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Highly sensitized (HS) patients in need of kidney transplantation (KTx) typically spend a longer time waiting for compatible kidneys, are unlikely to receive an organ offer, and are at increased risk of antibody-mediated rejection (AMR). Desensitization using imlifidase, which is more rapid and removes total body immunoglobulin G (IgG) to a greater extent than other methods, enables transplantation to occur between HLA-incompatible (HLAi) donor-recipient pairs and allows patients to have greater access to KTx. However, when the project was launched there was limited data and clinical experience with desensitization in general and with imlifidase specifically. Hence, this Delphi methodology was used to reach a consensus from a multi-disciplinary team (MDT) of experts from 15 countries on the management of HS patients undergoing imlifidase HLAi from a deceased donor (DD) KTx. This Delphi consensus provides clinical practice guidance on the use of imlifidase in the end-to-end management of HS patients undergoing an HLAi DD KTx and supports centers in the development of guidelines for the utilization and integration of imlifidase into clinical practice., 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 © 2025 Furian, Heemann, Bengtsson, Bestard, Binet, Böhmig, Boletis, Briggs, Claas, Couzi, Cozzi, Crespo, De Vries, Diekmann, Durlik, Glotz, Helantera, Jackson, Jordan, Kuypers, Lefaucheur, Legendre, Lorant, Maggiore, Mamode, Marinaki, Massart, Müller, Oberbauer, Renders, Roelen, Taupin, Viklický, Vittoraki, de Weerd and Naesens.)

Background: About 10-20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with graft thrombosis., Methods: We conducted a multicenter study including 899 pancreas transplant recipients between 2000 and 2018. Early pancreas failure due to complete thrombosis, long-term pancreas, kidney and patient survivals were analyzed and adjusted to donor, recipient and perioperative variables using a multivariate cause-specific Cox model stratified to transplant centers., Results: Pancreas from donors with history of hypertension (6.7%), as well as with high body mass index (BMI), were independently associated with an increased risk of pancreas failure within the first 30 post-operative days (respectively, HR= 2.57, 95% CI from 1.35 to 4.89 and HR= 1.11, 95% CI from 1.04 to 1.19). Interaction term between hypertension and BMI was negative. Donor hypertension also impacted long-term pancreas survival (HR= 1.88, 95% CI from 1.13 to 3.12). However, when pancreas survival was calculated after the postoperative day 30, donor hypertension was no longer a significant risk factor (HR= 1.22, 95% CI from 0.47 to 3.15). A lower pancreas survival was observed in patients receiving a pancreas from a hypertensive donor without RAAS (Renin Angiotensin Aldosterone System) blockers compared to others (50% vs 14%, p < 0.001). Pancreas survival was similar among non-hypertensive donors and hypertensive ones under RAAS blockers., Conclusion: Donor hypertension was a significant and independent risk factor of pancreas failure. The well-known pathogenic role of renin-angiotensin-aldosterone system seems to be involved in the genesis of this immediate graft failure., 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 Masset, Branchereau, Buron, Karam, Rabeyrin, Renaudin, Le Borgne, Badet, Matillon, Legendre, Glotz, Antoine, Giral, Dantal, Cantarovich and DIVAT Consortium.)

The microvascular endothelium of the renal transplant is the first site of graft interaction with the host immune system and is often injured in chronic Antibody Mediated Rejection (AMR). Microvascular inflammation is an independent determinant of AMR and heightens endothelial expression of HLA molecules thereby increasing the possibility of Donor Specific Antibody (DSA) binding. Endothelial cells produce IL-6 in the steady-state and this is increased by inflammation or by HLA-DR antibody binding in an allogeneic setting. Because IL-6 has been implicated in AMR, IL-6 blockade is currently under investigation as a therapeutic target. To further understand the role of IL-6 in endothelial cell immunogenicity, we have examined whether humanized antibody blockade of IL-6 altered endothelial cell interactions with allogeneic PBMC and after anti-HLA or DSA binding to endothelial cells in an in vitro human experimental model. Soluble factors, endothelial phenotype, Stat-3 activation, CD4 + -T differentiation, and C4d deposition were examined. Blockade of IL-6 reduced endothelial cell secretion of IL-6 and of the monocyte chemoattractant MCP-1. Pre-activation of endothelial cells by anti-HLA or DSA binding increased IL-6 secretion, that was further increased by concurrent binding of both antibodies and this was inhibited by IL-6 blockade. Activation of Stat-3 in CD4 + -T mediated by soluble factors produced in endothelial-PBMC interactions, and endothelial differentiation of CD4 + -T cell subsets (Th1, Th17, Treg), were impaired whereas activation of Complement by anti-HLA antibody binding remained unchanged by IL-6 blockade. Together, these data identify EC-mediated pro-inflammatory responses (T cell expansion, EC auto-activation, chemokine secretion) targeted by IL-6 blockade., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The demand for donors' kidneys continues to increase amid a shortage of available donors. Managing policies to thoughtfully allocate this scarce resource is a complex process. Although human leukocyte antigen (HLA) matching has been shown to prolong graft survival, its relative contribution to allocation schemes is empirically compromised owing to competing priorities. We explored using a new metric, Matched Donor Potential (MDP), to facilitate improved HLA matching while promoting equity. We interrogated all active kidney waitlist patients (N = 164 427), their corresponding unacceptable antigen files, and all effective donors in the Scientific Registry of Transplant Recipients (January 1, 2016-December 31, 2017). Cause-specific hazard functions were evaluated to assess the potential impact of the MDP metric on deceased donor transplant access rates for all candidates. Access was affected by ethnicity, blood group type, and calculated Panel Reactive Antibody (cPRA). Importantly, we show that access to transplantation is influenced by the patient's own HLA makeup regardless of their ethnicity and by the HLA makeup of effective donors. The MDP metric demonstrates a high association with access to transplantation. Adjusting Cox models to include this new metric resulted in improved access to kidney transplantation for waitlist candidates of minority heritage while significantly promoting HLA matching. Thus, the MDP metric accounts for balanced, equitable organ allocation algorithms., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: The aims of this study were to assess medication adherence to immunosuppressive treatment in kidney transplanted patients, to identify predictive factors of medication non-adherence and to analyse its impact on the development of Donor Specific Antibodies (DSA) de novo, biomarkers of rejection in transplant recipients., Methods: A cross-sectional single-centre study was conducted to assess medication adherence to immunosuppressive treatment with the BAASIS (Basel Assessment of Adherence Scale for Immunosuppressives) self-report questionnaire. Univariate and multivariate analyses were performed to determine non-adherence predictive factors and its role in the development of DSA de novo., Results: A total of 212 renal transplanted patients completed the BAASIS questionnaire: 36,3 % were non-adherent to their immunosuppressive treatment. Patient's age and taking azathioprine were independent predictors of non-adherence and "married or living together" family status was a protective factor in the multivariate analysis. Medication non-adherence was associated with DSA de novo development in the multivariate model and it multiplied their risk of development by 3., Conclusions: This study, which detected a large proportion of patients who did not adhere to immunosuppressive treatment, highlighted non-adherence predictors and showed the association between non-adherence and development of DSA de novo. In case of non-adherent behavior, it is crucial to set up a personalised support for patients with a multidisciplinary approach of therapeutic education, in which the clinical pharmacist has a role., (Copyright © 2022 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

