Determining donor‐specific antibody C1q‐binding ability improves the prediction of antibody‐mediated rejection in human leucocyte antigen‐incompatible kidney transplantation

Detrimental impact of preformed donor‐specific antibodies (DSAs) against human leucocyte antigens on outcomes after kidney transplantation are well documented, however, the value of their capacity to bind complement for predicting antibody‐mediated rejection (AMR) and graft survival still needs to be confirmed. We aimed to study DSA characteristics (strength and C1q binding) that might distinguish harmful DSA from clinically irrelevant ones. We retrospectively studied 60 kidney‐transplanted patients with preformed DSA detected by single antigen bead (SAB) assays (IgG and C1q kits), from a cohort of 517 kidney graft recipients (124 with detectable anti‐HLA antibodies). Patients were divided into DSA strength (MFI < vs. ≥ 15 000) and C1q‐binding ability. AMR frequency was high (30%) and it increased with DSA strength (P = 0.002) and C1q+ DSA (P < 0.001). The performance of DSA C1q‐binding ability as a predictor of AMR was better than DSA strength (diagnostic odds ratio 16.3 vs. 6.4, respectively). Furthermore, a multivariable logistic regression showed that C1q+ DSA was a risk factor for AMR (OR = 16.80, P = 0.001), while high MFI DSAs were not. Graft survival was lower in high MFI C1q+ DSA in comparison with patients with C1q? high or low MFI DSA (at 6 years, 38%, 83% and 80%, respectively; P = 0.001). Both DSA strength and C1q‐binding ability assessment seem valuable for improving pretransplant risk assessment. Since DSA C1q‐binding ability was a better predictor of AMR and correlated with graft survival, C1q‐SAB may be a particularly useful tool.     

Donor‐Specific HLA Antibodies in Living Versus Deceased Donor Liver Transplant Recipients

With less ischemia, improved donor selection and controlled procedures, living donor liver transplantation (LDLT) might lead to less HLA donor‐specific antibody (DSA) formation or fewer adverse outcomes than deceased donor liver transplantation (DDLT). Using the multicenter A2ALL (Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study) biorepository, we compared the incidence and outcomes of preformed and de novo DSAs between LDLT and DDLT. In total, 129 LDLT and 66 DDLT recipients were identified as having serial samples. The prevalence of preformed and de novo DSAs was not different between DDLT and LDLT recipients (p = 0.93). There was no association between patient survival and the timing (preformed vs. de novo), class (I vs. II) and relative levels of DSA between the groups; however, preformed DSA was associated with higher graft failure only in DDLT recipients (p = 0.01). De novo DSA was associated with graft failure regardless of liver transplant type (p = 0.005) but with rejection only in DDLT (p = 0.0001). On multivariate analysis, DSA was an independent risk factor for graft failure regardless of liver transplant type (p = 0.017, preformed; p = 0.002, de novo). In conclusion, although similar in prevalence, DSA may have more impact in DDLT than LDLT recipients. Although our findings need further validation, future research should more robustly test the effect of donor type and strategies to mitigate the impact of DSA.     

Donor‐specific antibodies after pediatric liver transplantation: a cross‐sectional study of 50 patients

The role of donor‐specific HLA antibodies (DSAs) after pediatric liver transplantation (LT) is inadequately established. We conducted a cross‐sectional study on the prevalence of DSAs and their association with liver histology and biochemical variables after pediatric LT. Serum samples were drawn for HLA antibody analyses from 50 patients (76% of 66 eligible patients) operated on at age <18 years between 1987 and 2007 with a median of 10.0 (interquartile range 4.0–16.4) years after deceased donor LT. Mixed and single‐antigen beads with Luminex were used for HLA antibody screening and detection. A mean fluorescence intensity (MFI) value of 1000 was used for positive cutoff. Twenty‐six patients (52%; 95% confidence interval (CI) 39% to 65%) had DSAs. In 22 (85%) patients, DSAs were against class II HLA antigens with a mean (standard deviation) MFI of 13 481 (4727). The unadjusted prevalence ratio for portal inflammation in DSA‐positive compared to DSA‐negative patients (n = 47; 9/24 vs. 1/23) was 8.6 (95% CI 1.6 to 50.9). Laboratory values at the time of study were comparable between DSA‐positive and DSA‐negative patients. In conclusion, approximately half of patients studied had DSAs after pediatric LT. Portal inflammation was associated with DSA positivity although the wide confidence interval around the ratio estimate warrants cautious interpretation.     

