prototypes of CAV trajectories including dynamics of progression and associated determinants have not been assessed. To identify distinct profiles of CAV trajectory following HTx and their determinants. We performed a retrospective multicenter observational study. We included all consecutive patients transplanted between 2004 and 2011 who had at least 2 coronary angiograms during follow-up. We performed an extensive evaluation of potential risk factors that might be associated with CAV. A semi-parametric mixture model was used to identify distinct trajectories of CAV progression from year 1 to year 8 post-transplantation. Multivariable logistic regression model was used to determine risk factors associated with each trajectory. Four hundred and forty-six patients met the inclusion criteria. Median follow-up time post transplant was 6.3 years. Three distinct profiles of CAV trajectories were identified: #1-non-progressors ( n = 280, 62.8%), #2- slow progressors ( n = 118, 26.5%) and #3- rapid progressors ( n = 48, 10.8%). Factors independently associated with CAV trajectory #2 were donor age, donor male gender, tobacco consumption of the donor and pre-HTx recipient dyslipidemia. In addition to the previous factors, ischemic etiology of heart failure and the presence of circulating C1q-binding DSA were independent risk factors for CAV trajectory #3. In a large and extensively phenotyped cohort of heart transplant recipients, we identified 3 distinct prototypes of CAV trajectories. In addition to traditional cardiovascular risk factors, the presence C1q-binding donor-specific anti-HLA antibodies was associated with an acceleration of CAV.

Preformed C1q-binding Donor-specific Anti-HLA Antibodies and Graft Function After Kidney Transplantation

De novo complement-binding donor-specific anti-human leukocyte antigen antibodies (DSAs) are reportedly associated with an increased risk of kidney graft failure, but there is little information on preformed complement-binding DSAs. This study investigated the correlation between preformed C1q-binding DSAs and medium-term outcomes in kidney transplantation (KT). We retrospectively studied 44 pretransplant DSA-positive patients, including 36 patients who underwent KT between April 2010 and October 2016. There were 17 patients with C1q-binding DSAs and 27 patients without C1q-binding DSAs. Clinical variables were examined in the 2 groups. Patients with C1q-binding DSAs had significantly higher blood transfusion history (53.0% vs 18.6%; P= .0174), complement-dependent cytotoxicity crossmatch (CDC-XM)-positivity (29.4% vs 0%; P= .0012), and DSA median fluorescence intensity (MFI) (10,974 vs 2764; P= .0009). Among patients who were not excluded for CDC-XM-positivity and underwent KT, there was no significant difference in cumulative biopsy-proven acute rejection rate (32.5% vs 33.5%; P= .8354), cumulative graft survival, and 3-month and 12-month protocol biopsy results between patients with and without C1q-binding DSAs. Although patients with C1q-binding DSAs showed a higher incidence of delayed graft function (54.6% vs 20.0%; P= .0419), multivariate logistic regression showed that DSA MFI (P= .0124), but not C1q-binding DSAs (P= .2377), was an independent risk factor for delayed graft function. In patients with CDC-XM-negativity, preformed C1q-binding DSAs were not associated with incidence of antibody-mediated rejection and medium-term graft survival after KT. C1q-binding DSAs were highly correlated with DSA MFI and CDC-XM-positivity.

C1q-binding Donor-Specific Anti-HLA Antibodies for Clinical Decision Making in Kidney Recipients with Antibody-Mediated Rejection Receiving Standard of Care Treatment