The microvascular endothelium of the renal transplant is the first site of graft interaction with the host immune system and is often injured in chronic Antibody Mediated Rejection (AMR). Microvascular inflammation is an independent determinant of AMR and heightens endothelial expression of human leukocyte antigen (HLA) molecules thereby increasing the possibility of Donor Specific Antibody (DSA) binding. Endothelial cells (ECs) produce IL-6 in the steady-state that is increased by inflammation or by HLA-DR antibody binding in an allogeneic setting. Because IL-6 has been implicated in AMR, IL-6 blockade is currently under investigation as a therapeutic target. To further understand the role of IL-6 in EC immunogenicity, we have examined whether humanized antibody blockade of IL-6 altered EC interactions with allogeneic PBMC and after anti-HLA or DSA binding to ECs in an in vitro human experimental model. Soluble factors, endothelial phenotype, Stat-3 activation, CD4 + -T differentiation and C4d deposition were examined. Blockade of IL-6 reduced EC secretion of IL-6 and of the monocyte chemoattractant MCP-1. Pre-activation of ECs by anti-HLA or DSA binding increased IL-6 secretion, that was further increased by concurrent binding of both antibodies and this was inhibited by IL-6 blockade. Activation of Stat-3 in CD4 + -T mediated by soluble factors produced in endothelial-PBMC interactions, and endothelial differentiation of CD4 + -T cell subsets (Th1, Treg), were impaired whereas activation of Complement by anti-HLA antibody binding remained unchanged by IL-6 blockade. Together, these data identify EC-mediated pro-inflammatory responses (T cell expansion, EC auto-activation, chemokine secretion) targeted by IL-6 blockade., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Conditional marketing authorization (CMA) facilitates timely access to new drugs for illnesses with unmet clinical needs, such as late graft failure after kidney transplantation. Late graft failure remains a serious, burdensome, and life-threatening condition for recipients. This article has been developed from content prepared by members of a working group within the European Society for Organ Transplantation (ESOT) for a Broad Scientific Advice request, submitted by ESOT to the European Medicines Agency (EMA), and reviewed by the EMA in 2020. The article presents the rationale for using surrogate endpoints in clinical trials aiming at improving late graft failure rates, to enable novel kidney transplantation therapies to be considered for CMA and improve access to medicines. The paper also provides background data to illustrate the relationship between primary and surrogate endpoints. Developing surrogate endpoints and a CMA strategy could be particularly beneficial for studies where the use of primary endpoints would yield insufficient statistical power or insufficient indication of long-term benefit following transplantation., Competing Interests: LH reports speaker fees from Astellas, consultancy and research support from Chiesi, consultancy for Novartis, and research support from Sandoz. RO has received grants/research support from Amgen, Astellas, and Chiesi; and speakers' bureaux/honoraria from Amgen, Astellas, Chiesi, Hansa, Neovii, Novartis, and Teva. SS has received grants/research support from Bridge to Life, Chiesi, Neovii, Novartis, Organ Recovery Systems, and Sandoz; speakers' bureaux/honoraria from Astellas, BMS, Chiesi, Novartis, OrganOx, and Sanofi; and consulting fees from Astellas, Atara, Merck, NefroHealth, Novartis, Sandoz, and Teva. DG reports consultancy agreements and scientific boards for AstraZeneca, BMS, Hansa, and Sanofi. UH has received grants/research support from Baxter, Chiesi, and Neovii; speakers' bureaux/honoraria from Chiesi and Hansa; and consulting fees from Astellas, Hansa, Neovii, Novartis, and Teva. IJ's institution has received speaker's fees from XVIVO Perfusion. MR has received lecture fees from Astellas and Chiesi; and research grant support (paid to institution) from Astellas and Chiesi for investigator-initiated studies. SS has received grants/research support from Bridge to Life, Chiesi, Neovii, Novartis, Organ Recovery Systems, and Sandoz; speakers' bureaux/honoraria from Astellas, BMS, Chiesi, Novartis, OrganOx, and Sanofi; and consulting fees from Astellas, Atara, Merck, NefroHealth, Novartis, Sandoz, and Teva. KB has received honoraria and/or research funding from Alexion, Astellas, Bristol Myers Squibb, Chiesi, Fresenius, Hansa, Hexal, Merck, Novartis, Otsuka, Pfizer, Roche, Sandoz, Siemens, and Veloxis. The remaining authors declare that the work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Naesens, Loupy, Hilbrands, Oberbauer, Bellini, Glotz, Grinyó, Heemann, Jochmans, Pengel, Reinders, Schneeberger and Budde.)

