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There are conflicting data about the role of transplant nephrectomy and immunosuppression withdrawal on the development of allosensitization and the impact on re-transplantation. We divided 109 first graft recipients into two groups according to whether they underwent nephrectomy (NX+, n = 61) or their graft was left in situ (NX-, n = 48). Sera were assessed for HLA-A/B/Cw/DR/DQ antibodies at the time of NX/transplant failure and after 3, 6, 12, 24 months. The NX+ group showed a higher rate of donor specific antibody (DSA) and non-DSA human leukocyte antigen (HLA) antibody production at all the time points. Multivariable analysis showed that nephrectomy was a strong, independent risk factor for the development of DSAs after 12 and 24 months (P = 0.005 and 0.008). In the NX- group, low tacrolimus levels correlated with DSA formation (AUC 0.817, P = 0.002; best cut-off level 2.9 ng/ml). Analysis with a standardized pool of UK donors showed a more difficult grade of HLA matchability following nephrectomy compared with the NX- group. Nephrectomy is followed by the long-term production of DSA and non-DSA HLA antibodies and negatively impacts on the chances of finding a HLA-compatible kidney. Tacrolimus levels ≥3 ng/ml are protective against the development of allosensitization and could facilitate re-transplantation in the NX- group., (© 2019 Steunstichting ESOT.)

Aim: The impact of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) on living donor liver transplantation (LDLT) is unclear. The aim of this study was to investigate the association between DSAs and short-term outcomes in LDLT recipients, and to clarify the clinical impact of DSAs., Method: Anti-HLA antibodies were screened in preoperative serum samples taken from 40 liver transplant recipients at Ehime University (Toon, Japan) between August 2001 and July 2015. Screening was carried out using the Flow-PRA method, and DSAs were detected in anti-HLA antibody-positive recipients using the Luminex single-antigen identification test. A mean fluorescence intensity of 1000 was used as the cut-off for positivity. We retrospectively reviewed the clinical courses of patients who were DSA-positive to elucidate early clinical manifestations in LDLT recipients., Results: Fifteen (12 female and 3 male) patients (38%) had anti-HLA antibodies. Eight of the 15 anti-HLA antibody-positive patients were positive for DSAs, and all were women. The 90-day survival rate of DSA-positive patients (50%) was significantly lower than that of DSA-negative patients (84.4%) (0.0112; Wilcoxon test). On univariate analysis, the DSA-positive rate was significantly higher in the 90-day mortality group. Postoperatively, the incidence of acute cellular rejection was higher in DSA-positive than DSA-negative patients. Thrombotic microangiopathy developed only in DSA-positive patients. We found no relationship between DSA status and bile duct stricture., Conclusion: Preformed DSAs could be associated with elevated 90-day mortality in LDLT recipients. Further large-scale studies are required to verify the risk associated with DSAs in LDLT., (© 2019 The Japan Society of Hepatology.)

Aim: Both donor-specific antibodies (DSA) and anti-angiotensin II type 1 receptor antibodies (AT1R-abs) have been associated with poor graft outcomes after kidney transplantation (KT). We aimed to understand the impact of pretransplant AT1R-abs with or without concomitant DSA on KT outcomes., Methods: Seventy-six patients transplanted in 2009 were studied. DSA (MFI > 1000) and/or AT1R-abs (>10UI) were detected by solid-phase assays in pre-KT sera. Multivariable Cox regression models were used to determine independent predictors of outcomes: acute rejection (AR) and graft failure., Results: At transplant, 48 patients were AT1R-abs (-)/DSA (-), 12 AT1R-abs (+)/DSA (-), 9 AT1R-abs (-)/DSA (+) and 7 AT1R-abs (+)/DSA (+). Incidence of acute rejection at 1-year increased from 6% in AT1R-abs (-)/DSA (-), to 35% in AT1R-abs (+)/DSA (-), 47% in AT1R-abs (-)/DSA (+) and 43% in AT1R-abs (+)/DSA (+) (P < 0.001). No difference in DSA strength and C1q-binding ability was observed between AT1R-abs (-) /DSA (+) and AT1R-abs (+)/DSA (+) patients. Graft survival at 6-years was the lowest in AT1R-abs (+)/DSA (+) (57%), followed by AT1R-abs (+)/DSA (-) (67%), and higher in AT1R-abs (-)/DSA (-) (94%) and AT1R-abs (-)/DSA (+) (89%) patients (P = 0.012). AT1R-abs (+)/DSA (-) (HR = 6.41, 95% CI: 1.43-28.68; P = 0.015) and AT1R-abs (+)/DSA (+) (HR = 7.75, 95% CI: 1.56-38.46; P = 0.012) were independent predictors of graft failure., Conclusion: Acute rejection incidence and graft failure were associated with both DSA and AT1R-abs. These results demonstrate a proper negative effect of AT1R-abs on graft outcomes, besides a synergistic one with DSA. Pretransplant AT1R-abs should be acknowledged to better stratify patients' immunological risk., (© 2018 Asian Pacific Society of Nephrology.)

