Impact of Early Blood Transfusion After Kidney Transplantation on the Incidence of Donor‐Specific Anti‐HLA Antibodies

Little is known about the impact of posttransplant blood transfusion on the sensitization of anti‐HLA antibodies and the formation of donor‐specific antibodies (DSAs). The aims of our study were to determine the 1‐year incidence of DSAs (assessed using a solid‐phase assay) and antibody‐mediated rejection (AMR) in kidney transplant patients who had or had not received a blood transfusion during the first year after transplantation. Included were 390 non–HLA‐sensitized patients who had received an ABO‐compatible kidney transplant and had not previously or simultaneously received a nonkidney transplant. Overall, 64% of patients received a red blood cell transfusion within the first year after transplantation, most within the first month. The overall 1‐year incidence of DSAs was significantly higher in patients that had undergone transfusion (7.2% vs. 0.7% in patients with no transfusion, p < 0.0001). AMR occurred more often in the transfusion group (n = 15, 6%) compared with the nontransfusion group (n = 2, 1.4%; p = 0.04). Blood transfusion was an independent predictive factor for de novo DSA formation but not for AMR. Patients who had a transfusion and developed DSAs were more often treated with cyclosporin A (n = 10, 55.5%) rather than tacrolimus (n = 45, 19.4%; p = 0.0001). In conclusion, early posttransplant blood transfusion may increase immunological risk, especially in underimmunosuppressed patients.     

Clinical relevance of the de novo production of anti‐HLA antibodies following intestinal and multivisceral transplantation

Despite a negative pretransplant cross‐match, intestinal transplant recipients can mount humoral immune responses soon after transplantation. Moreover, the development of donor‐specific anti‐HLA antibodies (DSAs) is associated with severe graft injury. Between June 2000 and August 2011, 30 patients (median age 37.6 ± 9.8 years) received isolated intestinal transplantations (ITX, n = 18) or multivisceral transplantations (MVTXs, n = 12) at our center. We screened for human leukocyte antigen (HLA) antibodies pre‐ and post‐transplant. If patients produced DSAs, treatment with plasmapheresis and intravenous immunoglobulin (IVIG) was initiated. In the event of DSA persistence and/or treatment‐refractory rejection, rituximab and/or bortezomib were added. Ten patients developed DSAs and simultaneously showed significant signs of rejection. These patients received plasmapheresis and IVIG. Eight patients additionally received rituximab, and two patients were treated with bortezomib. DSA values decreased upon antirejection therapy in 8 of the 10 patients. The development of DSAs following ITX is often associated with acute rejection. We observed that the number of mismatched antigens and epitopes correlates with the probability of developing de novo DSAs. Early diagnosis and therapy, including B‐cell depletion and plasma cell inhibition, are crucial to preventing further graft injury.     

De Novo Donor‐Specific HLA Antibodies Decrease Patient and Graft Survival in Liver Transplant Recipients

The role of de novo donor‐specific HLA antibodies (DSA) in liver transplantation remains unknown as most of the previous studies have only focused on preformed HLA antibodies. To understand the significance of de novo DSA, we designed a retrospective cohort study of 749 adult liver transplant recipients with pre‐ and posttransplant serum samples that were analyzed for DSA. We found that 8.1% of patients developed de novo DSA 1 year after transplant; almost all de novo DSAs were against HLA class II antigens, and the majority were against DQ antigens. In multivariable modeling, the use of cyclosporine (as opposed to tacrolimus) and low calcineurin inhibitor levels increased the risk of de novo DSA formation, while a calculated MELD score >15 at transplant and recipient age >60 years old reduced the risk. Multivariable analysis also demonstrated that patients with de novo DSA at 1‐year had significantly lower patient and graft survival. In conclusion, we demonstrate that de novo DSA development after liver transplantation is an independent risk factor for patient death and graft loss.     

Dynamics of anti‐human leukocyte antigen antibodies after renal transplantation and their impact on graft outcome