The identity of histocompatibility loci, besides human leukocyte antigen (HLA), remains elusive. The major histocompatibility complex (MHC) class I MICA gene is a candidate histocompatibility locus. Here, we investigate its role in a French multicenter cohort of 1,356 kidney transplants. MICA mismatches were associated with decreased graft survival (hazard ratio (HR), 2.12; 95% confidence interval (CI): 1.45-3.11; P < 0.001). Both before and after transplantation anti-MICA donor-specific antibodies (DSA) were strongly associated with increased antibody-mediated rejection (ABMR) (HR, 3.79; 95% CI: 1.94-7.39; P < 0.001; HR, 9.92; 95% CI: 7.43-13.20; P < 0.001, respectively). This effect was synergetic with that of anti-HLA DSA before and after transplantation (HR, 25.68; 95% CI: 3.31-199.41; P = 0.002; HR, 82.67; 95% CI: 33.67-202.97; P < 0.001, respectively). De novo-developed anti-MICA DSA were the most harmful because they were also associated with reduced graft survival (HR, 1.29; 95% CI: 1.05-1.58; P = 0.014). Finally, the damaging effect of anti-MICA DSA on graft survival was confirmed in an independent cohort of 168 patients with ABMR (HR, 1.71; 95% CI: 1.02-2.86; P = 0.041). In conclusion, assessment of MICA matching and immunization for the identification of patients at high risk for transplant rejection and loss is warranted., (© 2022. The Author(s).)

Introduction: Expanded-criteria donors (ECDs) are used to reduce the shortage of kidneys for transplantation. However, kidneys from ECDs are associated with an increased risk of delayed graft function (DGF), a risk factor for allograft loss and mortality. HYPOREME will be a multicentre randomised controlled trial (RCT) comparing targeted hypothermia to normothermia in ECDs, in a country where the use of machine perfusion for organ storage is the standard of care. We hypothesise that hypothermia will decrease the incidence of DGF., Methods and Analysis: HYPOREME is a multicentre RCT comparing the effect on kidney function in recipients of targeted hypothermia (34°C-35°C) and normothermia (36.5°C-37.5°C) in the ECDs. The temperature intervention starts from randomisation and is maintained until aortic clamping in the operating room. We aim to enrol 289 ECDs in order to analyse the kidney function of 516 recipients in the 53 participating centres. The primary outcome is the occurrence of DGF in kidney recipients, defined as a requirement for renal replacement therapy within 7 days after transplantation (not counting a single session for hyperkalemia during the first 24 hours). Secondary outcomes include the proportion of patients with individual organs transplanted in each group; the number of organs transplanted from each ECD and the vital status and kidney function of the recipients 7 days, 28 days, 3 months and 1 year after transplantation. An interim analysis is planned after the enrolment of 258 kidney recipients., Ethics and Dissemination: The trial was approved by the ethics committee of the French Intensive Care Society (CE-SRLF-16-07) on 26 April 2016 and by the competent French authorities on 20 April 2016 (Comité de Protection des Personnes-TOURS-Région Centre-Ouest 1, registration #2016-S3). Findings will be published in peer-reviewed journals and presented during national and international scientific meetings., Trial Registration Number: NCT03098706., Competing Interests: Competing interests: EC received fees for lectures and conference talks and had travel and accommodation expenses related to attending scientific meetings covered by Gilead, Baxter and Sanofi-Genzyme., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: The fact that metabolism and immune function are regulated by an endogenous molecular clock that generates circadian rhythms suggests that the magnitude of ischemia reperfusion, and subsequent inflammation on kidney transplantation, could be affected by the time of the day., Design, Setting, Participants, & Measurements: We evaluated 5026 individuals who received their first kidney transplant from deceased heart-beating donors. In a cause-specific multivariable analysis, we compared delayed graft function and graft survival according to the time of kidney clamping and declamping. Participants were divided into those clamped between midnight and noon ( ante meridiem [am] clamping group; 65%) or clamped between noon and midnight ( post meridiem [pm] clamping group; 35%), and, similarly, those who underwent am declamping (25%) or pm declamping (75%)., Results: Delayed graft function occurred among 550 participants (27%) with am clamping and 339 (34%) with pm clamping (adjusted odds ratio, 0.81; 95% confidence interval, 0.67 to 0.98; P =0.03). No significant association was observed between clamping time and overall death-censored graft survival (hazard ratio, 0.92; 95% confidence interval, 0.77 to 1.10; P =0.37). No significant association of declamping time with delayed graft function or graft survival was observed., Conclusions: Clamping between midnight and noon was associated with a lower incidence of delayed graft function, whereas declamping time was not associated with kidney graft outcomes., (Copyright © 2021 by the American Society of Nephrology.)