This article reviews the current evidence to classify donor-specific antibodies (DSAs) using Food and Drug Administration-National Institutes of Health Biomarkers, EndpointS, and other Tools (BEST) resource terms as diagnostic, prognostic, predictive, monitoring, and risk biomarkers for graft rejection. The emphasis is on DSA characteristics, including the DSA levels determined by mean fluorescence intensity and/or titers, the ability to activate a complement cascade (C1q, C3d, and C4d binding), and specific IgG subclasses to define distinct roles of DSAs as biomarkers in clinical practice. In addition, technical limitation of DSA testing is discussed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Luminex single antigen bead assays revolutionized human leukocyte antigen (HLA) antibody detection owing to their superior sensitivity compared to conventional methods. Nevertheless, the advent of higher sensitivity came at the expense of difficulty in clinical decision-making, since not all luminex detectable antibodies are clinically relevant. Therefore, new tools such as C1q/C3d assays and IgG subclass analysis emerged with the aim to discriminate the inert antibodies from the deleterious ones. Here, we provide an overview on the technical challenges related to these different HLA antibody detection systems and briefly refer to the recent literature regarding the clinical relevance of these assays, mainly in the field of kidney transplantation., (© 2018 Steunstichting ESOT.)

Aim: To evaluate the role of a therapeutic regimen with plasma exchange, intravenous immunoglobulins and rituximab in chronic-active antibody-mediated rejection (cAMR) settings., Methods: We compared 21 kidney transplant recipients (KTRs) with a diagnosis of cAMR in a retrospective case-control analysis: nine KTRs treated with plasmapheresis, intravenous immunoglobulins and rituximab (PE-IVIG-RTX group) vs 12 patients (control group) not treated with antibody-targeted therapies. We examined kidney survival and functional outcomes 24 mo after diagnosis. Histological features and donor-specific antibody (DSA) characteristics (MFI and C1q-fixing ability) were also investigated., Results: No difference in graft survival between the two groups was noted: three out of nine patients in the PE-IVIG-RTX group (33.3%) and 4/12 in the control group (33.3%) experienced loss of allograft function at a median time after diagnosis of 14 mo (min 12-max 18) and 15 mo (min 7-max 22), respectively. Kidney functional tests and proteinuria 24 mo after cAMR diagnosis were also similar in both groups. Only microvascular inflammation (glomerulitis + peritubular capillaritis score) was significantly reduced after PE-IVIG-RTX in seven out of eight patients (87.5%) in the PE-IVIG-RTX group (median score 3 in pre-treatment biopsy vs 1.5 in post-treatment biopsy; P = 0.047), without any impact on kidney survival and/or DSA characteristics. No functional or histological parameter at diagnosis was predictive of clinical outcome., Conclusion: Our data showed no difference in the two year post-treatment outcome of kidney grafts treated with PE-IVIG-RTX for cAMR diagnosis, however there were notable improvements in microvascular inflammation in post-therapy protocol biopsies. Further studies, especially involving innovative therapeutic approaches, are required to improve the management and long-term results of this severe condition., Competing Interests: Conflict-of-interest statement: On behalf of all authors, the corresponding author states that there is no conflict of interest.

