Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients

Sensitized renal transplant recipients with high levels of donor-specific alloantibody (DSA) commonly develop antibody-mediated rejection (AMR), which may cause acute graft loss or shorten allograft survival. We examined the efficacy of terminal complement inhibition with the humanized anti-C5 antibody, eculizumab, in the prevention AMR in renal transplant recipients with a positive crossmatch against their living donor. The incidence of biopsy-proven AMR in the first 3 months posttransplant in 26 highly sensitized recipients of living donor renal transplants who received eculizumab posttransplant was compared to a historical control group of 51 sensitized patients treated with a similar plasma exchange (PE)-based protocol without eculizumab. The incidence of AMR was 7.7% (2/26) in the eculizumab group compared to 41.2% (21/51) in the control group (p = 0.0031). Eculizumab also decreased AMR in patients who developed high levels of DSA early after transplantation that caused proximal complement activation. With eculizumab, AMR episodes were easily treated with PE reducing the need for splenectomy. On 1-year protocol biopsy, transplant glomerulopathy was found to be present in 6.7% (1/15) eculizumab-treated recipients and in 35.7% (15/42) of control patients (p = 0.044). Inhibition of terminal complement activation with eculizumab decreases the incidence of early AMR in sensitized renal transplant recipients (ClincalTrials.gov number NCT006707).     

Complement inhibition as potential new therapy for antibody‐mediated rejection

Antibody‐mediated rejection (ABMR) is a leading cause of kidney allograft failure. While the exact mechanisms contributing to donor‐specific antibody (DSA)‐triggered tissue injury are still incompletely understood, complement activation via the classical pathway is believed to be one of the key players. There is now growing interest in complement blockade as an antirejection treatment. One attractive strategy may be inhibition of terminal complex formation using anti‐C5 antibody eculizumab. Anecdotal reports, case series, and a unique cohort of flow crossmatch‐positive live donor kidney transplant recipients subjected to eculizumab‐based desensitization have demonstrated successful prevention and reversal of acute clinical ABMR. Nevertheless, maybe due to complement activation steps proximal of C5 or even complement‐independent mechanisms, subclinical rejection processes that might culminate in chronic injury were found to escape inhibition. Larger studies designed to clarify the actual clinical value of terminal complement inhibition as an antirejection treatment are currently underway. In addition, alternative concepts, such as therapies that target key component C1, are currently under development, and we will see in the near future whether new strategies in the pipeline will have the potential to beneficially impact clinical practice.     

Differential outcomes in 3 types of acute antibody‐mediated rejection

Abstract: Introduction: The aim of this study is to investigate the prevalence, predictors, and clinical outcomes of acute antibody‐mediated rejection (AAMR). Methods: Retrospective analysis of 833 adult patients who received kidney transplantation between 1/1/2001 and 8/15/2007. Results: The prevalence of AAMR and acute cellular rejection was 2% and 8.2%, respectively. Eight patients had type I, seven type II, and two type III AAMR. All patients had at least one strong donor‐specific anti‐HLA antibodies (DSA) with a median fluorescence intensity (MFI) value of over 6000 and the mean number of strong DSAs was 2.0 ± 0.7. Fifteen of 17 patients received pre‐transplant desensitization treatment. During a median 28 months of follow‐up (range: 12–38 months), two patients died (88% patient survival), and nine lost their allografts (35% graft survival). While all type I AAMR patients responded to treatment, all type III patients, and four of seven patients with type II AAMR lost their allografts earlier, and three type II AAMR patients later due to transplant glomerulopathy. Conclusions: AAMR is mainly seen in patients with pre‐transplant strong DSAs. There is a striking difference in clinical outcomes of AAMR that types II and III AAMR patients have poor prognosis compared to type I AAMR patients.     

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.     

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.     