High Mean Fluorescence Intensity Donor‐Specific Anti‐HLA Antibodies Associated With Chronic Rejection Postliver Transplant

In contrast to kidney transplantation where donor‐specific anti‐HLA antibodies (DSA) negatively impact graft survival, correlation of DSA with clinical outcomes in patients after orthotopic liver transplantation (OLT) has not been clearly established. We hypothesized that DSA are present in patients who develop chronic rejection after OLT. Prospectively collected serial serum samples on 39 primary OLT patients with biopsy‐proven chronic rejection and 39 comparator patients were blinded and analyzed for DSA using LABScreen^® single antigen beads test, where a 1000 mean fluorescence value was considered positive. In study patients, the median graft survival was 15 months, 74% received ≥ one retransplant, 20% remain alive and 87% had ≥ one episode of acute rejection. This is in contrast to comparator patients where 69% remain alive, and no patient needed retransplant or experienced rejection. Thirty‐six chronic rejection patients (92%) and 24 (61%) comparator patients had DSA (p = 0.003). Chronic rejection versus comparator patients had higher mean fluorescence intensity (MFI) DSA. Although a further study with larger numbers of patients is needed to identify clinically significant thresholds, there is an association of high‐MFI DSA with chronic rejection after OLT.     

Clinical impact of preformed donor‐specific denatured class I HLA antibodies after kidney transplantation

Class I single‐antigen flow beads (SAFB) carry native and denatured human leukocyte antigen (HLA) molecules. Using a cohort of 179 class I HLA‐sensitized kidney recipients, we described incidence and clinical relevance of preformed denatured HLA donor‐specific antibodies (DSA) using two different assays: an acid‐treated SAFB assay (anti‐dHLA DSA) and the iBeads assays (SAFB+/iBeads‐ DSA). Eighty‐five class I DSA were found in 67 patients (median mean fluorescence intensity [MFI] of 1729 [range 520–13 882]). Anti‐dHLA and SAFB+/iBeads‐ DSA represented 11% and 18% of class I DSA and were mainly low MFI DSA (500–1000 MFI). Concordance between these two assays was good (90%). None of the patients with only class I anti‐dHLA DSA or only SAFB+/iBeads‐ DSA developed acute clinical antibody‐mediated rejection in the first‐year post‐transplantation, and their five‐yr death‐censored graft survival was similar to that of patients without DSA. Moreover, all these patients displayed a negative current T‐cell flow cytometry cross‐match. Therefore, both anti‐dHLA DSA and SAFB+/iBeads‐ DSA appear irrelevant, which could explain the good outcome observed in some patients with preformed class I DSA.     

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 12 months 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.     

Failure to remove de novo donor‐specific HLA antibodies is influenced by antibody properties and identifies kidney recipients with late antibody‐mediated rejection destined to graft loss – a retrospective study

Current research is focusing on identifying bioclinical parameters for risk stratification of renal allograft loss, largely due to antibody‐mediated rejection (AMR). We retrospectively investigated graft outcome predictors in 24 unsensitized pediatric kidney recipients developing HLA de novo donor‐specific antibodies (dnDSAs), and treated for late AMR with plasmapheresis + low‐dose IVIG + Rituximab or high‐dose IVIG + Rituximab. Renal function and DSA properties were assessed before and longitudinally post treatment. The estimated GFR (eGFR) decline after treatment was dependent on a negative % eGFR variation in the year preceding treatment (P = 0.021) but not on eGFR at treatment (P = 0.74). At a median follow‐up of 36 months from AMR diagnosis, 10 patients lost their graft. Altered eGFR (P < 0.001) and presence of C3d‐binding DSAs (P = 0.005) at treatment, and failure to remove DSAs (P = 0.01) were negatively associated with graft survival in the univariable analysis. Given the relevance of DSA removal for therapeutic success, we analyzed antibody properties dictating resistance to anti‐humoral treatment. In the multivariable analysis, C3d‐binding ability (P < 0.05), but not C1q‐binding, and high mean fluorescence intensity (P < 0.05) were independent factors characterizing DSAs scarcely susceptible to removal. The poor prognosis of late AMR is related to deterioration of graft function prior to treatment and failure to remove C3d binding and/or high‐MFI DSAs.     

