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In ABO blood group incompatible kidney transplantation (ABO-I), potential issues on acute antibody-mediated rejection (ABMR) remain to be solved. This study aimed to assess the risk factors of acute ABMR using recipient- or donor-derived specimens. Quantitative analysis of A/B antigen expression was conducted in 104 donor kidney tissues (Kt), platelets (Plt), and red blood cells (RBC) by immunohistochemical staining or flow cytometry (FCM). ABO-I pre-transplant recipient serum samples (ABMR = 12, non-ABMR = 27) were extracted by propensity score matching. Anti-A antibody titers of IgM, IgG and IgG subclasses, and C1q binding ability (%) on antibody were measured using RBC-FCM. No association was observed between ABMR and A/B antigen expression levels in donor’s Plt, RBC, or Kt. In recipient’s sample, C1q-IgG binding ability was significantly higher in the ABMR group than in the non-ABMR group (C1q−IgG: 9.04% vs. 5.93% p = 0.049). Neither the A/B antigen expression level in donors (grafts) nor anti-blood group IgG/IgM antibodies in recipient sera before desensitization seemed to influence ABMR incidence in ABO-I. In contrast, C1q-IgG binding ability could be a potential predictor for ABMR in ABO-I. [ABSTRACT FROM AUTHOR]

Given the risk of rejection, the presence of preformed donor specific antibodies (DSA) contraindicates transplantation in most allocation systems. However, HLA-Cw and -DP DSA escape this censorship. We performed a multicentric observational study, in which the objective was to determinate risk factors of acute antibody-mediated rejection (aABMR) in recipients transplanted with preformed isolated Cw- or DP-DSA. Between 2010 and 2019, 183 patients were transplanted with a preformed isolated Cw- or DP-DSA (92 Cw-DSA; 91 DP-DSA). At 2 years, the incidence of aABMR was 12% in the Cw-DSA group, versus 28% in the DP-DSA group. Using multivariable Cox regression model, the presence of a preformed DP-DSA was associated with an increased risk of aABMR (HR = 2.32 [1.21-4.45 (p = 0.001)]) compared with Cw-DSA. We also observed a significant association between the DSA's MFI on the day of transplant and the risk of aABMR (HR = 1.09 [1.08-1.18], p = 0.032), whatever the DSA was. Interaction term analysis found an increased risk of aABMR in the DP-DSA group compared with Cw-DSA, but only for MFI below 3,000. These results may plead for taking these antibodies into account in the allocation algorithms, in the same way as other DSA. [ABSTRACT FROM AUTHOR]

Given the risk of rejection, the presence of preformed donor specific antibodies (DSA) contraindicates transplantation in most allocation systems. However, HLA-Cw and -DP DSA escape this censorship. We performed a multicentric observational study, in which the objective was to determinate risk factors of acute antibody-mediated rejection (aABMR) in recipients transplanted with preformed isolated Cw- or DP-DSA. Between 2010 and 2019, 183 patients were transplanted with a preformed isolated Cw- or DP-DSA (92 Cw-DSA; 91 DP-DSA). At 2 years, the incidence of aABMR was 12% in the Cw-DSA group, versus 28% in the DP-DSA group. Using multivariable Cox regression model, the presence of a preformed DP-DSA was associated with an increased risk of aABMR (HR = 2.32 [1.21–4.45 (p = 0.001)]) compared with Cw-DSA. We also observed a significant association between the DSA’s MFI on the day of transplant and the risk of aABMR (HR = 1.09 [1.08–1.18], p = 0.032), whatever the DSA was. Interaction term analysis found an increased risk of aABMR in the DP-DSA group compared with Cw-DSA, but only for MFI below 3,000. These results may plead for taking these antibodies into account in the allocation algorithms, in the same way as other DSA.

Introduction: Acute antibody-mediated rejection (ABMR) is an important threat to renal allograft survival in the early transplant period and the major single cause of graft loss in the first postoperative year. Semi-selective immunoadsorption (IA) remains one of the commonly applied treatments in ABMR, reducing allo-reactive antibody load. Adding double filtration plasmapheresis (DFPP) to IA might enhance therapeutic efficacy by also addressing innate humoral effectors like complement factors. Methods: Four patients with ABMR were treated with DFPP + IA. Clinical, histological, and immunological data and adverse events were retrospectively collected. Results: Here we present four high-risk treatment-refractory ABMR cases with C1q-binding donor-specific antibodies and histology of humoral rejection under treatment with DFPP + IA. While the earlier cases (within the first year after transplantation) showed marked reduction in ABMR severity and improvement of kidney function, the later cases did not respond accordingly. Late ABMR patient 1 stabilized, whereas late ABMR patient 2 did not respond to treatment. Conclusions: Our data support the consideration of DFPP + IA as a rescue treatment option in early, severe, high-risk ABMR cases in which other treatments failed. [ABSTRACT FROM AUTHOR]