Background: Posttransplant lymphoproliferative disorders (PTLDs) encompass a spectrum of heterogeneous entities. Because the vast majority of cases PTLD arise from B cells, available data on PTLD of T or NK phenotype (T/NK-cell PTLD) are scarce, which limits the quality of the management of these patients., Methods: All adult cases of PTLD diagnosed in France were prospectively recorded in the national registry between 1998 and 2007. Crosschecking the registry data with 2 other independent national databases identified 58 cases of T/NK-cell PTLD. This cohort was then compared with (i) the 395 cases of B-cell PTLD from the registry, and of (ii) a cohort of 148 T/NK-cell lymphomas diagnosed in nontransplanted patients., Results: T/NK-cell PTLD occurred significantly later after transplantation and had a worse overall survival than B-cell PTLD. Two subtypes of T/NK-cell PTLD were distinguished: (i) cutaneous (28%) and (ii) systemic (72%), the latter being associated with a worse prognosis. Compared with T/NK-cell lymphomas of nontransplanted patients, overall survival of systemic T/NK-cell PTLD was worse (hazard ratio: 2.64 [1.76-3.94]; P < 0.00001)., Conclusions: This difference, which persisted after adjustment on tumoral mass, histological subtype, and extension of the disease at diagnosis could be explained by the fact that transplanted patients were less intensively treated and responded less to chemotherapy., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

During allotransplantation, the endothelium acts as semi-professional antigen-presenting cells with the ability to activate proliferation and to promote differentiation of CD4 + -T subsets. These abilities are dependent on the luminal expression of HLA class II antigens by microvascular endothelial cells, which is regulated by inflammatory cytokines. The upregulation of HLA-DR and HLA-DQ during rejection implies significant intragraft inflammation. Furthermore, the microvascular inflammation is an independent determinant for renal allograft failure. In this study, the potential of inflammation to modify endothelial regulation of peripheral CD4 + Treg cells was examined. Microvascular endothelial cells were exposed to pro-inflammatory cytokines for varying durations before co-culture with PBMC from non-HLA matched donors. Proliferation and expansion of CD4 + Treg and soluble factor secretion was determined. Early interactions were detected by phosphorylation of Akt. Video microscopy was used to examine spatial and temporal endothelial-CD4 + T interactions. Highly inflammatory conditions led to increased endothelial expression of HLA-DR, the adhesion molecule ICAM-1, the costimulatory molecule PD-L1 and de novo expression of HLA-DQ. Treg differentiation was impaired by exposure of endothelial cells to a high level of inflammation. Neither IL-6, IL-2 nor TGFβ were implicated in reducing Treg numbers. High PD-L1 expression interfered with early endothelial cell interactions with CD4 + T lymphocytes and led to modified TCR signaling. Blocking endothelial PD-L1 resulted in a partial restoration of Treg. The allogenic endothelial cell-mediated expansion of Treg depends on a critical threshold of inflammation. Manipulation of the PD-L1/PD-1 pathway or endothelial activation post-transplantation may promote or interfere with this intrinsic mechanism of allospecific Treg expansion., 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 © 2021 Cross, Lion, Poussin, Glotz and Mooney.)

Multiple days assessments are frequent for the evaluation of candidates to living kidney donation, combined with an early GFR estimation (eGFR). Living kidney donation is questionable when eGFR is <90 ml/min/1.73 m 2 (KDIGO guidelines) or 80 ml/min/1.73 m 2 (most US centres). However, age-related GFR decline results in a lower eGFR for older candidates. That may limit the number of older kidney donors. Yet, continuing the screening with a GFR measure increases the number of eligible donors. We hypothesized that in-depth screening should be proposed to all candidates with a normal eGFR for age. We compared the evolution of eGFR after donation between three groups of predonation eGFR: normal for age (S age ) higher than 90 or 80 ml/min/1.73 m 2 (S 90 and S 80, respectively); across three age groups (<45, 45-55, >55 years) in a population of 1825 French living kidney donors with a median follow-up of 5.9 years. In donors younger than 45, postdonation eGFR, absolute- and relative-eGFR variation were not different between the three groups. For older donors, postdonation eGFR was higher in S 90 than in S 80 or S age but other comparators were identical. Postdonation eGFR slope was comparable between all groups. Our results are in favour of in-depth screening for all candidates to donation with a normal eGFR for age., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Background: Many kidneys donated for transplant in the United States are discarded because of abnormal histology. Whether histology adds incremental value beyond usual donor attributes in assessing allograft quality is unknown., Methods: This population-based study included patients who received a deceased donor kidney that had been biopsied before implantation according to a prespecified protocol in France and Belgium, where preimplantation biopsy findings are generally not used for decision making in the allocation process. We also studied kidneys that had been acquired from deceased United States donors for transplantation that were biopsied during allocation and discarded because of low organ quality. Using donor and recipient characteristics, we fit multivariable Cox models for death-censored graft failure and examined whether predictive accuracy (C index) improved after adding donor histology. We matched the discarded United States kidneys to similar kidneys transplanted in Europe and calculated predicted allograft survival., Results: In the development cohort of 1629 kidney recipients at two French centers, adding donor histology to the model did not significantly improve prediction of long-term allograft failure. Analyses using an external validation cohort from two Belgian centers confirmed the lack of improved accuracy from adding histology. About 45% of 1103 United States kidneys discarded because of histologic findings could be accurately matched to very similar kidneys that had been transplanted in France; these discarded kidneys would be expected to have allograft survival of 93.1% at 1 year, 80.7% at 5 years, and 68.9% at 10 years., Conclusions: In this multicenter study, donor kidney histology assessment during allocation did not provide substantial incremental value in ascertaining organ quality. Many kidneys discarded on the basis of biopsy findings would likely benefit United States patients who are wait listed., (Copyright © 2021 by the American Society of Nephrology.)