Antibody-mediated rejection (AMR) is the main barrier to renal graft survival, and mouse renal AMR models are important to study this process. Current mouse models are established by priming the recipient to donor skin for over 7 days before kidney transplantation. The robustness of AMR in these cases is too strong to mimic clinical AMR and it is unclear why altering the priming times ranging from 7 to 91 days fails to reduce the AMR potency in these models. In the present study, we found that the donor-recipient combination and skin graft size were determinants of donor-specific antibody (DSA) development patterns after skin transplantation. DSA-IgG was sustained for over 100 days after skin challenge, accounting for an identical AMR robustness upon different skin priming times over 7 days. However, decreasing the skin priming time within 7 days attenuated the robustness of subsequent renal allograft AMR in C3H to Balb/c mice. Four-day skin priming guaranteed that recipients develop acute renal AMR mixed with a high ratio of graft-infiltrating macrophages, renal grafts survived for a mean of 6.4 ± 2.1 days, characterized by typical AMR histological changes, such as glomerulitis, peritubular capillary (PTC) dilation, and capillaritis, deposition of IgG and C3d in PTCs, but less prevalence of microthrombus, whereas the cellular rejection histological change of tubulitis was absent to mild. With this scheme, we also found that the renal AMR model can be developed using common mouse strains such as C57BL/6 and Balb/c, with mean prolonged renal graft survival times of 14.4 ± 5.0 days. Finally, we proved that donor-matched skin challenge after kidney transplantation did not strongly affect DSA development and kidney graft outcome. These findings may facilitate an understanding and establishment of mouse renal allograft AMR models and promote AMR-associated studies.

Herein, we report a case of antibody-mediated rejection (ABMR) due to anti-HLA-DQ antibody after pregnancy and delivery in a female kidney transplant recipient. A 34-year-old female recipient was admitted at 2 years after delivery for an examination of an elevated serum creatinine (S-Cr) level. The patient had received a living kidney transplantation from her mother at 22 years of age, and her kidney graft function was almost stable. The episode biopsy showed peritubular capillaritis and transplant capillaropathy with C4d immunoreactivity in the peritubular capillaries. Additional examination revealed expression of a donor-specific antibody (DSA) against HLA-DQ5, leading to the diagnosis of chronic active ABMR. Intravenous immunoglobulin, plasma exchange, and rituximab were administered, and her S-Cr level was maintained stable. This case demonstrates a possible relationship between pregnancy/delivery and development of ABMR due to a de novo DSA in a female kidney transplant recipient., (© 2018 Asian Pacific Society of Nephrology.)

The presence of donor-specific antibodies directed against human leukocyte antigen significantly influences renal transplant because of antibody-mediated rejection. We performed the screening of pre-renal transplant patients for preformed anti-HLA antibodies using anti-human globulin augmented-complement-dependent lymphocytotoxicity crossmatch (AHG-CDCXm), luminex donor-specific crossmatch (LumXm) and HLA antibody screening. Seven hundred and fifty-four patients were assessed for LumXm. HLA antibody screening was possible in 325 out of 754 cases. All the three investigations viz. CDCXm, HLA antibody screening and LumXm was performed in 325 patients. All CDCXm positive patients (10/325, 3.08%) were also positive with LumXm and HLA antibody screen whereas 14 cases (4.31%) with CDCXm negative were positive with luminex-based assays. LumXm and HLA antibody screening were both positive in 24 (7.38%) cases, LumXm and HLA antibody screening were both negative in 275 (84.63%) cases and LumXm negative and HLA antibody screening was positive in 22 (6.76%) cases. However, there were four cases (1.23%) which were positive in LumXm in spite of being negative in HLA antibody testing. Single Antigen Bead (SAB) assay was performed in all patients positive for HLA antibody test. We suggest that LumXm is a useful and sensitive technique for the detection of anti-HLA antibodies in pre-transplant renal patients. However, other measures such as luminex antibody screen, SAB assay, history of the donor, and the class of antibodies involved should be taken into consideration for pre-transplant work up of renal patients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Acceptable outcomes of donor-specific antibody (DSA)-positive living kidney transplantation (LKT) have recently been reported. However, LKT in crossmatch (XM)-positive patients remains at high-risk and requires an optimal desensitization protocol. We report our intermediate-term outcomes of XM-positive LKT vs. XM-negative LKT in patients who underwent LKT between January 2012 and June 2015 in our institution. The rate of acute antibody-mediated rejection (ABMR) within 90 days postoperation, graft function, and patient, and graft survival rates at 4 years were investigated. Patients were divided into three groups: XM-DSA- (n = 229), XM-DSA+ (n = 36), and XM + DSA+ (n = 15). The XM + DSA+ group patients underwent desensitization with high-dose intravenous immunoglobulin, plasmapheresis, and rituximab. The rates of ABMR within 90 days in the XM-DSA-, XM-DSA+, and XM + DSA+ groups were 1.3%, 9.4%, and 60.0%, respectively (P < 0.001). There were no significant differences in the graft function throughout the observational period, the 4-year patient or graft survival rates among three groups. This study showed that intermediate-term outcomes of XM-positive LKT were comparable to XM-negative LKT. However, our current desensitization protocol cannot avert ABMR within 90 days, and XM positivity is still a significant risk factor for ABMR. Further refinement of the current desensitization regimen is required., (© 2018 Steunstichting ESOT.)