The purpose of this study was to sequentially monitor anti‐HLA antibodies and correlate the results with antibody‐mediated rejection (AMR), graft survival (GS), and graft function (GF). We collected sera from 111 kidney transplant recipients on transplant days 0, 7, 14, 30, 60, 90, 180, and 360 and analyzed PRA levels by ELISA. DSAs were analyzed by single‐antigen beads in rejecting kidneys. At pre‐transplant, 79.3% of the patients were non‐sensitized (PRA = 0%) and 20.7% were sensitized (PRA > 1%). After transplant, patients were grouped by PRA profile: no anti‐HLA antibodies pre‐ or post‐transplant (group HLApre?/post?; n = 80); de novo anti‐HLA antibodies post‐transplant (group HLApre?/post+; n = 8); sensitized pre‐transplant/increased PRA post‐transplant (group HLApre+/post↑; n = 9); and sensitized pre‐transplant/decreased PRA post‐transplant (group HLApre+/post↓; n = 14). De novo anti‐HLA antibodies were detected at 7–180 d. In sensitized patients, PRA levels changed within the first 30 d post‐transplant. Incidence of AMR was higher in HLApre?/post+ and HLApre+/post↑ than in HLApre?/post?, and HLApre+/post↓ (p < 0.001) groups. One‐yr death‐censored GS was 36% in group HLApre+/post↑, compared with 98%, 88% and 100% in groups HLApre?/post?, HLApre?/post+, and HLApre+/post↓, respectively (p < 0.001). Excluding first‐year graft losses, GF and GS were similar among the groups. In conclusion, post‐transplant antibody monitoring can identify recipients at higher risk of AMR.     

Posttransplant De Novo Donor‐Specific HLA Antibodies Identify Pediatric Kidney Recipients at Risk for Late Antibody‐Mediated Rejection

The emerging role of humoral immunity in the pathogenesis of chronic allograft damage has prompted research aimed at assessing the role of anti‐HLA antibody (Ab) monitoring as a tool to predict allograft outcome. Data on the natural history of allografts in children developing de novo Ab after transplantation are limited. Utilizing sera collected pretransplant, and serially posttransplant, we retrospectively evaluated 82 consecutive primary pediatric kidney recipients, without pretransplant donor‐specific antibodies (DSA), for de novo Ab occurrence, and compared results with clinical–pathologic data. At 4.3‐year follow up, 19 patients (23%) developed de novo DSA whereas 24 had de novo non‐DSA (NDSA, 29%). DSA appeared at a median time of 24 months after transplantation and were mostly directed to HLA‐DQ antigens. Among the 82 patients, eight developed late/chronic active C4d+ antibody‐mediated rejection (AMR), and four C4d‐negative AMR. Late AMR correlated with DSA (p < 0.01), whose development preceded AMR by 1‐year median time. Patients with DSA had a median serum creatinine of 1.44 mg/dL at follow up, significantly higher than NDSA and Ab‐negative patients (p < 0.005). In our pediatric cohort, DSA identify patients at risk of renal dysfunction, AMR and graft loss; treatment started at Ab emergence might prevent AMR occurrence and/or progression to graft failure.     

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.     

Allelic and Epitopic Characterization of Intra–Kidney Allograft Anti‐HLA Antibodies at Allograft Nephrectomy

The reasons for the increased incidence of de novo anti–human leukocyte antibody (HLA) donor‐specific antibodies (DSAs) observed after kidney allograft nephrectomy are not fully understood. One advocated mechanism suggests that at graft loss, DSAs are not detected in the serum because they are fixed on the nonfunctional transplant; removal of the kidney allows DSAs to then appear in the blood circulation. The aim of our study was to compare anti‐HLA antibodies present in the serum and in the graft at the time of an allograft nephrectomy. Using solid‐phase assays, anti‐HLA antibodies were searched for in the sera of 17 kidney transplant patients undergoing allograft nephrectomy. No anti‐HLA antibodies were detected in the graft if they were not also detected in the serum. Eleven of the 12 patients who had DSAs detected in their sera also had DSAs detected in the grafts. Epitopic analysis revealed that most anti‐HLA antibodies detected in removed grafts were directed against the donor. In summary, our data show that all anti‐HLA antibodies that were detected in grafts were also detected in the sera. These intragraft anti‐HLA antibodies are mostly directed against the donor at an epitopic level but not always at an antigenic level.     

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.     

Influenza vaccination and humoral alloimmunity in solid organ transplant recipients

Annual influenza vaccination is recommended in solid organ transplant (SOT) recipients. However, concerns have been raised about the impact of vaccination on antigraft alloimmunity. We evaluated the humoral alloimmune responses to influenza vaccination in a cohort of SOT recipients between October 2008 and December 2011. Anti‐HLA antibodies were measured before and 4–8 weeks after influenza vaccination using a solid‐phase assay. Overall, 169 SOT recipients were included (kidney = 136, lung = 26, liver = 3, and combined = 4). Five (2.9%) of 169 patients developed de novo anti‐HLA antibodies after vaccination, including one patient who developed donor‐specific antibodies (DSA) 8 months after vaccination. In patients with pre‐existing anti‐HLA antibodies, median MFI was not significantly different before and after vaccination (P = 0.73 for class I and P = 0.20 for class II anti‐HLA antibodies) and no development of de novo DSA was observed. Five episodes of rejection (2.9%) were observed within 12 months after vaccination, and only one patient had de novo anti‐HLA antibodies. The incidence of development of anti‐HLA antibodies after influenza vaccination in our cohort of SOT recipients was very low. Our findings indicate that influenza vaccination is safe and does not trigger humoral alloimmune responses in SOT recipients.     