Although the gold standard of monitoring kidney transplant function relies on glomerular filtration rate (GFR), little is known about GFR trajectories after transplantation, their determinants, and their association with outcomes. To evaluate these parameters we examined kidney transplant recipients receiving care at 15 academic centers. Patients underwent prospective monitoring of estimated GFR (eGFR) measurements, with assessment of clinical, functional, histological and immunological parameters. Additional validation took place in seven randomized controlled trials that included a total of 14,132 patients with 403,497 eGFR measurements. After a median follow-up of 6.5 years, 1,688 patients developed end-stage kidney disease. Using unsupervised latent class mixed models, we identified eight distinct eGFR trajectories. Multinomial regression models identified seven significant determinants of eGFR trajectories including donor age, eGFR, proteinuria, and several significant histological features: graft scarring, graft interstitial inflammation and tubulitis, microcirculation inflammation, and circulating anti-HLA donor specific antibodies. The eGFR trajectories were associated with progression to end stage kidney disease. These trajectories, their determinants and respective associations with end stage kidney disease were similar across cohorts, as well as in diverse clinical scenarios, therapeutic eras and in the seven randomized control trials. Thus, our results provide the basis for a trajectory-based assessment of kidney transplant patients for risk stratification and monitoring., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: COVID-19 has been associated with high morbidity and mortality in kidney transplant recipients. However, risk factors for COVID-19 disease in patients with kidney transplants remain poorly defined., Methods: We enrolled patients who underwent kidney transplantation and were actively followed up in two hospitals in Paris on March 1st, 2020. Patients were screened for baseline and transplant characteristics, functional parameters, comorbidities, and immunosuppressive therapies. COVID-19 disease was assessed. Patients were followed up during the pandemic until April 30th, 2020 by the COVID-19 SLS KT survey program, including teleconsulting, at-home monitoring for patients with COVID-19, and a dedicated phone hotline platform., Results: Among 1216 patients with kidney transplants enrolled, 66 (5%) patients were identified with COVID-19 disease, which is higher than the incidence observed in the general population in France (0.3%). Their mean age was 56.4±12.5 years, and 37 (56%) patients were men. The following factors were independently associated with COVID-19 disease: non-White ethnicity (adjusted odds ratio [OR], 2.17; 95% confidence interval [95% CI], 1.23 to 3.78; P =0.007), obesity (OR, 2.19; 95% CI, 1.19 to 4.05; P =0.01), asthma and chronic pulmonary disease (OR, 3.09; 95% CI, 1.49 to 6.41; P =0.002), and diabetes (OR, 3.33; 95% CI, 1.92 to 5.77; P <0.001). The mortality rate related to COVID-19 disease was 1% in the overall study population and 24% in COVID-19-positive patients., Conclusions: Patients with kidney transplants display a high risk of mortality. Non-White ethnicity and comorbidities such as obesity, diabetes, asthma, and chronic pulmonary disease were associated with higher risk of developing COVID-19 disease. It is imperative that policy makers urgently ensure the integration of such risk factors on response operations against COVID-19., (Copyright © 2020 by the American Society of Nephrology.)

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Numerous studies have reported a weekend effect on outcomes for diseases treated at hospitals. No study has been conducted in France for kidney transplantation. We therefore performed a cohort-based study to evaluate whether outcomes of kidney transplant recipients display a weekend effect. Data were extracted from the French DIVAT cohort. Patients aged 18 years and older, transplanted with a single kidney from deceased donors between 2005 and 2017 were studied. Linear regression, logistic regression, and cause-specific Cox model were used. Among the 6652 studied patients, 4653 patients were transplanted during weekdays (69.9%) versus 1999 during weekends (30.1%). The only statistically significant difference was the percentage of patients with vascular surgical complication(s) at 30 days: 13.3% in the weekend group versus 16.2% in the weekday group 0.79 (95% CI: 0.68; 0.92). We did not observe other significant differences for the other outcomes: patient or graft survival, the risk of acute rejection episodes, the 30-day percentage of urological complications, and the 1-year estimated glomerular filtration rate. Our study highlights a small protective weekend effect with less post-surgery vascular complications compared to weekdays. This paradox might be explained by a different handling of weekend transplantations., (© 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Background: Most studies comparing the efficacy of hypothermic machine perfusion (HMP) versus static cold storage (SCS) are based on short-term outcomes. We aimed to better evaluate the mid-term impact of HMP in patients receiving expanded criteria donor (ECD) kidneys., Methods: The analyses were based on the French Données Informatisées et VAlidées en Transplantation (DIVAT) observational cohort. Patients aged ≥45 years transplanted for the first or second times from an ECD donor since 2010 were studied. Our study reported the graft and/or patient survivals and the incidence of acute rejection episode. The Cox models and the Kaplan-Meier estimators, weighted on the propensity score, were used to study the times-to-events., Results: Among the 2019 included patients, 1073 were in the SCS group versus 946 in the HMP group. The mean life expectancy with functioning graft was 5.7 years [95% confidence interval (CI) 5.4-6.1] for the HMP cohort followed-up for 8 years post-transplantation versus 6.0 years (95% CI 5.7-6.2) for the SCS group. These mid-term results were comparable in the patients receiving grafts from donors aged ≥70 years and in the transplantations with cold ischaemia time ≥18 h., Conclusions: Our study challenges the utility of using HMP to improve mid-term patient and graft survival. Nevertheless, the improvement of the short-term outcomes is indisputable. It is necessary to continue technological innovations to obtain long-term results., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Delayed graft function (DGF) is a form of acute renal failure which results in increased post-transplantation allograft immunogenicity and risk of acute rejection episodes in addition to decreased long-term survival. Its incidence and risk factors have been extensively studied, especially after deceased donation. Until now, only few data has been  published on DGF in living donor kidney transplant recipients. The present study was performed to investigate the frequency and risk factors of DGF among living- kidney transplant recipients. In this retrospective study, data had been collected from existing local hospital registries in three countries (Iran, Kingdom of Saudi Arabia (KSA) , and Kuwait ).