Background and Objectives: The risk of de novo donor-specific antibody (dnDSA) development following BK viremia (BKV) or nephropathy (BKN) after kidney transplant remains unclear. We aimed to evaluate the relationships among dnDSA, BKV (BK blood PCR > 15 000 copies), BKN, antibody-mediated rejection (AMR), and allograft loss., Patients and Methods: We performed a retrospective cohort study of 904 solitary kidney transplant recipients transplanted between 10/2007 and 5/2014. Cox proportional hazards regression with time-dependent covariates were used to assess the relationships among BKN, isolated BKV, dnDSA, and the subsequent risk of AMR and allograft loss., Results: In multivariate analysis, we observed that BKN, but not BKV was a risk factor for dnDSA (HR, 3.18, P = .008). Of the patients with BK nephropathy, 14.0% (6/43) developed dnDSA, which occurred within 14 months of BK diagnosis. DnDSA in this setting remains a risk factor for subsequent AMR (HR 4.75, P = .0001) and allograft loss (HR 2.63, P = .018)., Conclusions: BKN is an independent risk factor for development of dnDSA. Improved understanding of the characteristics of patients with BKN who are at highest risk for development of dnDSA would be valuable to customize immunosuppression reduction in this population., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Antibody-mediated rejection is currently the leading cause of transplant failure. Prevailing dogma predicts that B cells differentiate into anti-donor-specific antibody (DSA)-producing plasma cells only with the help of CD4+ T cells. Yet, previous studies have shown that dependence on helper T cells decreases when high amounts of protein antigen are recruited to the spleen, two conditions potentially met by organ transplantation. This could explain why a significant proportion of transplant recipients develop DSA despite therapeutic immunosuppression. Using murine models, we confirmed that heart transplantation, but not skin grafting, is associated with accumulation of a high quantity of alloantigens in recipients' spleen. Nevertheless, neither naive nor memory DSA responses could be observed after transplantation of an allogeneic heart into recipients genetically deficient for CD4+ T cells. These findings suggest that DSA generation rather result from insufficient blockade of the helper function of CD4+ T cells by therapeutic immunosuppression. To test this second theory, different subsets of circulating T cells: CD8+, CD4+, and T follicular helper [CD4+CXCDR5+, T follicular helper cells (Tfh)], were analyzed in 9 healthy controls and 22 renal recipients. In line with our hypothesis, we observed that triple maintenance immunosuppression (CNI + MMF + steroids) efficiently blocked activation-induced upregulation of CD25 on CD8+, but not on CD4+ T cells. Although the level of expression of CD40L and ICOS was lower on activated Tfh of immunosuppressed patients, the percentage of CD40L-expressing Tfh was the same than control patients, as was Tfh production of IL21. Induction therapy with antithymocyte globulin (ATG) resulted in prolonged depletion of Tfh and reduction of CD4+ T cells number with depleting monoclonal antibody in murine model resulted in exponential decrease in DSA titers. Furthermore, induction with ATG also had long-term beneficial influence on Tfh function after immune reconstitution. We conclude that CD4+ T cell help is mandatory for naive and memory DSA responses, making Tfh cells attractive targets for improving the prevention of DSA generation and to prolong allograft survival. Waiting for innovative treatments to be translated into the clinical field ATG induction seems to currently offer the best clinical prospect to achieve this goal.