Development and Impact of De Novo Anti‐HLA Antibodies in Pediatric Heart Transplant Recipients

There is increasing evidence that de novo anti‐HLA antibodies, more specifically de novo donor‐specific antibodies (DSA) following solid organ transplantation may be associated with negative outcomes including rejection in the first year and graft loss. Limited data are available in pediatric heart transplant recipients. We sought to prospectively determine the incidence, class and early impact of de novo anti‐HLA antibodies in a cohort of pediatric heart transplant recipients. Serial panel reactive antibody testing posttransplant was performed in 25 patients (14 males) transplanted between January 2008 and June 2010. Five patients were sensitized pretransplant; all patients had negative direct crossmatch. Seventy‐two percent developed de novo anti‐HLA antibodies at a median of 2.6 weeks (IQR 1.2 weeks to 6.2 months) posttransplant; 67% of these were DSA. The majority of recipients in our cohort developed de novo anti‐HLA antibodies within the first year posttransplant, with two‐thirds being donor‐specific. Acute cellular rejection, though frequent, was not different in patients with antibody development regardless of class or specificity, and there was no antibody‐mediated rejection, graft loss or early cardiac allograft vasculopathy.     

mTOR inhibitors and risk of chronic antibody‐mediated rejection after kidney transplantation: where are we now?

Antibody‐mediated rejection (AMR) usually starts with generation of donor‐specific anti‐HLA antibodies (DSAs), arising from a B‐cell response to antigen recognition. In vitro and preclinical data demonstrate that mammalian target of rapamycin (mTOR) inhibition attenuates the mTOR‐mediated intracellular signaling pathway involved in AMR‐related kidney damage. The limited available data from immunological studies in kidney transplant patients, however, have not shown such effects in vivo. In terms of clinical immunosuppression, the overriding influence on rates of de novo DSA (dnDSA) or AMR—regardless of the type of regimen—is patient adherence. To date, limited data from patients given mTOR inhibitor therapy with adequate concurrent immunosuppression, such as reduced‐exposure calcineurin inhibitor (CNI) therapy, have not shown an adverse effect on the risk of dnDSA or AMR. Early switch to an mTOR inhibitor (<6–12 months post‐transplant) in a CNI‐free regimen, in contrast, can increase the risk of dnDSA, especially if adjunctive therapy is inadequate. Late conversion to CNI‐free therapy with mTOR inhibition does not appear to affect the risk of dnDSA. More data, from prospective studies, are required to fully understand that association between use of mTOR inhibitors with different types of concomitant therapy and risk of dnDSA and AMR.     

De novo membranous nephropathy and antibody‐mediated rejection in transplanted kidney

Honda K, Horita S, Toki D, Taneda S, Nitta K, Hattori M, Tanabe K, Teraoka S, Oda H, Yamaguchi Y. De novo membranous nephropathy and antibody‐mediated rejection in transplanted kidney.
Clin Transplant 2011: 25: 191–200. © 2010 John Wiley & Sons A/S. Abstract: Background: The etiology of de novo membranous nephropathy (MN) after kidney transplantation is still uncertain. Immunological response to various allograft antigens is speculated to be a candidate for the etiology. Methods: Seventeen patients with post‐transplant de novo MN were studied clinically and pathologically in comparison with control post‐transplant patients without MN. Double immunofluorescent staining was performed to identify the presence of donor‐specific human leukocyte antigen (HLA) combined with IgG in the deposits on glomerular capillary walls. Results: De novo MN occurs in relatively late period after transplantation (102.1 ± 68.3 months), presenting various degree of proteinuria. Histological findings associated with antibody‐mediated rejection (AMR), such as peritubular capillaritis and C4d deposition in peritubular capillary, were more frequently observed in the patients with de novo MN than the non‐MN control patients. Donor‐specific antibody (DSA) was detected in five patients at the time of biopsy. In one case of de novo MN with DSA, a donor‐derived HLA was identified in the subepithelial deposits on the glomerular capillary walls combined with IgG deposition. Conclusions: DSA and AMR might play some roles for the pathogenesis in some patients with de novo MN after kidney transplantation.     