Impact of pretransplant donor‐specific antibodies on kidney allograft recipients with negative flow cytometry cross‐matches

The Luminex test can detect low levels of donor‐specific antibody (DSA) that cannot be detected by flow‐cytometric cross‐matching (FCXM) in kidney transplantation (KT). This study evaluated the impact of DSA on clinical outcomes in KT recipients negative on FCXM. Of 575 consecutive patients who underwent living donor KT between January 2013 and July 2016, 494 (85.9%) were DSA‐negative and 81 (14.1%) were DSA‐positive. Although rates of acute cellular rejection (ACR) at 1 year were similar in the 2 groups (P = .54), the incidence of antibody‐mediated rejection (ABMR) was significantly higher in the DSA‐positive group (P < .01). There was no statistically significant association between rejection‐free graft survival (RFGS) rates and pretransplant class I DSA. However, evaluation of pretransplant class II DSA showed that RFGS rates were significantly lower in patients with mean fluorescence intensity (MFI) >3000 than in patients with DSA‐negative (P < .01). On multivariate analyses, class II DSA MFI ≥5000 was a significant risk factor for acute rejection (hazard ratio, 7.48; P < .01). These findings suggested that pretransplant DSA alone did not affect graft survival in KT recipients without desensitization. However, class II DSA MFI >5000 was an independent predictor of acute rejection in DSA‐positive patients.     

Living Donor Liver Transplantation for Patients Older Than Age 70 Years: A Single‐Center Experience

Over the past two decades, the age of liver transplantation (LT) recipients has been increasing. We reviewed our experience with LT for patients aged ≥70 years (range: 70–78 years) and investigated the feasibility of performing LT, especially living donor LT (LDLT), for older patients. We retrospectively reviewed the medical records of 25 patients (15 LDLT recipients, 10 deceased donor LT recipients) aged ≥70 years who underwent LT from January 2000 to April 2016. Their perioperative morbidity rate was 28.0%, and the in‐hospital mortality rate was 16.0%; these results were comparable to those of matched patients in their 60s (n = 73; morbidity, p = 0.726; mortality, p = 0.816). For patients in their 70s, the 1‐ and 5‐year patient survival rates were 84.0% and 69.8%, and the 1‐ and 5‐year graft survival rates were 83.5% and 75.1%, respectively. Comparisons of patient and graft survival rates between matched patients in their 60s and 70s showed no statistically significant differences (patient survival, p = 0.372; graft survival, p = 0.183). Our experience suggests that patients aged ≥70 years should not be excluded from LT, or even LDLT, based solely on age and implies that careful selection of recipients and donors as well as meticulous surgical technique are necessary for successful results.     

Acquisition of C3d‐Binding Activity by De Novo Donor‐Specific HLA Antibodies Correlates With Graft Loss in Nonsensitized Pediatric Kidney Recipients

Alloantibody‐mediated graft injury is a major cause of kidney dysfunction and loss. The complement‐binding ability of de novo donor‐specific antibodies (dnDSAs) has been suggested as a prognostic tool to stratify patients for clinical risk. In this study, we analyzed posttransplant kinetics of complement‐fixing dnDSAs and their role in antibody‐mediated rejection development and graft loss. A total of 114 pediatric nonsensitized recipients of first kidney allograft were periodically monitored for dnDSAs using flow bead assays, followed by C3d and C1q assay in case of positivity. Overall, 39 patients developed dnDSAs, which were C1q⁺ and C3d⁺ in 25 and nine patients, respectively. At follow‐up, progressive acquisition over time of dnDSA C1q and C3d binding ability, within the same antigenic specificity, was observed, paralleled by an increase in mean fluorescence intensity that correlated with clinical outcome. C3d‐fixing dnDSAs were better fit to stratify graft loss risk when the different dnDSA categories were evaluated in combined models because the 10‐year graft survival probability was lower in patients with C3d‐binding dnDSA than in those without dnDSAs or with C1q⁺/C3d^? or non‐complement‐binding dnDSAs (40% vs. 94%, 100%, and 100%, respectively). Based on the kinetics profile, we favor dnDSA removal or modulation at first confirmed positivity, with treatment intensification guided by dnDSA biological characteristics.     