Antibody-mediated rejection (AMR) is a pivotal cause of long-term graft failure following renal transplantation. De novo donor-specific antibody reduction is essential to prevent AMR and improve long-term graft survival in renal transplant recipients. Although the number of early AMR episodes can be successfully controlled by attenuating de novo donor-specific antibodies, the long-term outcomes are unsatisfactory. Numerous studies have focused on new strategies to reverse AMR, but the available evidence suggests that maintenance immunosuppressive agents play important roles. This article reviews data on the use of various maintenance immunosuppressive strategies in the management of AMR, with a focus on antibody-mediated kidney transplant rejection. Its aim is to help provide options benefitting long-term graft survival in renal transplant recipients.

Aim: To investigate the incidence, risk factors and clinical outcomes of acute antibody-mediated rejection (ABMR) after intestinal transplantation (ITx)., Methods: A retrospective single-center analysis was performed to identify cases of acute ABMR after ITx, based on the presence of donor-specific antibody (DSA), acute tissue damage, C4d deposition, and allograft dysfunction., Results: Acute ABMR was identified in 18 (10.3%) out of 175 intestinal allografts with an average occurrence of 10 d (range, 4-162) after ITx. All acute ABMR cases were presensitized to donor human leukocyte antigens class I and/or II antigens with a detectable DSA. A positive cross-match was seen in 14 (77.8%) cases and twelve of 18 patients (66.7%) produced newly-formed DSA following ITx. Histological characteristics of acute ABMR include endothelial C4d deposits, interstitial hemorrhage, and severe congestion with focal fibrin thrombin in the lamina propria capillaries. Multivariate analysis identified a liver-free graft and high level of panel reactive antibody as a significant independent risk factor. Despite initial improvement after therapy, eleven recipients (61.1%) lost transplant secondary to rejection. Of those, 9 (50%) underwent graft removal and 4 (22.2%) received second transplantation following acute ABMR. At an average follow-up of 32.3 mo (range, 13.3-76.4), 8 (44.4%) recipients died., Conclusion: Our results indicate that acute ABMR is an important cause of intestine graft dysfunction, particularly in a liver-exclusive graft and survivors are at an increased risk of developing refractory acute rejection and chronic rejection. More effective strategies to prevent and manage acute ABMR are needed to improve outcomes., Competing Interests: Conflict-of-interest statement: The author declares no conflict of interests for this article.

We sought to clarify the controversial issue of whether detecting low-level anti-donor-specific HLA antibody (HLA-DSA) by single-antigen flow-bead assay (SAFB) may have a potential role in reducing acute and chronic antibody-mediated rejection (AMR). We retrospectively studied the preoperative serum of ABO-compatible living kidney transplantation recipients transplanted between 2001 and 2004 by SAFB using a Luminex platform. HLA-DSA was detected only by SAFB in 24 patients, although all of them showed negative T-cell and B-cell complement-dependent cytotoxicity (CDC) crossmatches. The HLA-DSA patients went on to have surprisingly high levels of acute and chronic AMR despite being only weakly sensitized (acute AMR, 33.3%; chronic AMR, 41.7%). After 2005, we implemented SAFB routinely and any patient having a positive HLA-DSA was considered to be a desensitization candidate. The 52 patients found to have HLA-DSA underwent kidney transplantation after prior treatment with a single dose of rituximab (RIT) and three or four sessions of double-filtration plasmapheresis (DFPP) in addition to regimens commonly used between 2001 and 2004. After 2005, there was a significant reduction in the occurrence of acute and chronic AMR (acute AMR, 4.7%, P < 0.001; chronic AMR, 4.7%, P < 0.001). The 5-year graft survival rate also improved after implementing SAFB (83.3-98.1%, P = 0.032). The RIT/DFPP-induction protocol may improve graft survival even in patients with low-level DSA. [ABSTRACT FROM AUTHOR]