Importance: Approximately 3500 donated kidneys are discarded in the United States each year, drawing concern from Medicare and advocacy groups., Objective: To estimate the effects of more aggressive allograft acceptance practices on the donor pool and allograft survival for the population of US wait-listed kidney transplant candidates., Design, Setting, and Participants: A nationwide study using validated registries from the United States and France comprising comprehensive cohorts of deceased donors with organs offered to kidney transplant centers between January 1, 2004, and December 31, 2014. Data were analyzed between September 1, 2018, and April 5, 2019., Main Outcomes and Measures: The primary outcome was kidney allograft discard. The secondary outcome was allograft failure after transplantation. We used logistic regression to model organ acceptance and discard practices in both countries. We then quantified using computer simulation models the number of kidneys discarded in the United States that a more aggressive system would have instead used for transplantation. Finally, based on actual survival data, we quantified the additional years of allograft life that a redesigned US system would have saved., Findings: In the United States, 156 089 kidneys were recovered from deceased donors between 2004 and 2014, of which 128 102 were transplanted, and 27 987 (17.9%) were discarded. In France, among the 29 984 kidneys recovered between 2004 and 2014, 27 252 were transplanted, and 2732 (9.1%, P < .001 vs United States) were discarded. The mean (SD) age of kidneys transplanted in the United States was 36.51 (17.02) years vs 50.91 (17.34) years in France (P < .001). Kidney quality showed little change in the United States over time (mean [SD] kidney donor risk index [KDRI], 1.30 [0.48] in 2004 vs 1.32 [0.46] in 2014), whereas a steadily rising KDRI in France reflected a temporal trend of more aggressive organ use (mean [SD] KDRI, 1.37 [0.47] in 2004 vs 1.74 [0.72] in 2014; P < .001). We applied the French-based allocation model to the population of US deceased donor kidneys and found that 17 435 (62%) of kidneys discarded in the United States would have instead been transplanted under the French system. We further determined that a redesigned system with more aggressive organ acceptance practices would generate an additional 132 445 allograft life-years in the United States over the 10-year observation period., Conclusions and Relevance: Greater acceptance of kidneys from deceased donors who are older and have more comorbidities could provide major survival benefits to the population of US wait-listed patients., Trial Registration: ClinicalTrials.gov identifier: NCT03723668.

The presence of preformed donor-specific antibodies in transplant recipients increases the risk of acute antibody-mediated rejection (AMR). Results of an open-label single-arm trial to evaluate the safety and efficacy of eculizumab in preventing acute AMR in recipients of deceased-donor kidney transplants with preformed donor-specific antibodies are reported. Participants received eculizumab as follows: 1200 mg immediately before reperfusion; 900 mg on posttransplant days 1, 7, 14, 21, and 28; and 1200 mg at weeks 5, 7, and 9. All patients received thymoglobulin induction therapy and standard maintenance immunosuppression including steroids. The primary end point was treatment failure rate, a composite of biopsy-proved grade II/III AMR (Banff 2007 criteria), graft loss, death, or loss to follow-up, within 9 weeks posttransplant. Eighty patients received transplants (48 women); the median age was 52 years (range 24-70 years). Observed treatment failure rate (8.8%) was significantly lower than expected for standard care (40%; P < .001). By 9 weeks, 3 of 80 patients had experienced AMR, and 4 of 80 had experienced graft loss. At 36 months, graft and patient survival rates were 83.4% and 91.5%, respectively. Eculizumab was well tolerated and no new safety concerns were identified. Eculizumab has the potential to provide prophylaxis against injury caused by acute AMR in such patients (EudraCT 2010-019631-35)., (© 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