Background: Acute antibody-mediated rejection (AMR) is an uncommon complication after ABO-compatible liver transplantation (LT). This case series investigated the clinicopathologic characteristics and outcomes of acute AMR in LT recipients with autoimmune liver disease (ALD). Patients and Methods: Among 809 patients who underwent LT from January 2014 to December 2020, four ALD patients developed AMR, which was confirmed based on clinical features, histopathology of liver biopsy, donor-specific antibodies (DSA) or panel reactive antibody (PRA) level. Therapies were individualized based on clinical manifestations. Results: The incidence of acute AMR was 0.49%, and the incidence of acute AMR with ALD and non-ALD recipients was 11.1% and 0%, respectively. Three patients had strongly positive HLA class II DSA, and one patient was with the PRA class I and II sensitivities, which were >80%; complement component 4d (C4d) staining was negative in all patients. The first patient underwent re-LT, and the other three patients had good prognoses with treatments. Conclusions: ALD patients are prone to acute AMR after LT, thus should be kept vigilant against the occurrence of acute AMR. [ABSTRACT FROM AUTHOR]

In ABO blood group incompatible kidney transplantation (ABO-I), potential issues on acute antibody-mediated rejection (ABMR) remain to be solved. This study aimed to assess the risk factors of acute ABMR using recipient- or donor-derived specimens. Quantitative analysis of A/B antigen expression was conducted in 104 donor kidney tissues (Kt), platelets (Plt), and red blood cells (RBC) by immunohistochemical staining or flow cytometry (FCM). ABO-I pre-transplant recipient serum samples (ABMR = 12, non-ABMR = 27) were extracted by propensity score matching. Anti-A antibody titers of IgM, IgG and IgG subclasses, and C1q binding ability (%) on antibody were measured using RBC-FCM. No association was observed between ABMR and A/B antigen expression levels in donor's Plt, RBC, or Kt. In recipient's sample, C1q-IgG binding ability was significantly higher in the ABMR group than in the non-ABMR group (C1q-IgG: 9.04% vs. 5.93% p = 0.049). Neither the A/B antigen expression level in donors (grafts) nor anti-blood group IgG/IgM antibodies in recipient sera before desensitization seemed to influence ABMR incidence in ABO-I. In contrast, C1q-IgG binding ability could be a potential predictor for ABMR in ABO-I., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Miwa, Iwasaki, Murotani, Okada, Nagasaka, Watarai, Takeda, Shizuku, Ashimine, Ishiyama, Maruyama and Kobayashi.)

Context: There are concerns regarding the use of induction immunosuppression during deceased donor renal transplantation in the coronavirus disease 2019 (COVID-19) pandemic and whether lower doses may suffice. Aims: We aimed to compare different induction immunosuppression regimens in deceased donor renal transplantation during the COVID-19 pandemic. Settings and Design: A multicenter, prospective observational study of patients undergoing deceased donor renal transplantation during the COVID-19 pandemic in Southern Kerala from April to June 2020 with differing induction immunosuppression and follow-up for at least 6 months. Subjects and Methods: Patients were from Government (Group A) and Private hospitals (Group B). Induction immunosuppression included low dose rituximab and/or low dose anti-thymocyte globulin in group A and higher dose induction with anti-thymocyte globulin or basiliximab in Group B. Graft function at 1 and 6 months, infectious complications, and cost of induction immunosuppression were compared. Statistical Analysis Used: Mood's median, Chi-square, Fisher Exact, and Mann–Whitney U test. Results: Of eleven deceased donor kidney transplantations, six were from Group A and 5 from Group B. Three in Group A and two in Group B had reversible antibody-mediated rejections. Median serum creatinine (interquartile range) in both groups at 1 month was 1.35 (1.1, 3) and 1.5 (1.1, 3.5) mg/dl, respectively, and by 6 months 1.5 (1.05, 2.33) mg/dl and 1.7 (1.15, 2.6) mg/dl, respectively. Two patients in Group A died, one due to Gram-negative septicemia at the 2nd month and the second by the 3rd month following a cardiovascular event. Mean cost of induction immunosuppression in both groups was INR 40,500 ± 22,827 and 107,200 ± 57,595 (P = 0.01). There was no difference in infection episodes in both groups. Rituximab in a dose of 100 mg was used as induction in 4 patients with comparable graft functions and cost-benefit with a mean cost of INR 33,750 ± 26,196 and Rs. 92,000 ± 53,715 in the rituximab and nonrituximab groups, respectively (P = 0.056). Conclusions: Low-dose induction immunosuppression in the COVID pandemic was cheaper with comparable graft functions at 1 and 6 months.

Context: There are concerns regarding the use of induction immunosuppression during deceased donor renal transplantation in the coronavirus disease 2019 (COVID-19) pandemic and whether lower doses may suffice. Aims: We aimed to compare different induction immunosuppression regimens in deceased donor renal transplantation during the COVID-19 pandemic. Settings and Design: A multicenter, prospective observational study of patients undergoing deceased donor renal transplantation during the COVID-19 pandemic in Southern Kerala from April to June 2020 with differing induction immunosuppression and follow-up for at least 6 months. Subjects and Methods: Patients were from Government (Group A) and Private hospitals (Group B). Induction immunosuppression included low dose rituximab and/or low dose anti-thymocyte globulin in group A and higher dose induction with anti-thymocyte globulin or basiliximab in Group B. Graft function at 1 and 6 months, infectious complications, and cost of induction immunosuppression were compared. Statistical Analysis Used: Mood's median, Chi-square, Fisher Exact, and Mann–Whitney U test. Results: Of eleven deceased donor kidney transplantations, six were from Group A and 5 from Group B. Three in Group A and two in Group B had reversible antibody-mediated rejections. Median serum creatinine (interquartile range) in both groups at 1 month was 1.35 (1.1, 3) and 1.5 (1.1, 3.5) mg/dl, respectively, and by 6 months 1.5 (1.05, 2.33) mg/dl and 1.7 (1.15, 2.6) mg/dl, respectively. Two patients in Group A died, one due to Gram-negative septicemia at the 2nd month and the second by the 3rd month following a cardiovascular event. Mean cost of induction immunosuppression in both groups was INR 40,500 ± 22,827 and 107,200 ± 57,595 (P = 0.01). There was no difference in infection episodes in both groups. Rituximab in a dose of 100 mg was used as induction in 4 patients with comparable graft functions and cost-benefit with a mean cost of INR 33,750 ± 26,196 and Rs. 92,000 ± 53,715 in the rituximab and nonrituximab groups, respectively (P = 0.056). Conclusions: Low-dose induction immunosuppression in the COVID pandemic was cheaper with comparable graft functions at 1 and 6 months. [ABSTRACT FROM AUTHOR]