Prevention and treatment of alloantibody‐mediated kidney transplant rejection

Summary Antibody‐mediated rejection (AMR), which is commonly caused by preformed and/or de novo HLA alloantibodies, has evolved as a leading cause of early and late kidney allograft injury. In recent years, effective treatment strategies have been established to counteract the deleterious effects of humoral alloreactivity. One major therapeutic challenge is the barrier of a positive pretransplant lymphocytotoxic crossmatch. Several apheresis‐ and/or IVIG‐based protocols have been shown to enable successful crossmatch conversion, including a strategy of peritransplant immunoadsorption for rapid crossmatch conversion immediately before deceased donor transplantation. While such protocols may increase transplant rates and allow for acceptable graft survival, at least in the short‐term, it has become evident that, despite intense treatment, many patients still experience clinical or subclinical AMR. This reinforces the need for innovative strategies, such as complementary allocation programs to improve transplant outcomes. For acute AMR, various studies have suggested efficiency of plasmapheresis‐ or immunoadsorption‐based protocols. There is, however, no established treatment for chronic AMR and the development of strategies to reverse or at least halt chronic active rejection remains a big challenge. Major improvements can be expected from studies evaluating innovative therapeutic concepts, such as proteasome inhibition or complement blocking agents.     

Antibody‐mediated rejection (AMR) after pancreas and pancreas–kidney transplantation

Antibody‐mediated rejection (AMR) requires specific diagnostic tools and treatment and is associated with lower graft survival. We prospectively screened C4d in pancreas (n = 35, in 27 patients) and kidney (n = 33, in 21 patients) for cause biopsies. Serum amylase and lipase, amylasuria, fasting blood glucose (FBG) and 2‐h capillary glucose (CG) were also analysed. We found that 27.3% of kidney biopsies and 43% of pancreatic biopsies showed C4d staining (66.7% and 53.3% diffuse in peritubular and interacinar capillaries respectively). Isolated exocrine dysfunction was the main indication for pancreas biopsy (54.3%) and was followed by both exocrine and endocrine dysfunctions (37.1%) and isolated endocrine dysfunction (8.6%). Laboratorial parameters were comparable between T‐cell mediated rejection and AMR: amylase 151.5 vs. 149 U/l (P = 0.075), lipase 1120 vs. 1288.5 U/l (P = 0.83), amylasuria variation 46.5 vs. 61% (P = 0.97), FBG 69 vs. 97 mg/dl (P = 0.20) and 2‐h CG maximum 149.5 vs. 197.5 mg/dl (P = 0.49) respectively. Amylasuria values after treatment correlated with pancreas allograft loss (P = 0.015). These data suggest that C4d staining should be routinely investigated when pancreas allograft dysfunction is present because of its high detection rate in cases of rejection.     

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.     

The therapeutic challenge of late antibody‐mediated kidney allograft rejection

Late antibody‐mediated rejection (ABMR) is a cardinal cause of kidney allograft failure, manifesting as a continuous and, in contrast with early rejection, often clinically silent alloimmune process. While significant progress has been made towards an improved understanding of its molecular mechanisms and the definition of diagnostic criteria, there is still no approved effective treatment. In recent small randomized controlled trials, therapeutic strategies with promising results in observational studies, such as proteasome inhibitor bortezomib, anti‐C5 antibody eculizumab, or high dose intravenous immunoglobulin plus rituximab, had no significant impact in late and/or chronic ABMR. Such disappointing results reinforce a need of new innovative treatment strategies. Potential candidates may be the interference with interleukin‐6 to modulate B cell alloimmunity, or innovative compounds that specifically target antibody‐producing plasma cells, such as antibodies against CD38. Given the phenotypic heterogeneity of ABMR, the design of adequate systematic trials to assess the safety and efficiency of such therapies, however, is challenging. Several trials are currently being conducted, and new developments will hopefully provide us with effective ways to counteract the deleterious impact of antibody‐mediated graft injury. Meanwhile, the weight of evidence would suggest that, when approaching using existing treatments for established antibody‐mediated rejection, “less may be more”.     

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.     