Eculizumab Salvage Therapy for Antibody‐Mediated Rejection in a Desensitization‐Resistant Intestinal Re‐Transplant Patient

The presence of elevated calculated panel reactive antibody (cPRA) and anti‐HLA donor specific antibodies (DSA) are high risk factors for acute antibody‐mediated rejection (AAMR) in intestinal transplantation that may lead to graft loss. Eculizumab has been used for the treatment of AAMR in kidney transplantation of sensitized patients that do not respond to other treatment. Here, we report a case where eculizumab was used to treat AAMR in a desensitization‐resistant intestinal re‐transplant patient. A male patient lost his intestinal graft to AAMR 8.14 years after his primary transplant. He received a second intestinal graft that had to be explanted a month later due to refractory AAMR. The patient remained highly sensitized despite multiple treatments. He received a multivisceral graft and presented with severe AAMR on day 3 posttransplantation. The AAMR was successfully treated with eculizumab. The patient presently maintains an elevated cPRA level above 90% but his DSAs have decreased from 18 000 MFI (mean fluorescent intensity) to below the positive cut‐off value of 3000 MFI and remains rejection free with a 2‐year follow‐up since his multivisceral transplant. Eculizumab offers an alternative to treat AAMR in intestinal transplantation in desensitization‐resistant patients.     

Preformed donor‐specific HLA antibodies are associated with increased risk of early mortality after liver transplantation

There is limited evidence for a negative impact of preformed, donor‐specific HLA antibodies (DSA) identified by cross‐matching on outcomes after liver transplantation. Three recent studies have suggested an association between preformed DSA detected by Luminex and reduced graft or recipient survival in liver transplant cohorts with a high prevalence of hepatitis C. This study investigated the impact of preformed DSA identified by Luminex in the Scottish liver transplant population. All recipients of liver transplants in Scotland between 2007 and 2015 with samples available for day of transplant antibody testing and donor HLA typing were included (n=459); 96% of the cohort were white and 19% had a primary diagnosis of hepatitis C. The median follow‐up time was 36 months. Preformed DSA were detected in 88 recipients. In multivariate analysis, preformed DSA with a median fluorescent intensity ≥10 000 were associated with recipient mortality at 1 year. There was no association between DSA and overall graft or recipient survival. This study adds to the growing body of evidence supporting a detrimental impact of preformed, high‐level DSA in a subset of liver transplant recipients by identifying an association in an ethnically and demographically distinct liver transplant population.     

Outcome of Kidney Transplantations Performed With Preformed Donor‐Specific Antibodies of Unknown Etiology

The detection of preformed donor‐specific alloantibodies (DSA) with multiplex‐bead arrays has led to the common observation that individuals without a history of pregnancy, transfusion or transplantation can have circulating anti‐HLA antibodies of unknown etiology. We retrospectively analyzed the risk of antibody‐mediated rejection (AMR) and graft outcome in 41 kidney transplant recipients with DSA of unknown etiology (DSA cause‐unk) at the time of transplantation. Twenty‐one patients received a posttransplantation desensitization protocol, and 20 received standard immunosuppressive therapy. The mean number of DSA was 1.4 ± 0.8, ranging from 1 to 5. Complement‐dependent cytotoxicity crossmatches were negative for all the patients. Flow cytometry crossmatches were positive in 47.6% of cases. The incidence of acute AMR was 14.6% at 1 year, regardless of the immunosuppressive regimen. No patients experienced graft loss following AMR. At month 12, across the entire population of patients with DSA cause‐unk, the outcomes were favorable: the measured glomerular filtration rate was 63.8 ± 16.4 mL/min/1.73 m², the screening biopsies showed low frequencies of microvascular inflammation and no transplant glomerulopathy, and graft and patient survival were 100%. In conclusion, patients with DSA cause‐unk are able to mount AMR but have favorable 1‐year outcomes.     

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

Background

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).