BackgroundThe impact of de novo anti-HLA donor-specific alloantibodies (DSA) which develop after long-term liver transplantation (LT) remains controversial and unclear. The aim of this study was to investigate the role of de novo DSAs on the outcome in LT.MethodsWe did a systematic review and meta-analysis of observational studies published until Dec 31, 2019, that reported de novo DSA outcome data (≥1 year of follow-up) after liver transplant. A literature search in the MEDLINE/PubMed, EMBASE, Cochrane Library, Scopus and Web of Science Core Collection databases was performed.ResultsOf 5,325 studies identified, 15 fulfilled our inclusion criteria. The studies which reported 2016 liver transplant recipients with de novo DSAs showed an increased complication risk, i.e. graft loss and chronic rejection (OR 3.61; 95% CI 1.94–6.71, P < 0.001; I2 58.19%), and allograft rejection alone (OR 6.43; 95% CI: 3.17–13.04; P < 0.001; I2 49.77%); they were compared to patients without de novo DSAs. The association between de novo DSAs and overall outcome failure was consistent across all subgroups and sensitivity analysis.ConclusionsOur study suggested that de novo DSAs had a significant deleterious impact on the liver transplant risk of rejection. The routine detection of de novo DSAs may be beneficial as noninvasive biomarker-guided risk stratification.

Background: The impact of de novo anti-HLA donor-specific alloantibodies (DSA) which develop after long-term liver transplantation (LT) remains controversial and unclear. The aim of this study was to investigate the role of de novo DSAs on the outcome in LT. Methods: We did a systematic review and meta-analysis of observational studies published until Dec 31, 2019, that reported de novo DSA outcome data (≥1 year of follow-up) after liver transplant. A literature search in the MEDLINE/PubMed, EMBASE, Cochrane Library, Scopus and Web of Science Core Collection databases was performed. Results: Of 5,325 studies identified, 15 fulfilled our inclusion criteria. The studies which reported 2016 liver transplant recipients with de novo DSAs showed an increased complication risk, i.e. graft loss and chronic rejection (OR 3.61; 95% CI 1.94–6.71, P < 0.001; I2 58.19%), and allograft rejection alone (OR 6.43; 95% CI: 3.17–13.04; P < 0.001; I2 49.77%); they were compared to patients without de novo DSAs. The association between de novo DSAs and overall outcome failure was consistent across all subgroups and sensitivity analysis. Conclusions: Our study suggested that de novo DSAs had a significant deleterious impact on the liver transplant risk of rejection. The routine detection of de novo DSAs may be beneficial as noninvasive biomarker-guided risk stratification. [ABSTRACT FROM AUTHOR]

• An atypical clinical presentation of early antibody-mediated rejection in COVID era. • The radiological features mimicked SARS-CoV2 pneumonia, but tests were negative. • This is the first report of lung transplantation in the COVID era in Europe. • Decide whether to keep lung transplantation programmes open in a COVID Hospital. In addition to morbidity and mortality rate per se , COVID-19 outbreak leads to potential 'side effects', which are difficult to evaluate and predict. Lung transplantation is a consolidated treatment for end-stage chronic lung disease requiring significantly demanding management. Deciding whether to keep transplant programmes open during an epidemic of this size is not easy, as immunosuppressed subjects face the risk of infection and related mortality. Additionally, there is a chance for the patient's standard care process to be compromised. We report the case of a patient undergoing bilateral lung transplantation during the explosion of COVID-19 epidemic in Lombardy; he died from definite early acute antibody-mediated rejection, clinically (persistent high fever, unresponsive to treatment) and radiologically mimicking viral pneumonia but persistently negative for SARS-CoV-2. The diagnosis was difficult given this atypical presentation, confounded by global scenario. Grafts were procured from a donation after circulatory death donor in an uncontrolled setting and a donor-recipient transmission was possible. Our institute became a COVID-Hospital right during the first post-transplantation days. Radiological imaging had the same features of SARS-CoV-2 pneumonia. This is the first report of lung transplantation of the COVID-19 era in Europe. Our extremely fragile patient was COVID-19 free up to the end. Donor-recipient transmission is conceivable, but the risk should be assessed with respect to waiting list mortality. Ultimately, treating COVID-19 patients can be a resource-consuming activity but we decided to keep our centre open. [ABSTRACT FROM AUTHOR]