Kidney Intragraft Donor‐Specific Antibodies as Determinant of Antibody‐Mediated Lesions and Poor Graft Outcome

Allograft pathology, antibody–tissue interaction as demonstrated by C4d deposition and serological evidence of donor‐specific antibodies (DSA) are the cardinal diagnostic features of antibody‐mediated lesions (AML) in kidney transplantation. However, discrepancy between histological and serological findings is common, and more reliable diagnostic tools are called for. Here, we asked whether the in situ detection of DSA could serve as marker for AML. To that end, we applied the anti‐HLA single antigen flow bead assay to eluates from 51 needle core graft biopsies performed for cause. Intragraft antibody profiles were correlated to serum DSA (sDSA), histological data and transplant outcome. The prevalence and the mean number of intragraft DSA (gDSA) were lower than that of sDSA (15/51 gDSA+ vs. 37/51 sDSA+ patients; 1.64 gDSA vs. 2.24 sDSA per patient). DSA were detected in all anti‐HLA antibody‐positive biopsies (15/15). The presence of gDSA was significantly associated with (1) microcirculation lesions taken individually (g, cg) and analyzed in functional clusters (ptc + g + cg > 0, cg + mm > 0), (2) C4d positivity and (3) a worse short‐term transplant outcome (p = 0.05). These associations were not found for patients presenting only sDSA. Taken together, these results indicate that gDSA is a severity marker of antibody‐mediated pathogenic process.     

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.     

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.     

Poor graft outcome in recipients with de novo donor-specific anti-HLA antibodies after living related kidney transplantation

Antibody-mediated rejection (AMR) is now widely recognized as a major problem in organ transplantation. This study was conducted to investigate the relationship between newly developing anti-HLA antibodies post-transplantation (de novo Abs) and the outcome of living related kidney transplantation (LRKT). The subjects included 87 patients who had received living donor kidney allografts at our institution. Panel reactive Ab assay (Flow-PRA) and graft biopsies were performed in all the recipients before and 6 months after the LRKT. The incidence of AMR, the donor specificity and time of appearance of the de novo Abs were retrospectively studied. Among the 87 LRKT recipients, 47 (54%) showed negative/negative (N/N) results, 15 (17%) showed positive/positive (P/P) results, 12 (14%) showed positive/negative results (P/N), and 13 (15%) showed negative/positive (N/P) results (de novo Abs) in the pre-/post-transplant Flow-PRA analysis. Among the 13 cases with de novo Abs, 5 (38%) had donor-specific Abs (DSA) and the remaining 8 (62%) had nondonor-specific Abs, as determined by LAB single antigen analysis. Eighty percent of the recipients with DSA showed evidence of AMR in the graft biopsies. The 5-year graft survival rate of the recipients with de novo Abs (N/P) was 69%, as compared with 96% in the N/N, 88% in the P/N and 93% in the P/P recipient groups (P = 0.009). LRKT recipients developing de novo Abs, especially those with DSA, showed a much higher incidence of AMR and a worse prognosis. Cautious monitoring for the appearance of anti-HLA Abs should be adopted after transplantation, even in patients without anti-HLA Abs prior to the transplantation.     

Intravenous immunoglobulins and rituximab therapy for severe transplant glomerulopathy in chronic antibody‐mediated rejection: a pilot study

Outcome of patients with transplant glomerulopathy (TG) is poor. Using B‐cell targeting molecules represent a rational strategy to treat TG during chronic antibody‐mediated rejection. In this pilot study, 21 patients with this diagnosis received four doses of intravenous immunoglobulins and two doses of rituximab (IVIG/RTX group). They were retrospectively compared with a untreated control group of 10 patients. At 24 months post‐biopsy, graft survival was similar and poor between the treated and the untreated group, 47% vs. 40%, respectively, p = 0.69. This absence of response of IVIG/RTX treatment was observed, regardless the phenotype of TG. Baseline estimated glomerular filtration rate (eGFR) and decline in eGFR during the first six months after the treatment were risk factors associated with 24‐month graft survival. The IVIG/RTX therapy had a modest effect on the kinetics of donor‐specific alloantibodies at M24, compared to the untreated group, not associated with an improvement in graft survival. The mean number of adverse events per patient was higher in the IVIG/RTX group than in the control group (p = 0.03). Taken together, IVIG/RTX treatment for severe TG during chronic antibody‐mediated rejection does not seem to change the natural history of TG and is associated with a high incidence of adverse events.     