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.     

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.     

Incidence of donor‐specific antibodies in kidney transplant patients following conversion to an everolimus‐based calcineurin inhibitor‐free regimen

Scarce data exist regarding the incidence of donor‐specific antibodies (DSAs) in kidney transplant patients receiving everolimus‐based immunosuppression without calcineurin inhibitors (CNIs). The aim of this retrospective case–control study was to compare the incidence of de novo DSAs in patients converted to an everolimus‐based regimen without CNIs with that seen in patients maintained on CNIs. Sixty‐one DSA‐free kidney transplant patients who had been converted to an everolimus‐based regimen (everolimus group) were compared to 61 other patients maintained on CNIs‐based regimen (control group). Patients were matched according to age, gender, induction therapy, date of transplantation, and being DSA‐free at baseline. At last follow‐up, the incidence of DSAs was 9.8% in the everolimus group and 5% in the control group (p = ns). In the everolimus group, the increased incidence of DSAs between baseline and last follow‐up was statistically significant. Antibody‐mediated rejection occurred in 6.5% in the everolimus group and 0% in the CNIs group. The incidence of DSAs is numerically increased in kidney transplant patients treated with an everolimus‐based without CNIs. A study including a larger number of patients is required to determine whether a CNI‐free everolimus‐based immunosuppression significantly increases DSAs formation.     

De novo donor‐specific anti‐HLA antibodies after kidney transplantation are associated with impaired graft outcome independently of their C1q‐binding ability

Many aspects of post‐transplant monitoring of donor‐specific (DSA) and non‐donor‐specific (nDSA) anti‐HLA antibodies on renal allograft survival are still unclear. Differentiating them by their ability to bind C1q may offer a better risk assessment. We retrospectively investigated the clinical relevance of de novo C1q‐binding anti‐HLA antibodies on graft outcome in 611 renal transplant recipients. Acute rejection (AR), renal function, and graft survival were assessed within a mean follow‐up of 6.66 years. Post‐transplant 6.5% patients developed de novo DSA and 11.5% de novo nDSA. DSA (60.0%; P < 0.0001) but not nDSA (34.1%, P = 0.4788) increased rate of AR as compared with controls (27.4%). C1q‐binding anti‐HLA antibodies did not alter rate of AR in both groups. Renal function was only significantly diminished in patients with DSAC1q⁺. However, DSA significantly impaired 5‐year graft survival (65.2%; P < 0.0001) in comparison with nDSA (86.7%; P = 0.0054) and controls (90.7%). While graft survival did not differ between DSAC1q⁻ and DSAC1q⁺ recipients, 5‐year allograft survival was reduced in nDSAC1q⁺ (80.9%) versus nDSAC1q⁻ (90.7%, P = 0.0251). De novo DSA independently of their ability to bind C1q are associated with diminished graft survival.     

Immediate and Catastrophic Antibody‐Mediated Rejection in a Lung Transplant Recipient With Anti–Angiotensin II Receptor Type 1 and Anti–Endothelin‐1 Receptor Type A Antibodies

Preexisting donor‐specific anti‐HLA antibodies (DSAs) have been associated with reduced survival of lung allografts. However, antibodies with specificities other than HLA may have a detrimental role on the lung transplant outcome. A young man with cystic fibrosis underwent lung transplantation with organs from a suitable deceased donor. At the time of transplantation, there were no anti‐HLA DSAs. During surgery, the patient developed a severe and intractable pulmonary hypertension associated with right ventriular dysfunction, which required arteriovenous extracorporeal membrane oxygenation. After a brief period of clinical improvement, a rapid deterioration in hemodynamics led to the patient's death on postoperative day 5. Postmortem studies showed that lung specimens taken at the end of surgery were compatible with antibody‐mediated rejection (AMR), while terminal samples evidenced diffuse capillaritis, blood extravasation, edema, and microthrombi, with foci of acute cellular rejection (A3). Immunological investigations demonstrated the presence of preexisting antibodies against the endothelin‐1 receptor type A (ET_AR) and the angiotensin II receptor type 1 (AT₁R), two of the most potent vasoconstrictors reported to date, whose levels slightly rose after transplantation. These data suggest that preexisting anti‐ET_AR and anti‐AT₁R antibodies may have contributed to the onset of AMR and to the catastrophic clinical course of this patient.     