Introduction: Immunoadsorption (IA) represents a therapeutic option for acute antibody-mediated rejection (ABMR) after kidney transplantation. The addition of membrane filtration (MF) to enhance elimination of macromolecular components that potentially contribute to rejection, such as key complement component C1q and alloreactive IgM, may be an effective strategy to further improve its therapeutic efficiency. Results: Here we present 4 consecutive patients with episodes of HLA donor-specific antibody-positive ABMR nonresponsive to cycles of 6–16 sessions of IA treatment. Rejection episodes were characterized by severe microvascular injury (high-grade microcirculation inflammation and/or signs of thrombotic microangiopathy) and evidence of intense complement activation in peritubular capillaries (diffuse C4d-positivity). IA combined with MF led to substantial morphologic improvement (follow-up biopsies: g + ptc and C4d scores ≤1) and stabilization of allograft function. Conclusions: Our findings provide evidence for an effect of combination of IA + MF in refractory early acute/active ABMR in kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Background: The longitudinal relationship between HLA class I and II eplet mismatches, de novo donor-specific antibodies (dnDSA) development, and acute rejection after transplantation in childhood is unknown. Methods: Eplet mismatches at HLA class I and II loci were calculated retrospectively for each donor/recipient pair transplanted between 2005 and 2015 at a single Australian center. Logistic regression analyses were conducted to determine the association between the number of eplet mismatches, dnDSA, and acute rejection. Results: The cohort comprised 59 children (aged 0–18 years) who received their first kidney allograft and were followed for median (interquartile range) 4.5 (± 2.6) years. Overall, 32% (19/59) developed dnDSA (class I 3% (2/59), class II 14% (8/59), 15% class I and II (9/59)), and 24% (14/59) developed biopsy-proven acute rejection. Every unit increase in class I and II eplet mismatches corresponded to an increase in risk of class I (odds ratio (OR) 1.22, 95% CI 1.07–1.39, p < 0.01) and class II (OR 1.06, 95% CI 1.01–1.11, p = 0.02) dnDSA development. Compared with recipients without dnDSA, class I and II dnDSA were associated with direction of effect towards increased risk of acute cellular rejection (class I: OR 5.87, 95% CI 0.99–34.94, p = 0.05; class II: OR 12.00, 95% CI 1.25–115.36, p = 0.03) and acute antibody-mediated rejection (class I: OR 25.67, 95% CI 3.54–186.10, p < 0.01; class II: OR 9.71, 95% CI 1.64–57.72, p = 0.01). Conclusions: Increasing numbers of HLA class I or II eplet mismatches were associated with the development of dnDSA. Children who developed dnDSA were also more likely to develop acute rejection compared with children without dnDSA. [ABSTRACT FROM AUTHOR]

A 56-year-old man who had undergone cadaveric kidney transplantation 21 months earlier was admitted to our hospital for a protocol biopsy; he had a serum creatinine level of 1.2 mg/dL and no proteinuria. Histological features showed two distinct entities: (i) inflammatory cell infiltration, in the glomerular and peritubular capillaries and (ii) focal, aggressive tubulointerstitial inflammatory cell infiltration, predominantly plasma cells, with mild tubulitis (Banff 13 classification: i2, t1, g2, ptc2, v0, ci1, ct1, cg0, cv0). Immunohistological studies showed mildly positive C4d immunoreactivity in the peritubular capillaries. The patient had donor specific antibody to human-leucocyte-antigen-DR53. We diagnosed him with subclinical antibody-mediated rejection accompanied by plasma cell-rich acute rejection. Both antibody-mediated rejection due to anti- human-leucocyte-antigen -DR53 antibodies and plasma cell-rich acute rejection are known to be refractory and have a poor prognosis. Thus, we started plasma exchange with intravenous immunoglobulin and rituximab for the former and 3 days of consecutive steroid pulse therapy for the latter. Three months after treatment, a follow-up allograft biopsy showed excellent responses to treatment for both histological features. This case report considers the importance of an early diagnosis and appropriate intervention for subclinical antibody-mediated rejection due to donor specific antibody to human-leucocyte-antigen-DR53 and plasma cell-rich acute rejection. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells have been implicated in graft dysfunction. Here, we formulated hypothesis that distinct patterns of expression NK cells markers correlated with acute rejection in kidney transplantation. Therefore, we studied the pattern of NK cell markers CD56, CD57, and CD16 in different compartments of biopsies obtained from recipients diagnosed with acute graft rejection, with or without donor-specific antibodies (DSA). DSA-negative biopsies-from patients with acute T-cell mediated rejection (aTCMR) had an increased expression of CD56+ and CD57+ cells ( P = 0.004 and P = 0.001) in the interstitial compartment in comparison with DSA-positive biopsies from patients acute antibody-mediated rejection (aABMR) with (aABMR C4d+) and without C4d deposition (aABMR C4d-). CD16+ cells was increased ( P = 0.03) in the glomerular compartment in DSA-positive biopsies. We assume that CD16+ expression and antibody-dependent cellular cytotoxicity (ADCC) in microvascular injury can be associated with aABMR. IFN-γ release from cytoplasmic granules of NK cell could be associated with aTCMR. Our findings suggest that NK cells need to be carefully evaluated because variations in NK cell marker expression might imply the involvement of different immune system pathways in graft rejection. [ABSTRACT FROM AUTHOR]