Background: The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial., Methods: We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA)., Results: We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 [4.53 to 9.59]; p < 0.001) for BOS and high-grade BOS (Stage ≥ 2) (HR = 5.76 [3.48 to 9.52]; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 [4.91 to 19.78]; p < 0.001)., Conclusions: Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Anti-HLA donor-specific antibodies (DSAs) cause acute and chronic antibody-mediated rejection (AMR). However, the clinical relevance of anti-HLA-C antibodies remains unclear. We evaluated the clinical relevance of the presence of anti-HLA-C DSA at day 0 in renal transplant recipients. In this retrospective, case-controlled study, 608 patients who underwent kidney transplantation between August 2008 and March 2012 were screened for the presence of isolated anti-HLA-C DSA at day 0. A total of 22 renal transplant recipients were selected and followed for a period of 1 year. AMR was classified according to the Banff classification. The 22 patients were compared with 88 immunized patients. Acute AMR was diagnosed in six patients (27.3%). The median level of DSA at day 0 was 1179 (530-17,941). The mean fluorescence intensity in the anti-C group was 4966 (978-17,941) in the AMR group and 981 (530-8012) in the group of patients without AMR. Acute AMR was diagnosed less frequently in the 88 immunized individuals (9.1%) than in the DSA anti-C group (p = 0.033). The level of DSA at day 0 was predictive for AMR (p = 0.017). Patients with a high level of pretransplant anti-HLA-C DSAs are likely to develop acute AMR during the first year after transplantation., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Animal models of antibody-mediated rejection (ABMR) may provide important evidence supporting proof of concept. We elicited donor-specific antibodies (DSA) by transfusion of donor blood (Brown Norway RT1(n) ) into a complete mismatch recipient (Lewis RT1(l) ) 3 weeks prior to kidney transplantation. Sensitized recipients had increased anti-donor splenocyte IgG1, IgG2b and IgG2c DSA 1 week after transplantation. Histopathology was consistent with ABMR characterized by diffuse peritubular capillary C4d and moderate microvascular inflammation with peritubular capillaritis + glomerulitis > 2. Immunofluorescence studies of kidney allograft tissue demonstrated a greater CD68/CD3 ratio in sensitized animals, primarily of the M1 (pro-inflammatory) phenotype, consistent with cytokine gene analyses that demonstrated a predominant T helper (TH )1 (interferon-γ, IL-2) profile. Immunoblot analyses confirmed the activation of the M1 macrophage phenotype as interferon regulatory factor 5, inducible nitric oxide synthase and phagocytic NADPH oxidase 2 were significantly up-regulated. Clinical biopsy samples in sensitized patients with acute ABMR confirmed the dominance of M1 macrophage phenotype in humans. Despite the absence of tubulitis, we were unable to exclude the effects of T cell-mediated rejection. These studies suggest that M1 macrophages and TH 1 cytokines play an important role in the pathogenesis of acute mixed rejection in sensitized allograft recipients., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The effectiveness of a tonsillectomy before kidney transplantation (KTx) in suppressing the recurrence of IgA nephropathy (IgAN) has never been studied. The aim of this study was to analyze the effectiveness of a preoperative tonsillectomy for preventing IgAN recurrence and to identify predictive risk factors for IgAN recurrence. Of the 462 recipients who underwent a KTx between 2006 and 2011, a total of 78 patients had biopsy-proven IgAN as their primary disease. Among these 78 patients, 28 patients (group 1) underwent a tonsillectomy and 50 patients (group 2) did not undergo a tonsillectomy before KTx. The time to recurrence was 15.5±8.7months, in group 1 and 20.2±18.6months in group 2. No significant difference was observed between the two groups (P=0.63). Using a multivariate Cox regression analysis, ABO incompatible KTx and acute rejection were associated with a lower incidence of recurrence (P=0.02 and 0.002 respectively). These results suggested that a preoperative tonsillectomy might not affect the recurrence of IgAN during a short-term follow-up period, whereas preoperative desensitization and the use of a higher steroid dose were effective for suppressing the recurrence of IgAN., (Copyright © 2013 Elsevier B.V. All rights reserved.)