Outcomes and risk stratification for late antibody‐mediated rejection in recipients of ABO‐incompatible kidney transplants: a retrospective study

The required intensity of monitoring for antibody‐mediated rejection (AMR) after of ABO‐incompatible (ABOi) kidney transplantation is not clearly formulized. We retrospectively evaluated a single‐center cohort of 115 ABO‐incompatible (ABOi) kidney transplant recipients, of which 32% were also HLA incompatible (ABOi/HLAi) with their donors. We used an adjusted negative binomial model to evaluate risk factors for late AMR. Using this model, we risk‐stratified patients into high‐ and low‐risk groups for the development of late AMR; 26% of patients had at least one AMR episode; 49% of AMR episodes occurred within 30‐days after transplant and were considered early AMR. Patients with an early AMR episode had a 5.5‐fold greater incidence of developing late AMR [IRR = 5.5, (95% CI: 1.5–19.3), P = 0.01]. ABOi/HLAi recipients trended toward increased late AMR risk [IRR = 1.9, (95% CI: 0.5–6.6), P = 0.3]. High‐risk recipients (those with an early AMR or those who were ABOi/HLAi) had a sixfold increased incidence of late AMR [IRR = 6.3, (95% CI: 1.6–24.6), P = 0.008] versus low‐risk recipients. The overall incidence of late AMR was 20.8% vs. 1.5% in low‐risk recipients. Changes in anti‐A/B titer did not correlate with late AMR (IRR = 0.9 per log titer increase, P = 0.7). This risk‐stratification scheme uses information available within 30 days of ABOi transplantation to determine risk for late AMR and can help direct longitudinal follow‐up for individual patients.     

Comparison of de novo IgM and IgG anti‐HLA DSAs between belatacept‐ and calcineurin‐treated patients: An analysis of the BENEFIT and BENEFIT‐EXT trial cohorts

Preventing conversion of donor‐specific anti‐HLA antibodies (DSAs) from an IgM‐to‐IgG could a way to prevent chronic rejection. We evaluated whether belatacept‐treated patients (belatacept less‐intensive [LI] or more‐intensive [MI] regimens) have a lower rate of conversion than do cyclosporine A (CsA)–treated patients. We included 330 HLA‐mismatched patients from 2 phase 3 trials with either (a) complete donor/recipient HLA‐A, ‐B, ‐DR, and ‐DQ loci typing or (b) incomplete HLA typing with IgG DSAs detected pretransplant or posttransplant. IgM and IgG DSAs were tested with single antigen beads at 0, 6, 12, 24, and 36 months posttransplant. The overall (preexisting or de novo) rates of IgM‐ and IgG‐positive DSAs were 29% and 34%, respectively. The pretransplant IgM and IgG DSA‐positive frequencies were similar between treatment groups. The IgG‐positive dnDSA rate was significantly higher in the CsA‐treated group (34%) compared with the belatacept‐LI (8%) and belatacept‐MI (11%) (P < .001) groups. In IgM‐positive dnDSA patients, the IgG‐positive dnDSA rate of conversion was 2.8 times higher in the CsA group than in the combined belatacept groups (P = .006). However, the observed association between belatacept treatment and more limited conversion of IgM‐to‐IgG dnDSAs was based on a limited number of patients and requires further validation.     

Difference in outcomes after antibody‐mediated rejection between abo‐incompatible and positive cross‐match transplantations

Graft survival seems to be worse in positive cross‐match (HLAi) than in ABO‐incompatible (ABOi) transplantation. However, it is not entirely clear why these differences exist. Sixty‐nine ABOi, 27 HLAi and 10 combined ABOi+HLAi patients were included in this retrospective study, to determine whether the frequency, severity and the outcome of active antibody‐mediated rejection (AMR) were different. Five‐year death‐censored graft survival was better in ABOi than in HLAi and ABOi+HLAi patients (99%, 69% and 64%, respectively, P = 0.0002). Features of AMR were found in 38%, 95% and 100% of ABOi, HLAi and ABOi+HLAi patients that had a biopsy, respectively (P = 0.0001 and P = 0.001). After active AMR, a declining eGFR and graft loss were observed more frequently in HLAi and HLAi+ABOi than in ABOi patients. The poorer prognosis after AMR in HLAi and ABOi+HLAi transplantations was not explained by a higher severity of histological lesions or by a less aggressive treatment. In conclusion, ABOi transplantation offers better results than HLAi transplantation, partly because AMR occurs less frequently but also because outcome after AMR is distinctly better. HLAi and combined ABOi+HLAi transplantations appear to have the same outcome, suggesting there is no synergistic effect between anti‐A/B and anti‐HLA antibodies.