aAMR in renal allografts is uncommon and remains a challenge as it is often refractory to treatment modalities. Aggressive therapy is essential to reverse the rejection as it results in renal allograft loss in approximately 27-40% of cases. There are anecdotal case reports of use of bortezomib, a proteasome inhibitor in the treatment of resistant AMR cases in solid organ transplant recipients; however, the experience is limited. We herein report successful reversal of resistant aAMR in two pediatric patients with bortezomib. Patients were initially treated with IV methylprednisolone pulse therapy with IVIG and PP three times weekly for a total of 10 treatments. After the standard therapy used at our institution persistence of DSA associated with graft dysfunction prompted the use of bortezomib to further treat the rejection. We did not have any neurologic side effects, but one patient did experience significant infections after bortezomib infusions requiring prolonged antimicrobial therapy. The long-term outcome of both children was excellent with preservation of normal renal function and persistent reduction in DSA titers. [ABSTRACT FROM AUTHOR]

Herein, we report a complicated case of acute T-cell-mediated rejection ( ACR) accompanied by C4d-negative acute antibody-mediated rejection ( AMR) and cell debris in tubulus. A 32 year-old male was admitted for an episode biopsy with a serum creatinine ( S- Cr) level of 1.83 mg/d L and pyuria (20-29 white blood cells per high power field) 49 days following kidney transplantation. Histological features included three distinct entities, mainly, in one of the three specimens: 1) focal aggressive tubulointerstitial inflammatory cell infiltration with moderate tubulitis, 2) inflammatory cell infiltration in peritubular capillaries (including neutrophils) and glomerular capillaries, and 3) cell debris consisting mainly of neutrophils in tubulus. Laboratory examination revealed evidence of non-human leukocyte antigen donor-specific antibodies. However, urinary culture and gram staining were negative. Considering both the histological and laboratory findings, the patient was diagnosed with ACR accompanied by C4d-negative AMR and suspicion of a urinary tract infection ( UTI). The patient was treated for three consecutive days with steroid pulse therapy. The patient's S- Cr level decreased to ∼1.5 mg/d L following treatment and did not increase thereafter. A second biopsy 133 days following kidney transplantation showed an excellent response to treatment and revealed no evidence of rejection. This case report demonstrates the difficulty in the diagnosis of, and therapy for, the complicated pathological findings of ACR, AMR and suspicion of a UTI. [ABSTRACT FROM AUTHOR]

The purpose of this study is to examine whether postoperative antiblood type antibody rebound is attributed to kidney allograft rejection in ABO blood typeincompatible (ABO-I) living-related kidney transplantation (KTx). A total of 191 ABO-I recipients who received ABO-I living-related KTx between 2001 and 2013 were divided into two groups: Group 1 consisted of low rebound [(≦1:32), N = 170] and Group 2 consisted of high rebound [(≧1:64), N = 21], according to the levels of the rebounded antiblood type antibodies within 1 year after transplantation. No prophylactic treatment for rejection was administered for elevated antiblood type antibodies, regardless of the levels of the rebounded antibodies. Within 1 year after transplantation, T-cell-mediated rejection was observed in 13 of 170 recipients (13/170, 8%) in Group 1 and in 2 of 21 recipients (2/21, 10%) in Group 2 (Groups 1 vs. 2, P = 0.432). Antibody-mediated rejection was observed in 15 of 170 recipients (15/170, 9%) and 2 of 21 recipients (2/21, 10%) in Groups 1 and 2, respectively (P = 0.898). In this study, we found no correlation between the postoperative antiblood type antibody rebound and the incidence of acute rejection. We concluded that no treatment is necessary for rebounded antiblood type antibodies. [ABSTRACT FROM AUTHOR]

Background: Cardiac allograft vasculopathy (CAV) continues to be a limiting factor in long-term survival of heart transplant recipients (HTRs). Pathophysiologic and immunologic factors affecting CAV are complex, and criteria for early diagnosis remain elusive. Methods: We performed a retrospective analysis of the relationship between donor-specific antibody (DSA), C4d immunofluorescence, and the development of CAV. Results: We evaluated 330 endomyocardial biopsy (EMB) specimens from 112 cardiac grafts. Twenty-four (21%) of 112 grafts developed CAV, and 18 (75%) of 24 were positive for C4d. Patients with DSA (n = 51) against human leukocyte antigen class I (n = 5), II (n = 26), or both (n = 20) developed CAV at a rate of 40%, 38%, and 20% and a mean time to CAV of 89, 47, and 25 months, respectively. Of 61 grafts without DSA, only 13% developed CAV, with a mean time to CAV of 116 months. Conclusions: Compared with the general HTR population, patients with graft dysfunction and DSA or positive C4d on EMB show a statistically significant increased incidence of CAV and allograft failure, suggesting an antibody-mediated injury. The presence of pre- and posttransplant DSA, even in the absence of positive C4d immunofluorescence, may identify a group of HTRs at increased risk of developing CAV. [ABSTRACT FROM AUTHOR]