One of the major issues in the clinical management of kidney recipients with antibody-mediated rejection (ABMR) is the lack of early and reliable markers that surrogate long-term allograft outcomes. We investigated the role of C1q-binding donor-specific anti-HLA antibodies (DSAs) for decision making in kidney recipients with ABMR receiving standard of care (SOC) treatment. Among 1196 kidney recipients transplanted between 2008 and 2011, we prospectively enrolled all patients with biopsy-proven active ABMR according to the most recent Banff criteria, who received standardized treatment, incuding plasma exchange, high-dose intravenous immunoglobulin, rituximab and steroids. Patients were systematically assessed at the time of ABMR diagnosis and 3-month post-treatment initiation for clinical data, histological characteristics and DSA characteristics (specificity, mean fluorescence intensity [MFI] and C1q-binding capacity). We included 139 kidney recipients with ABMR diagnosed at a median time of 15.5 months (IQR, 5.8-36.8) post-transplant receiving SOC treatment. At ABMR diagnosis, patients with C1q-binding DSAs (N=91, 65%) showed similar 6-year allograft survival compared to patients with non-C1q-binding DSAs (N=48, 35%) (66% vs 83%, p=0.07). At the time of post-treatment evaluation, patients with C1q-binding DSAs (N=38, 27%) had decreased 6-year graft survival compared to patients with non-C1q-binding DSAs (N=101, 73%) (44% vs 83%, p<0.001). After adjusting for GFR, proteinuria, all histological Banff scores and DSA characteristics, post-treatment C1q-binding DSAs were independent predictors of allograft loss (adjusted HR=2.6, p=0.007) and outperformed DSA MFI level to predict allograft loss (increase in C-statistic from 0.63 to 0.68; cNRI: 0.83, P<0.001; IDI: 0.08, P=0.002). We built a conditional inference tree for evidence-based clinical decision making including the most informative variables after treatment (cross-validated accuracy: 0.77): GFR, presence of cg lesion and presence of C1q-binding DSA. The decision tree segregated 5 groups of patients with distinct outcomes; for instance, patients with GFR >33 mL/min and without C1q-binding DSA showed a 5-year allograft survival of 93% vs 35% in patients with GFR ≤33 mL/min, without cg lesion and with C1q-binding DSA. C1q-binding anti-HLA DSAs are strong and independent predictors of long-term kidney allograft loss after SOC treatment of ABMR and allowed to build a clinical decision tree showing high accuracy in risk stratifying allograft outcomes.

Role of C1q-binding donor-specific anti-HLA antibodies in Premature and Accelerated Kidney Allograft Interstitial Fibrosis

Role of C1q-binding donor-specific anti-HLA antibodies in Premature and Accelerated Kidney Allograft Interstitial Fibrosis

Complement-binding anti-HLA antibodies are independent predictors of response to treatment in kidney recipients with antibody-mediated rejection

A major hurdle to improving clinical care in the field of kidney transplantation is the lack of biomarkers of the response to antibody-mediated rejection (ABMR) treatment. To discover these we investigated the value of complement-binding donor-specific anti-HLA antibodies (DSAs) for evaluating the response to treatment. The study encompassed a prospective cohort of 139 kidney recipients with ABMR receiving the standard of care treatment, including plasma exchange, intravenous immunoglobulin and rituximab. Patients were systematically assessed at the time of diagnosis and three months after treatment initiation for clinical and allograft histological characteristics and anti-HLA DSAs, including their C1q-binding ability. After adjusting for clinical and histological parameters, post-treatment C1q-binding anti-HLA DSA was an independent and significant determinant of allograft loss (adjusted hazard ratio 2.57 (95% confidence interval 1.29-5.12). In 101 patients without post-treatment C1q-binding anti-HLA DSA there was a significantly improved glomerular filtration rate with significantly reduced glomerulitis, peritubular capillaritis, interstitial inflammation, tubulitis, C4d deposition, and endarteritis compared with 38 patients with posttreatment C1q-binding anti-HLA DSA. A conditional inference tree model identified five prognostic groups at the time of post-treatment evaluation based on glomerular filtration rate, presence of cg lesion and C1q-binding anti-HLA DSA (cross-validated accuracy: 0.77). Thus, circulating complement-binding anti-HLA DSAs are strong and independent predictors of allograft outcome after standard of care treatment in kidney recipients with ABMR.

Impact of Preformed Donor-Specific Anti-Human Leukocyte Antigen Antibody C1q-Binding Ability on Kidney Allograft Outcome.

The consolidation of single antigen beads (SAB-panIgG) assay in the detection of preformed anti-human leukocyte antigen (HLA) antibodies has improved transplantation success. However, its high sensitivity has limited the allograft allocation for sensitized patients, increasing their waiting time. A modification of the standard SAB-panIgG assay allows the detection of that subset of antibodies capable of binding C1q (SAB-C1q assay). However, the clinical usefulness of SAB-C1q assay for determining the unacceptable mismatches is under discussion. We retrospectively analyzed the impact of preformed donor-specific anti-HLA antibodies (DSA) according to the C1q-binding ability on allograft outcome, examining 389 single-kidney transplanted patients from deceased donors. Recipients with preformed C1q-binding DSA showed the lowest allograft survival up to 7 years (40.7%) compared to patients with preformed non-C1q-binding DSA (73.4%; p = 0.001) and without DSA (79.1%; p < 0.001). Allograft survival rate was similar between patients with preformed non-C1q-binding DSA and patients without preformed DSA (p = 0.403). Interestingly, among the high-mean fluorescence intensity DSA (≥10,000) population (n = 46), those patients whose DSA were further capable of binding C1q showed a poorer allograft outcome (38.4 vs. 68.9%; p = 0.041). Moreover, in our multivariate predictive model for assessing the risk of allograft loss, the presence of C1q-binding DSA (HR 4.012; CI 95% 2.326–6.919; p < 0.001) but not of non-C1q-binding DSA (HR 1.389; CI 95% 0.784–2.461; p = 0.260) remained an independent predictor after stratifying the DSA population according to the C1q-binding ability and adjusting the model for other pre-transplantation predictive factors including donor age, cold-ischemia time, and HLA-DR mismatches. In conclusion, the unacceptable mismatch definition according to the SAB-C1q assay would improve the risk stratification of allograft loss and increase the limited allograft allocation of highly sensitized patients, shortening their waiting time.