De novo donor-specific antibody (dnDSA) develops in 15-25% of renal transplant recipients within 5 years of transplantation and is associated with 40% lower graft survival at 10 years. HLA epitope matching is a novel strategy that may minimize dnDSA development. HLAMatchmaker software was used to characterize epitope mismatches at 395 potential HLA-DR/DQ/DP conformational epitopes for 286 donor-recipient pairs. Epitope specificities were assigned using single antigen HLA bead analysis and correlated with known monoclonal alloantibody epitope targets. Locus-specific epitope mismatches were more numerous in patients who developed HLA-DR dnDSA alone (21.4 vs. 13.2, p < 0.02) or HLA-DQ dnDSA alone (27.5 vs. 17.3, p < 0.001). An optimal threshold for epitope mismatches (10 for HLA-DR, 17 for HLA-DQ) was defined that was associated with minimal development of Class II dnDSA. Applying these thresholds, zero and 2.7% of patients developed dnDSA against HLA-DR and HLA-DQ, respectively, after a median of 6.9 years. Epitope specificity analysis revealed that 3 HLA-DR and 3 HLA-DQ epitopes were independent multivariate predictors of Class II dnDSA. HLA-DR and DQ epitope matching outperforms traditional low-resolution antigen-based matching and has the potential to minimize the risk of de novo Class II DSA development, thereby improving long-term graft outcome., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Antibody-mediated rejection (AMR) after pancreas transplantation is a recently identified entity. We describe the incidence of, risk factors for, and outcomes after AMR, and the correlation of C4d immunostaining and donor-specific antibody (DSA) in the diagnosis of AMR. We retrospectively analyzed 162 pancreas transplants in 159 patients who underwent 94 pancreas allograft biopsies between 2006 and 2009. Univariate and multivariate analyses were performed to evaluate risk factors for pancreas graft AMR. One-year rejection rates and survival after rejection were calculated by Kaplan-Meier methods. AMR occurred in 10% of patients by 1-year posttransplant. Multivariate risk factors identified for AMR include nonprimary simultaneous pancreas-kidney (SPK) transplant, primary solitary pancreas (PAN) transplant and race mismatch. After pancreas rejection, patient survival was 100% but 20% (8 of 41) of pancreas grafts failed within 1 year. Graft survival after acute cellular rejection (ACR), AMR and mixed rejection was similar. Of biopsies that stained >5% C4d, 80% were associated with increased Class I DSA. In summary, AMR occurs at a measurable rate after pancreas transplantation, and the diagnosis should be actively sought using C4d staining and DSA levels in patients with graft dysfunction, especially after nonprimary SPK and primary PAN transplantation., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Donor-specific antibodies (DSA) in sera of sensitized transplant patients are often produced against the specific epitopes on mismatched HLA antigens. In this study, we selected sera from 30 kidney transplant patients with DSA and AMR to define DQ epitopes. Using adsorption and elution assays, we identified 18 antibody reaction patterns to define 6 new epitopes and to confirm 12 previously defined epitopes. In one patient case, one mismatched antigen produced 3 different antibodies and, in another, antibodies were produced against the alpha and beta chains of the same antigen. For some sera, a single epitope can explain reactions for 27 of the 29 DQ beads in the single antigen panel. Several studies highlighted the prevalence of anti-DQ antibodies. In 2011, Almeshari et al. observed DQ DSA in 34/46 (74%) of rejection episodes - 44 patients had DSA and 20 lost their graft due to AMR. Other studies have shown a high prevalence of anti-DQ antibodies and an association with adverse effects on the graft. We conclude that analysis of the epitopes of the DQ antibodies using Adsorption/Elution and testing on single antigen DQ beads helps to better understand the specificities and cross-reactions of DQ antibodies in transplant patients., (Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)