We report a case of plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. A 33-year-old man was admitted for an episode biopsy; he had a serum creatinine ( S- Cr) level of 5.7 mg/dL 1 year following primary kidney transplantation. Histological features included two distinct entities: (1) a focal, aggressive tubulointerstitial inflammatory cell (predominantly plasma cells) infiltration with moderate tubulitis; and (2) inflammatory cell infiltration (including neutrophils) in peritubular capillaries. Substantial laboratory examination showed that the patient had donor-specific antibodies for DQ4 and DQ6. Considering both the histological and laboratory findings, we diagnosed him with plasma cell-rich rejection accompanied by acute antibody-mediated rejection. We started 3 days of consecutive steroid pulse therapy three times every 2 weeks for the former and plasma exchange with intravenous immunoglobulin ( IVIG) for the latter histological feature. One month after treatment, a second allograft biopsy showed excellent responses to treatment for plasma cell-rich rejection, but moderate, acute antibody-mediated rejection remained. Therefore, we added plasma exchange with IVIG again. After treatment, allograft function was stable, with an S- Cr level of 2.8 mg/dL. This case report demonstrates the difficulty of the diagnosis of, and treatment for, plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. We also include a review of the related literature. [ABSTRACT FROM AUTHOR]

We investigated the relationship between preoperative anti- HLA antibodies (donor-specific antibody, DSA) and the graft survival rate in recipients who had or had not received rituximab (Rit) treatment. The subjects were categorized into four groups as follows: DSA+Rit−, n = 39; DSA−Rit−, n = 121; DSA+Rit+, n = 74; and DSA−Rit+, n = 47. We examined the influence of preoperative DSA on the incidence of graft rejection and the survival rate of recipients who had or who had not received rituximab before transplantation. The 6-month acute rejection rates based on graft biopsies were 39%, 19%, 15%, and 0% for the DSA+Rit−, DSA−Rit−, DSA+Rit+, and DSA−Rit+ groups. The rates of chronic antibody-mediated rejection after more than 6 months were 50%, 22%, 18%, and 0%. The 5-year graft survival rate was significantly lower in the DSA+Rit− group (84%) than in the other groups (95% for DSA−Rit−, 98% for DSA+Rit+, and 91% for DSA−Rit+). The rate of the appearance of de novo anti- HLA antibodies was higher in the groups that did not receive rituximab treatment. The rate of graft loss associated with chronic antibody-mediated rejection was also higher in the DSA+Rit− group than in the other groups ( P = 0.01). The presence of DSA and the administration of rituximab had strong impacts on not only short-term graft rejection, but also long-term graft rejection and its association with the graft survival time. [ABSTRACT FROM AUTHOR]

Background: Antibody-mediated rejection (AMR) after lung transplantation remains enigmatic, and there is no consensus on the characteristic clinical, immunologic and histologic features. Methods: We performed a retrospective, single-center cohort study and identified cases of acute AMR based on the presence of circulating donor-specific human leukocyte antigen (HLA) antibodies (DSA), histologic evidence of acute lung injury, C4d deposition and clinical allograft dysfunction. Results: We identified 21 recipients with acute AMR based on the aforementioned criteria. AMR occurred a median 258 days after transplantation; 7 recipients developed AMR within 45 days of transplantation. All patients had clinical allograft dysfunction, DSA, histology of acute lung injury and capillary endothelial C4d deposition. Fifteen recipients improved clinically and survived to hospital discharge, but 6 died of refractory AMR. One survivor had bronchiolitis obliterans syndrome at the time of AMR diagnosis; 13 of the 14 remaining survivors developed chronic lung allograft dysfunction (CLAD) during follow-up. Overall, 15 recipients died during the study period, and the median survival after the diagnosis of AMR was 593 days. Conclusions: Acute AMR can be a fulminant form of lung rejection, and survivors are at increased risk of developing CLAD. The constellation of acute lung injury, DSA and capillary endothelial C4d deposition is compelling for acute AMR in recipients with allograft dysfunction. This clinicopathologic definition requires validation in a multicenter cohort, but may serve as a foundation for future studies to further characterize AMR. [ABSTRACT FROM AUTHOR]

Objective: To study the effects and mechanisms of the imbalance in B cell-expressed nucleoside triphosphate diphosphohydrolase 1 (NTPDase 1)-induced ADP degradation on graft injury during acute antibody-mediated rejection (AMR). Methods: The acute AMR animal model was established in male NTPDase 1-wild-type Balb/c nude mice. The levels of NTPDase 1 in B cells and NTPDasel mRNA in grafted skin, changes in platelet activation markers and average platelet velocities were determined by luciferin/luciferase enzymatic, real-time fluorescent quantitative PCR, flow cytometry and inverted microscope. The pathological changes in grafted skin were observed by electron microscopy. The effects of pretreatment with different doses of exogenous NTPDase 1 on platelet activation and graft injury were studied. Results: The expression of B-cell NTPDase 1 was significantly increased at 30 min after the induction of acute AMR and restored to baseline levels after 7 days. The levels of NTPDase 1 mRNA in grafted skin were decreased at 30 min after the induction of acute AMR After the induction of acute AMR, the levels of platelet activation markers increased significantly, whereas the average platelet velocity significantly decreased. After pretreatment with exogenous NTPDase 1, the expression of platelet activation markers significantly decreased, the average velocity of platelets increased significantly, and the necrosis of grafted skin and inflammatory reaction significantly reduced. Conclusions: An imbalance in the NTPDase 1-induced degradation of extracellular ADP may be a major cause of graft injury in acute AMR. Pretreatment with exogenous NTPDase 1 may effectively inhibit platelet activation and protect grafted skin. [ABSTRACT FROM AUTHOR]