OR12 Complement-binding donor-specific anti-HLA antibodies predict the response to complement-targeting therapy: A multicenter international study

Aim We investigated whether circulating complement-binding donor-specific anti-HLA antibodies (DSA) influence response to complement-targeting therapy. Methods We included 116 kidney recipients transplanted between 2011 and 2014 in 10 referral centers (US and Europe) from two prospective clinical trials investigating the effect of complement inhibition for rejection prophylaxis in kidney recipients with anti-HLA DSAs at transplantation (NCT01567085 and 01399593). They received either Eculizumab in the first nine weeks post-transplantation (N = 52) or standard of care (SOC) consisting in plasma exchange and intravenous immunoglobulin (N = 64). All patients were screened for C1q-binding DSAs using SAB in sera collected at transplantation and underwent allograft biopsy at day 14 to assess histological characteristics and allograft gene expression (microarray). We also compared the 3-month incidence of biopsy-proven antibody-mediated rejection (AMR) according to therapy. Results Patient baseline characteristics were similar between the 2 treatment groups. 69 (59%) patients had pre-transplant C1q-binding DSA (32 receiving SOC and 37 receiving Eculizumab) and 47 (41%) had non-C1q-binding DSA (32 receiving SOC and 15 receiving Eculizumab). In patients with C1q-binding DSAs, compared with patients receiving SOC, Eculizumab was associated with decreased glomerulitis (P = 0.001), peritubular capillaritis (P Conclusions Circulating complement-activating anti-HLA DSAs identify kidney transplant recipients who respond to complement inhibition.

P101 Development of C1Q binding donor specific anti-HLA antibodies in pediatric kidney transplant recipients

Aim De novo donor specific anti-HLA antibodies (DSA) have been associated with poor allograft outcomes in kidney transplantation. However, the value of post-transplant DSA monitoring in pediatric kidney transplant recipients is still debated. In this study, we investigated the incidence of de novo DSA, their ability to bind complement and their relationship with clinical outcomes in a population of pediatric kidney transplant recipients. Methods Serial samples of serum from 34 pediatric kidney transplant recipients without pre-transplant DSA were tested using the conventional and C1q single antigen bead assays (One Lambda/ThermoFisher). Patients were transplanted at our center from July 2009 to September 2015. All patients had negative flow crossmatches at the time of transplant. The MFI cutoff values used in the conventional and C1q assays were 1000 and 500, respectively. Typing of HLA-A, B, C, DR and DQB genes was performed by SSO. Results During the follow up interval (median 4 years), 9 (26%) out of 34 recipients developed DSA. Median time from transplant to DSA development was 12 months. At the time of detection, DSA were C1q positive in 8 of 9 patients. The mean number of C1q + DSA per patient was 2.7. Seven out of 8 patients had C1q + DSA directed to the donor HLA-DQB antigen(s). C1q + DSA persisted over time and were associated with worse graft function at 1 year ( p = 0.004), increased incidence of antibody mediated rejection (AMR; p p = 0.08). Despite treatment for AMR, 5 (63%) of 8 patients with C1q + DSA lost their grafts during the follow up interval. In contrast, only 2 (8%) out of 26 patients without DSA lost their graft during the same interval ( p Conclusions The incidence of de novo C1q binding DSA in our pediatric patient population is high, likely due to increased non-compliance. C1q + DSA identified patients at high risk for graft loss. These findings support the role of frequent monitoring of DSA, particularly during the first year post-transplantation, and highlight the need for prompt therapeutic intervention in patients with C1q + DSA.

The prevalence and clinical significance of C1q-binding donor-specific anti-HLA antibodies early and late after kidney transplantation.