Pediatric heart transplantation across a positive crossmatch: First year results from the CTOTC‐04 multi‐institutional study

Sensitization is common in pediatric heart transplant candidates and waitlist mortality is high. Transplantation across a positive crossmatch may reduce wait time, but is considered high risk. We prospectively recruited consecutive candidates at eight North American centers. At transplantation, subjects were categorized as nonsensitized or sensitized (presence of ≥1 HLA antibody with MFI ≥1000 using single antigen beads). Sensitized subjects were further classified as complement‐dependent cytotoxicity crossmatch (CDC‐crossmatch) positive or negative and as donor‐specific antibodies (DSA) positive or negative. Immunosuppression was standardized. CDC‐crossmatch–positive subjects also received perioperative antibody removal, maintenance corticosteroids, and intravenous immunoglobulin. The primary endpoint was the 1 year incidence rate of a composite of death, retransplantation, or rejection with hemodynamic compromise. 317 subjects were screened, 290 enrolled and 240 transplanted (51 with pretransplant DSA, 11 with positive CDC‐crossmatch). The incidence rates of the primary endpoint did not differ statistically between groups; nonsensitized 6.7% (CI: 2.7%, 13.3%), sensitized crossmatch positive 18.2% (CI: 2.3%, 51.8%), sensitized crossmatch negative 10.7% (CI: 5.7%, 18.0%), P = .2354. The primary endpoint also did not differ by DSA status. Freedom from antibody‐mediated and cellular rejection was lower in the crossmatch positive group and/or in the presence of DSA. Follow‐up will determine if acceptable outcomes can be achieved long‐term.     

Incidence,characterization, and impact of newly detected donor‐specific anti‐HLA antibody in the first year after pediatric heart transplantation: A report from the CTOTC‐04 study

Data on the clinical importance of newly detected donor‐specific anti‐HLA antibodies (ndDSAs) after pediatric heart transplantation are lacking despite mounting evidence of the detrimental effect of de novo DSAs in solid organ transplantation. We prospectively tested 237 pediatric heart transplant recipients for ndDSAs in the first year posttransplantation to determine their incidence, pattern, and clinical impact. One‐third of patients developed ndDSAs; when present, these were mostly detected within the first 6 weeks after transplantation, suggesting that memory responses may predominate over true de novo DSA production in this population. In the absence of preexisting DSAs, patients with ndDSAs had significantly more acute cellular rejection but not antibody‐mediated rejection, and there was no impact on graft and patient survival in the first year posttransplantation. Risk factors for ndDSAs included common sensitizing events. Given the early detection of the antibody response, memory responses may be more important in the first year after pediatric heart transplantation and patients with a history of a sensitizing event may be at risk even with a negative pretransplantation antibody screen. The impact on late graft and patient outcomes of first‐year ndDSAs is being assessed in an extended cohort of patients.     

Posttransplant reduction in preexisting donor‐specific antibody levels after belatacept‐ versus cyclosporine‐based immunosuppression: Post hoc analyses of BENEFIT and BENEFIT‐EXT

BENEFIT and BENEFIT‐EXT were phase III studies of cytotoxic T‐cell crossmatch–negative kidney transplant recipients randomized to belatacept more intense (MI)‐based, belatacept less intense (LI)‐based, or cyclosporine‐based immunosuppression. Following study completion, presence/absence of HLA‐specific antibodies was determined centrally via solid‐phase flow cytometry screening. Stored sera from anti‐HLA–positive patients were further tested with a single‐antigen bead assay to determine antibody specificities, presence/absence of donor‐specific antibodies (DSAs), and mean fluorescent intensity (MFI) of any DSAs present. The effect of belatacept‐based and cyclosporine‐based immunosuppression on MFI was explored post hoc in patients with preexisting DSAs enrolled to BENEFIT and BENEFIT‐EXT. In BENEFIT, preexisting DSAs were detected in 4.6%, 4.9%, and 6.3% of belatacept MI‐treated, belatacept LI‐treated, and cyclosporine‐treated patients, respectively. The corresponding values in BENEFIT‐EXT were 6.0%, 5.7%, and 9.2%. In both studies, most preexisting DSAs were of class I specificity. Over the first 24 months posttransplant, a greater proportion of preexisting DSAs in belatacept‐treated versus cyclosporine‐treated patients exhibited decreases or no change in MFI. MFI decline was more apparent with belatacept MI‐based versus belatacept LI‐based immunosuppression in both studies and more pronounced in BENEFIT‐EXT versus BENEFIT. Although derived post hoc, these data suggest that belatacept‐based immunosuppression decreases preexisting DSAs more effectively than cyclosporine‐based immunosuppression.     