We report results of a phase 2, randomized, multicenter, open-label, two-arm study evaluating the safety and efficacy of eculizumab in preventing acute antibody-mediated rejection (AMR) in sensitized recipients of living-donor kidney transplants requiring pretransplant desensitization (NCT01399593). In total, 102 patients underwent desensitization. Posttransplant, 51 patients received standard of care (SOC) and 51 received eculizumab. The primary end point was week 9 posttransplant treatment failure rate, a composite of: biopsy-proven acute AMR (Banff 2007 grade II or III; assessed by blinded central pathology); graft loss; death; or loss to follow-up. Eculizumab was well tolerated with no new safety concerns. No significant difference in treatment failure rate was observed between eculizumab (9.8%) and SOC (13.7%; P = .760). To determine whether data assessment assumptions affected study outcome, biopsies were reanalyzed by central pathologists using clinical information. The resulting treatment failure rates were 11.8% and 21.6% for the eculizumab and SOC groups, respectively (nominal P = .288). When reassessment included grade I AMR, the treatment failure rates were 11.8% (eculizumab) and 29.4% (SOC; nominal P = .048). This finding suggests a potential benefit for eculizumab compared with SOC in preventing acute AMR in recipients sensitized to their living-donor kidney transplants (EudraCT 2010-019630-28)., (© 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Development of donor-specific antibodies is associated with reduced allograft survival in renal transplantation. Recent clinical studies highlight the prevalence of human leukocyte antigen (HLA)-DQ antibodies amongst de novo donor-specific antibodies (DSAs), yet the specific contribution of these DSAs to rejection has not been examined. Antibody-mediated rejection primarily targets the microvasculature, so this study explored how patient HLA-DQ alloantibodies can modulate endothelial activation and so immunoregulation. HLA-DQ antibodies phosphorylated Akt and S6 kinase in microvascular endothelial cells. This activation prior to culture with alloreactive lymphocytes increased IL-6 and RANTES secretion. The antibody-mediated upregulation of IL-6 was indeed Akt-dependent. The binding of HLA-DQ antibodies to endothelial cells selectively reduced T cell alloproliferation and FoxP3 high Treg differentiation. In clinical studies, detection of HLA-DQ DSAs with other DSAs is associated with worse graft survival than either alone. Endothelial cells stimulated with HLA-DR and HLA-DQ antibodies showed a synergistic increase in pro-inflammatory cytokine secretion and a decrease in Treg expansion. HLA-DQ antibodies strongly promote pro-inflammatory responses in isolation and in combination with other HLA antibodies. Thus, our data give new insights into the pathogenicity of HLA-DQ DSAs., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The recent recognition of complex and chronic phenotypes of T cell-mediated rejection (TCMR) has fostered the need to better evaluate the response of acute TCMR-a condition previously considered to lack relevant consequences for allograft survival-to the standard of care. In a prospective cohort of kidney recipients (n = 256) with biopsy-proven acute TCMR receiving corticosteroids, we investigated clinical, histological, and immunological phenotypes at the time of acute TCMR diagnosis and 3 months posttreatment. Independent posttreatment determinants of allograft loss included the glomerular filtration rate (GFR) (HR = 0.94; 95% CI = 0.92-0.96; P < .001), proteinuria (HR = 1.40; 95% CI = 1.10-1.79; P = .007), time since transplantation (HR = 1.02; 95% CI = 1.00-1.03; P = .016), peritubular capillaritis (HR = 2.27; 95% CI = 1.13-4.55; P = .022), interstitial inflammation in sclerotic cortical parenchyma (i-IF/TA) (HR = 1.87; 95% CI = 1.08-3.25; P = .025), and donor-specific anti-HLA antibodies (DSAs) (HR = 2.67; 95% CI = 1.46-4.88; P = .001). Prognostic value was improved using a composite evaluation of response to treatment versus clinical parameters only (cNRI = 0.68; 95% CI = 0.41-0.95; P < .001). A classification tree for allograft loss identified five patterns of response to treatment based on the posttreatment GFR, i-IF/TA, and anti-HLA DSAs (cross-validated accuracy = 0.80). Compared with responders (n = 155, 60.5%), nonresponders (n = 101, 39.5%) had a higher incidence of de novo DSAs, antibody-mediated rejection, and allograft loss at 10 years (P < .001 for all comparisons). Thus, clinical, histological, and immunological assessment of response to treatment of acute TCMR revealed different profiles of the response to treatment with distinct outcomes., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Anti-angiotensin II type 1 receptor (AT1R) antibodies have been associated with allograft rejection. We hypothesized that circulating AT1R antibodies might identify kidney transplant recipients at increased risk of allograft rejection and loss who are not identified by the HLA system. We prospectively enrolled 1845 kidney transplant recipients from two centers. Donor-specific HLA antibodies (DSAs) and AT1R antibodies were measured at the time of the first acute rejection episode or at 1 year post-transplant. Allograft biopsy was performed to evaluate the rejection phenotype and to assess for endothelial activation. Overall, 371 (20.1%) participants had AT1R antibodies, 334 (18.1%) had DSAs, and 133 (7.2%) had both. AT1R antibodies were associated with an increased risk of allograft loss (adjusted HR 1.49, 95% CI 1.07-2.06 for AT1R antibodies alone and 2.26, 95% CI 1.52-3.36 for AT1R antibodies and DSAs). Participants with AT1R antibodies had a higher incidence of antibody-mediated rejection (AMR) compared with participants without AT1R antibodies (25.0% vs. 12.9%). Among 77 participants with histological features of AMR but without DSAs, 51 (66.2%) had AT1R antibodies. Compared to participants with prototypical DSA-mediated rejection, those with AT1R antibody-associated rejection had a higher prevalence of hypertension, more vascular rejection with arterial inflammation, higher levels of endothelial-associated transcripts, and lack of complement deposition in allograft capillaries. Thus, AT1R antibodies may identify kidney transplant recipients at high risk of allograft rejection and loss, independent of the HLA system. Recognition of complement-independent AT1R antibody-mediated vascular rejection could lead to the development of new treatment strategies to improve allograft survival., (Copyright © 2019. Published by Elsevier Inc.)