We aimed to determine the prevalence and clinical significance of complement-binding donor-specific antibodies (DSA) detected up to 30 years after kidney transplantation. Group 1 patients included 284 consecutive DSA negative patients who underwent kidney transplantation after 1 May 2009. Group 2 included 405 patients transplanted before this date and followed at our center with functioning allografts. DSA were tested using Luminex Single Antigen and the C1q assay. In Group 1 patients, who were monitored prospectively, 31 (11%) developed de novo DSA during a median follow-up of 2.5 (1.9, 3.6) years. Of these, 11 (4%) had C1q+ and 20 (7%) had C1q negative DSA. In Group 2 patients, 77 (19%) displayed DSA. Among these, 33 (8%) had C1q+ and 44 (11%) had C1q negative DSA. The incidence of acute antibody-mediated rejection (AMR) was significantly higher in C1q+DSA patients in both Group 1 (45%) and Group 2 (15%) compared with C1q negative DSA (5% and 2%) and DSA negative patients (1% and 3%; P < 0.001 and P = 0.001). The incidence of chronic AMR was 36% (Group 1) and 51% (Group 2) in patients with C1q+DSA. In contrast, chronic AMR occurred in 5% and 25% of C1q negative DSA, and 2% and 6% of DSA negative Group 1 and 2 patients, respectively (P < 0.001). Although the graft survival was lower in Group 1 C1q+DSA patients (73%) compared with C1q negative DSA (95%) and DSA negative (94%) patients, the difference was not statistically significant by Kaplan-Meier survival analysis (P = 0.21). Our results indicated that the presence of C1q+ DSA was associated with acute and chronic AMR.

De novo donor-specific anti-HLA antibodies mediated rejection in liver-transplant patients.

The incidence and consequences of de novo donor-specific anti-HLA antibodies (DSAs) after liver transplantation (LT) are not well known. We investigated the incidence, risk factors, and complications associated with de novo DSAs in this setting. A total of 152 de novo liver-transplant patients, without preformed anti-HLA DSAs, were tested for anti-HLA antibodies, with single-antigen bead technology, before, at transplantation, at 1, 3, 6 and 12months after transplantation, and thereafter annually and at each time they presented with increased liver-enzyme levels until the last follow-up, that is, 34 (1.5-77) months. Twenty-one patients (14%) developed de novo DSAs. Of these, five patients had C1q-binding DSAs (24%). Younger age, low exposure to calcineurin inhibitors, and noncompliance were predictive factors for de novo DSA formation. Nine of the 21 patients (43%) with de novo DSAs experienced an acute antibody-mediated rejection (AMR). Positive C4d staining was more frequently observed in liver biopsies of patients with AMR (9/9 vs. 1/12, P<0.0001). Eight patients received a B-cell targeting therapy, and one patient received polyclonal antibodies. Only one patient required retransplantation. Patient- and graft-survival rates did not differ between patients with and without DSAs. In conclusion, liver-transplant patients with liver abnormalities should be screened for DSAs and AMR.

Complement-Binding Donor-Specific Anti-HLA Antibodies and Risk of Primary Graft Failure in Hematopoietic Stem Cell Transplantation

Detection of donor-specific anti-HLA antibodies (DSA) has been associated with graft rejection in all forms of transplantation. The mechanism by which DSA increase the risk of graft failure remains unclear. We hypothesized that complement-binding DSA are associated with engraftment failure in hematopoietic stem cell transplantation (HSCT) and analyzed 122 haploidentical transplant recipients tested prospectively for DSA. Retrospective analysis to detect C1q binding DSA (C1q+DSA) was performed on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had DSA, 19 of which were women (86%). Seven patients with DSA (32%) rejected the graft. Median DSA level at transplant for patients who failed to engraft was 10,055 mean fluorescence intensity (MFI) versus 2065 MFI for those who engrafted (P = .007). Nine patients with DSA were C1q positive in the initial samples with median DSA levels of 15,279 MFI (range, 1554 to 28,615), compared with 7 C1q-negative patients with median DSA levels of 2471 MFI (range, 665 to 12,254) (P = .016). Of 9 patients who were C1q positive in the initial samples, 5 patients remained C1q positive at time of transplant (all with high DSA levels [median, 15,279; range, 6487 to 22,944]) and experienced engraftment failure, whereas 4 patients became C1q negative pretransplant and all engrafted the donor cells (P = .008). In conclusion, patients with high DSA levels (>5000 MFI) and complement-binding DSA antibodies (C1q positive) appear to be at much higher risk of primary graft failure. The presence of C1q+DSA should be assessed in allosensitized patients before HSCT. Reduction of C1q+DSA levels might prevent engraftment failure in HSCT.

The Prevalence and Clinical Significance of C1q Binding Donor-Specific Anti-HLA Antibodies in Patients With Functioning Allografts More Than 5 Years After Kidney Transplantation.

The Prevalence and Clinical Significance of C1q Binding Donor-Specific Anti-HLA Antibodies in Patients With Functioning Allografts More Than 5 Years After Kidney Transplantation.

Research Highlights

Research Highlights