Preformed Donor-Specific Antibodies in Kidney Transplant: A Center Experience

BackgroundThe presence of preformed donor-specific alloantibodies (DSAs) at the time of transplantation has been associated with an increased risk of rejection, dysfunction, and shorter survival. Detection and identification of these antibodies have improved with more sensitive assays, but their clinical relevance and influence on long-term outcomes are unclear.MethodsWe investigate the impact of pretransplant DSAs on the outcomes of kidney transplantation. A retrospective analysis was conducted on all patients who received a deceased donor kidney transplant in our center between January 2017 and December 2021. The study population consisted of 75 kidney transplantations, and DSAs were detected in 15 patients (20%) before transplantation.ResultsThere was no significant difference in delayed graft function, serum creatinine level at discharge and the first year after transplant, acute rejection rates, or graft survival in patients with and without preformed DSAs.ConclusionsDetecting pretransplant DSAs by highly sensitive assays may not necessarily impact long-term graft outcomes, and the mismatch should be individually evaluated.     

De novo donor‐specific antibodies in belatacept‐treated vs cyclosporine‐treated kidney‐transplant recipients: Post hoc analyses of the randomized phase III BENEFIT and BENEFIT‐EXT studies

Donor‐specific antibodies (DSAs) are associated with an increased risk of antibody‐mediated rejection and graft failure. In BENEFIT and BENEFIT‐EXT, kidney‐transplant recipients were randomized to receive belatacept more intense (MI)–based, belatacept less intense (LI)–based, or cyclosporine‐based immunosuppression for up to 7 years (84 months). The presence/absence of HLA‐specific antibodies was determined at baseline, at months 6, 12, 24, 36, 48, 60, and 84, and at the time of clinically suspected episodes of acute rejection, using solid‐phase flow‐cytometry screening. Samples from anti‐HLA‐positive patients were further tested with a single‐antigen bead assay to determine antibody specificities, presence/absence of DSAs, and mean fluorescence intensity (MFI) of any DSAs present. In BENEFIT, de novo DSAs developed in 1.4%, 3.5%, and 12.1% of belatacept MI‐treated, belatacept LI‐treated, and cyclosporine‐treated patients, respectively. The corresponding values in BENEFIT‐EXT were 3.8%, 1.1%, and 11.2%. Per Kaplan‐Meier analysis, de novo DSA incidence was significantly lower in belatacept‐treated vs cyclosporine‐treated patients over 7 years in both studies (P < .01). In patients who developed de novo DSAs, belatacept‐based immunosuppression was associated with numerically lower MFI vs cyclosporine‐based immunosuppression. Although derived post hoc, these data suggest that belatacept‐based immunosuppression suppresses de novo DSA development more effectively than cyclosporine‐based immunosuppression.     

Donor‐specific HLA antibody‐mediated complement activation is a significant indicator of antibody‐mediated rejection and poor long‐term graft outcome during lung transplantation: a single center cohort study

Complement‐mediated allograft injury, elicited by donor‐specific HLA antibodies (DSA ), is a defining pathophysiological characteristic of allograft damage. We aimed to study DSA ‐induced complement activation as a diagnostic marker of antibody‐mediated rejection (AMR ) and a risk stratification tool for graft loss in the context of lung transplantation (LT ). We identified 38 DSA ‐positive patients whose serum samples were submitted for C3d deposition testing via the C3d assay. Among these 38 patients, 15 had AMR (DSA^{P os}AMR^{P os}). Results were reported for each patient as the C3d ratio for each DSA , the immunodominant DSA , and the C3d ratio for all DSA present in a sample (C3d ratio_SUM ). DSA^{P os}AMR^{P os} patients had higher C3d ratio_SUM values (58.66 (?1.32 to 118.6) vs. 1.52 (0.30 to 2.74), P  = 0.0016) and increased immunodominant C3d ratios (41.87 (1.72 to 82.02) vs. 0.69 (0.21 to 1.19), P  = 0.001) when compared with DSA^{P os}AMR^{N eg} patients. Specificity and calculated positive predictive value of the immunodominant C3d ratio and BCM sum tests for AMR diagnosis were both 100% (CI  = 17.4–100) in this cohort. Worst graft survival was associated with both immunodominant C3d ratio ≥4 or C3d ratio_SUM ≥10 or BCM sum >7000, suggesting that the antibody composition and/or strength are the principal determinants of an HLA DSA 's capacity to activate complement.