ute antibody-mediated rejections (aAMR) after renal transplantation are defined by rapidly deteriorating graft function, detection of donor-specific antibodies (DSA) and characteristic histological features. In adults, anti-rejection strategies comprise intravenous immunoglobulin (IVIG), steroid pulses, plasmapheresis and rituximab. Data of children with aAMR are scarce. We report four episodes of aAMR in three children (aged 10, 10 and 11 years respectively) occurring early after renal transplantation. Pre-transplant complement-dependent cytotoxicity crossmatches were negative; in the case of re-transplantation repeated antigens were excluded. Basic immunosuppression comprised cyclosporine A, MMF and steroids. All four rejection episodes were histologically proven and associated with acute renal failure. De novo DSAs were detected in two aAMRs; one patient was additionally tested positive for AT1-receptor antibodies. All aAMRs were treated with steroid pulses, tacrolimus, MMF, IVIG, plasmapheresis and one single dose of rituximab. Despite therapy one graft was lost; in the remaining three cases kidney function re-established within 1-8 weeks. At follow-up, 14, 15 and 22 months' post-rejection their GFRs were 65, 88 and 105 ml/min/1.73 m respectively. A combined therapy of steroid pulses, IVIG, plasmapheresis and rituximab is potentially effective in the treatment of aAMR in children. [ABSTRACT FROM AUTHOR]

Atsumi H, Asaka M, Kimura S, Imura J, Fujimoto K, Chikazawa Y, Nakagawa M, Okuyama H, Yamaya H, Moriyama M, Tanaka T, Suzuki K, Yokoyama H. A case of second renal transplantation with acute antibody-mediated rejection complicated with BK virus nephropathy. Clin Transplant 2010: 24 (Suppl. 22): 35–38. © 2010 John Wiley & Sons A/S. We reported a 40-year-old female case of second renal transplantation with antibody-mediated rejection (AMR) complicated by BK virus nephropathy. She started hemodialysis (HD) at the age of 17 because of IgA nephropathy. At the age of 18, she underwent living-donor kidney transplantation from her father, but two and a half years after transplantation, she developed chronic rejection. This time, she received cadaveric renal transplantation under the negative cross-match (AHG-LCT), and HLA-AB 1 mismatch and -DR 1 mismatch. Immunosuppressive therapy was initiated using the following four immunosuppressants: methylprednisolone, mycophenolate mofetil, cyclosporine, and basiliximab. However, renal graft showed delayed function, the biopsy showed glomerulitis (g2), endarteritis (v1), and cellular infiltration (ptc3) consisting mainly of mononuclear cells in the peritubular capillary with diffusely positive C4d and anti-SV 40 large T-antigen-positive renal tubular epithelial cells on post-operative day 19. The donor-specific antibody for HLA-B46 was proven by the LAB screen method. We performed plasma exchange three times and administered immunoglobulin (15 g in total). Then, methylprednisolone pulse therapy was added, and the serum creatinine (SCr) levels gradually decreased. On post-operative day 44, the patient was removed from HD and was discharged with SCr level of 3.3 mg/dL. [ABSTRACT FROM AUTHOR]

ABO-incompatible kidney transplantation is possible after pre-treatment with rituximab, intravenous immunoglobulin and basiliximab combined with tacrolimus, mycophenolate mofetil and prednisolone. We report on the first patient treated with this protocol who developed acute antibody-mediated rejection (Banff grade II with IgG deposits) caused by ABO antibodies (anti-B). Anti-rejection treatment with anti-B-specific immunoadsorption, intravenous immunoglobulin and methylprednisolone efficiently cleared deposited IgG from the kidney allograft and re-established normal kidney function. We suggest that ABO-incompatible kidney transplantation complicated by acute antibody-mediated rejection, caused by ABO antibodies, may successfully be treated with this regime. [ABSTRACT FROM PUBLISHER]

We report a case of tacrolimus vascular toxicity found on a protocol biopsy shortly after a deceased donor renal transplantation. The patient was immunologically high-risk and acute antibody-mediated rejection during post-transplant dialysis phase was suspected on the protocol biopsy. Although the patient was stable after treatment of rejection, a further examination showed a very rare but specific side-effect of tacrolimus. It is sometimes difficult to make a differential diagnosis during postoperative dialysis period among AMR, primary non-functioning, drug toxicity, infection or just prolonged recovery from the damage of a long agonal phase on the non-heart beating donor. Although the possibilities of coexistence of rejection or other causes such as infection have not been completely excluded, it is important to be aware of this unusual side effect of tacrolimus. [ABSTRACT FROM AUTHOR]