IVIG and rituximab for treatment of chronic antibody‐mediated rejection: a prospective study in paediatric renal transplantation with a 2‐year follow‐up

Chronic antibody‐mediated rejection (AMR) is the major cause of late renal allograft loss. There is, however, no established treatment for this condition. We report the results of a prospective pilot study on an antihumoral therapy (AHT) consisting of high‐dose intravenous immunoglobulin G (IVIG) and rituximab in 20 paediatric renal transplant recipients. Donor‐specific HLA antibodies (HLA DSA) were quantified by Luminex‐based bead array technology. Loss of eGFR decreased significantly from 7.6 ml/min/1.73 m² during 6 months prior to AHT to 2.1 ml/min/1.73 m² (P = 0.0013) during 6 months after AHT. Fourteen patients (70%) responded: nine of nine patients (100%) without and five of 11 (45%) with transplant glomerulopathy (P = 0.014). C4d positivity in PTC decreased from 40 ± 18.5% in the index biopsy to 11.6 ± 12.2% (P = 0.002) in the follow‐up biopsy. In four of nine biopsies (44%) C4d staining turned negative. During 2 years of follow‐up, the median loss of eGFR in each of the four 6‐month periods remained significantly lower compared with prior to AHT. Class I DSA declined in response to AHT by 61% (p = 0.044), class II DSA by 63% (p = 0.033) 12 months after intervention. AHT with IVIG and rituximab significantly reduces or stabilizes the progressive loss of transplant function in paediatric patients with chronic AMR over an observation period of 2 years, apparently by lowering circulating DSA and reducing intrarenal complement activation.     

Human pregnancy and generation of anti‐angiotensin receptor and anti‐perlecan antibodies

Non‐HLA antibodies against the angiotensin II type 1 receptor (AT₁R) and the C‐terminal fragment of perlecan (i.e., LG3) are associated with the development of renal allograft rejection. It is currently unknown how humans develop anti‐AT₁R or anti‐LG3 antibodies. The aim of this study was to investigate whether pregnancy—as a model of sensitization to polymorphic proteins—induces anti‐AT₁R and/or anti‐LG3 antibodies. We included 104 samples from women obtained after physiologic full‐term pregnancy and 80 samples from healthy nonsensitized controls (40 women and 40 men). Both anti‐AT₁R and anti‐LG3 antibody levels were lower in pregnancy samples than in controls (both P < 0.05). By multivariate analysis, male gender was an independent predictor for high anti‐AT₁R antibody levels (OR 3.66, P = 0.04) and pregnancy was predictive for low anti‐LG3 antibody levels (OR 6.53, P = 0.0001). There was no correlation of anti‐AT₁R with anti‐LG3 antibody levels, either in the pregnancy or in the control samples (r² ≤ 0.03, P ≥ 0.26). In conclusion, physiologic full‐term pregnancy does not induce anti‐AT₁R or anti‐LG3 antibodies and may even lower their levels. Therefore, anti‐AT₁R and anti‐LG3 antibodies are likely not caused by allosensitization. The lack of correlation of anti‐AT₁R with anti‐LG3 antibodies suggests different mechanisms of generation, which remain to be elucidated.     

The possible critical role of T‐cell help in DSA‐mediated graft loss

In this review, we discuss a possible central role of T‐cell help in severe forms of graft damage mediated by donor‐specific HLA antibodies (DSA). Some kidney transplant recipients with pretransplant DSA show a high graft failure rate, whereas in other patients DSA do not harm the transplanted kidney and in most cases, disappear shortly after transplantation. Analyzing 80 desensitized highly immunized kidney transplant recipients and another multicenter cohort of 385 patients with pretransplant HLA antibodies, we reported recently that an ongoing T‐cell help from an activated immune system, as measured by an increased level of soluble CD30 in serum, might be necessary for the DSA to exert a deleterious effect. Patients positive for both pretransplant DSA and sCD30 appear to require special measures, such as the elimination of DSA from the circulation, potent immunosuppression, good HLA‐matching, and intense post‐transplant monitoring, whereas exclusion of DSA‐positive patients from transplantation in the absence of high sCD30 may not be justified in all cases, even if the pretransplant DSA are strong and complement‐activating.     

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.