Although a majority of acute rejection (AR) in non-sensitized recipients is T-cell-mediated by primed T cells, recent studies have shown that antibody-mediated acute rejection occurs in 20–30% of AR, and that it is often refractory to conventional antirejection therapy; possibly leading to graft loss. We report a case of severe acute-hybrid rejection consisting of both features in a non-sensitized kidney recipient, which was rescued by the orchestration of antirejection therapies. A 33-yr-old Japanese male, with advanced-stage chronic kidney disease with an unknown etiology, underwent a HLA 3/6 mismatch and ABO-compatible living-related kidney transplantation preemptively. He had an excellent clinical course, except for initial cytomegalovirus infection, with good graft function [serum creatinine (sCr) 1.1 mg/dL]. Nine months later, his creatinine abruptly increased to 2.1 mg/dL, when graft biopsy revealed acute T cell-mediated rejection (ATMR) grade IA, and simultaneous acute antibody-mediated rejection (AAMR) grade I. Antirejeciton therapy, comprising methyl-prednisolone pulse and 15-deoxyspergualin, and second line rituximab and plasmapheresis, was ineffective. Moreover, histologically and clinically, the rejection status deteriorated (ATMR grade III and AAMR grade III, max sCr 4.0 mg/dL). Next, we administered muromonab CD3 and basiliximab, which could eradicate the complicated severe AR without opportunistic infection, even under the strong immunosuppression. The present case implies that high-grade combined rejection can respond to anti-CD 20 and anti-CD25 mAbs, without serious complication; however, post-operative, thorough appropriate monitoring of immunosuppression is important because its effects are limited. [ABSTRACT FROM AUTHOR]

Alloimmune reactions are, besides various infections, the major cause for impaired lung allograft function following transplant. Acute cellular rejection is not only a major trigger of acute allograft failure but also contributes to development of chronic lung allograft dysfunction. Analogous to other solid organ transplants, acute antibody-mediated rejection has become a recognized entity in lung transplant pathology. Adequate sensitivity and specificity in the diagnosis of alloimmune reactions in the lung can only be achieved by synoptic analysis of histopathologic, clinical, and radiological findings together with serologic and microbiologic findings., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Competing Interests: None declared by authors.

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.

Natural killer (NK) cells have been implicated in graft dysfunction. Here, we formulated hypothesis that distinct patterns of expression NK cells markers correlated with acute rejection in kidney transplantation. Therefore, we studied the pattern of NK cell markers CD56, CD57, and CD16 in different compartments of biopsies obtained from recipients diagnosed with acute graft rejection, with or without donor-specific antibodies (DSA). DSA-negative biopsies-from patients with acute T-cell mediated rejection (aTCMR) had an increased expression of CD56+ and CD57+ cells (P = 0.004 and P = 0.001) in the interstitial compartment in comparison with DSA-positive biopsies from patients acute antibody-mediated rejection (aABMR) with (aABMR C4d+) and without C4d deposition (aABMR C4d-). CD16+ cells was increased (P = 0.03) in the glomerular compartment in DSA-positive biopsies. We assume that CD16+ expression and antibody-dependent cellular cytotoxicity (ADCC) in microvascular injury can be associated with aABMR. IFN-γ release from cytoplasmic granules of NK cell could be associated with aTCMR. Our findings suggest that NK cells need to be carefully evaluated because variations in NK cell marker expression might imply the involvement of different immune system pathways in graft rejection., (© 2015 Steunstichting ESOT.)

Antibody-mediated rejection (AMR) caused by donor-specific anti-human leukocyte antigen antibodies (DSA) is widely accepted to be a risk factor for decreased graft survival after kidney transplantation. This entity also plays a pathogenic role in other solid organ transplants as it appears to be an increasingly common cause of heart graft dysfunction and an emerging issue in lung transplantation. In contrast, the liver appears relatively resistant to DSA-mediated injury. This "immune-tolerance" liver property has been sustained by a low rate of liver graft loss in patients with preformed DSA and by the intrinsic liver characteristics that favor the absorption and elimination of DSA; however, alloantibody-mediated adverse consequences are increasingly being recognized, and several cases of acute AMR after ABO-compatible liver transplant (LT) have been reported. Furthermore, the availability of new solid-phase assays, allowing the detection of low titers of DSA and the refinement of objective diagnostic criteria for AMR in solid organ transplants and particularly in LT, have improved the recognition and management of this entity. A cost-effective strategy of DSA monitoring, avoidance of class II human leukocyte antigen mismatching, judicious immunosuppression attached to a higher level of clinical suspicion of AMR, particularly in cases unresponsive to conventional anti-rejection therapy, can allow a rational approach to this threat.

The purpose of this study is to examine whether postoperative antiblood type antibody rebound is attributed to kidney allograft rejection in ABO blood type-incompatible (ABO-I) living-related kidney transplantation (KTx). A total of 191 ABO-I recipients who received ABO-I living-related KTx between 2001 and 2013 were divided into two groups: Group 1 consisted of low rebound [(≦1:32), N = 170] and Group 2 consisted of high rebound [(≧1:64), N = 21], according to the levels of the rebounded antiblood type antibodies within 1 year after transplantation. No prophylactic treatment for rejection was administered for elevated antiblood type antibodies, regardless of the levels of the rebounded antibodies. Within 1 year after transplantation, T-cell-mediated rejection was observed in 13 of 170 recipients (13/170, 8%) in Group 1 and in 2 of 21 recipients (2/21, 10%) in Group 2 (Groups 1 vs. 2, P = 0.432). Antibody-mediated rejection was observed in 15 of 170 recipients (15/170, 9%) and 2 of 21 recipients (2/21, 10%) in Groups 1 and 2, respectively (P = 0.898). In this study, we found no correlation between the postoperative antiblood type antibody rebound and the incidence of acute rejection. We concluded that no treatment is necessary for rebounded antiblood type antibodies., (© 2014 Steunstichting ESOT.)