Background: A significant number of studies have compared graft outcomes between patients with Pre-emptive Kidney Transplantation (PreKT) and patients on Dialysis before their Kidney Transplantation (DiaKT). These studies have suffered from the limitation that the DiaKT group is composed of all the dialysed patients, including those placed on a waiting list at the time of their first dialysis session. This seriously questions the comparability of these patients with those placed on the waiting list a long time before the need for renal replacement therapy. The aim of this study was to precisely evaluate the causal effect of PreKT from deceased donors., Methods: Data were extracted from the multicentric French DIVAT (Données Informatisées et VAlidées en Transplantation) cohort. The DiaKT group was composed of patients placed on the waiting list with an initial intention of pre-emptive transplantation. Cause-specific Cox models with propensity scores (inverse probability weighting) were used to study the patient and graft outcomes., Results: Among the 1138 included patients, 554 patients were in the PreKT group. The outcomes of the PreKT group were similar compared with the DiaKT group. In particular, the life expectancy with a functioning graft was 8.51 years [95% confidence interval (CI) 8.20-8.81] for the PreKT recipients versus 8.49 years (95% CI 8.15-8.84) for the DiaKT recipients., Conclusions: Our results challenge the utility of PreKTs from deceased donors, especially with regard to the consequential increase in the waiting list., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Transplant glomerulopathy, a common glomerular lesion observed after kidney transplant that is associated with poor prognosis, is not a specific entity but rather the end stage of overlapping disease pathways. Its heterogeneity has not been precisely characterized to date., Methods: Our study included consecutive kidney transplant recipients from three centers in France and one in Canada who presented with a diagnosis of transplant glomerulopathy (Banff cg score ≥1 by light microscopy), on the basis of biopsies performed from January of 2004 through December of 2014. We used an unsupervised archetype analysis of comprehensive pathology findings and clinical, immunologic, and outcome data to identify distinct groups of patients., Results: Among the 8207 post-transplant allograft biopsies performed during the inclusion period, we identified 552 biopsy samples (from 385 patients) with transplant glomerulopathy (incidence of 6.7%). The median time from transplant to transplant glomerulopathy diagnosis was 33.18 months. Kidney allograft survival rates at 3, 5, 7, and 10 years after diagnosis were 69.4%, 57.1%, 43.3%, and 25.5%, respectively. An unsupervised learning method integrating clinical, functional, immunologic, and histologic parameters revealed five transplant glomerulopathy archetypes characterized by distinct functional, immunologic, and histologic features and associated causes and distinct allograft survival profiles. These archetypes showed significant differences in allograft outcomes, with allograft survival rates 5 years after diagnosis ranging from 88% to 22%. Based on those results, we built an online application, which can be used in clinical practice on the basis of real patients., Conclusions: A probabilistic data-driven archetype analysis approach applied in a large, well defined multicenter cohort refines the diagnostic and prognostic features associated with cases of transplant glomerulopathy. Reducing heterogeneity among such cases can improve disease characterization, enable patient-specific risk stratification, and open new avenues for archetype-based treatment strategies and clinical trials optimization., (Copyright © 2019 by the American Society of Nephrology.)

Background: Kaposi sarcoma is a vascular tumor related to herpesvirus-8 and is promoted by immunosuppression. For the last 15 years, human immunodeficiency virus (HIV) patients have had access to organ transplantation. The dual immunosuppression of HIV and immunosuppressive treatments might increase the risk and severity of Kaposi sarcoma., Methods: We conducted a multicentric retrospective study by collecting cases from French databases and society members of transplanted patients, among which 7 HIV-infected patients who subsequently developed Kaposi sarcoma were included., Results: In the CRISTAL database (114 511 patients) and the DIVAT (Données Informatisées et VAlidées en Transplantation) database (19 077 patients), the prevalence of Kaposi sarcoma was 0.18% and 0.46%, respectively, in transplanted patients; these values compare with 0.66% and 0.50%, respectively, in transplanted patients with HIV. The median time from HIV infection to Kaposi sarcoma was 20 years. Kaposi sarcoma occurred during the first year after transplantation in most cases, whereas HIV viral load was undetectable. Only 2 patients had visceral involvement. Five patients were treated with conversion of calcineurin inhibitor to mammalian target of rapamycin inhibitor, and 5 patients were managed by decreasing immunosuppressive therapies. At 1 year, 4 patients had a complete response, and 3 had a partial response., Conclusions: In our study, Kaposi sarcoma in transplanted patients with HIV did not show any aggressive features and was treated with the usual posttransplant Kaposi sarcoma management protocol.

Immune checkpoint inhibitors are new therapeutic options for metastatic melanoma, but few data are available in organ transplant recipient populations. Six French patients, three men and three women, mean age 66 years (range 44-74), all kidney transplant recipients, received ipilimumab (CTLA-4 inhibitor) for metastatic melanoma. At diagnosis of advanced melanoma, immunosuppressive therapy had been minimized in all but one. Adverse effects included one case of grade 1 diarrhea and one of grade 1 pruritus. One patient had acute T cell-mediated rejection confirmed by histology after the first injection of ipilimumab. After a median follow-up of 4.5 (3-20) months, one patient achieved partial response, one had stable disease, and four had disease progression. All the patients died, five from melanoma, one from another cause. In this series and in the literature, ipilimumab proved to be safe and possibly active. The acute rejection we encountered was probably related to both a rapid, drastic reduction of immunosuppression and the use of ipilimumab. Our safety data on ipilimumab contrast with the organ transplant rejections already reported with PD-1 inhibitors. We consider that immunosuppression should not be minimized, as the impact on metastatic disease control is probably small., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

A major hurdle to improving clinical care in the field of kidney transplantation is the lack of biomarkers of the response to antibody-mediated rejection (ABMR) treatment. To discover these we investigated the value of complement-binding donor-specific anti-HLA antibodies (DSAs) for evaluating the response to treatment. The study encompassed a prospective cohort of 139 kidney recipients with ABMR receiving the standard of care treatment, including plasma exchange, intravenous immunoglobulin and rituximab. Patients were systematically assessed at the time of diagnosis and three months after treatment initiation for clinical and allograft histological characteristics and anti-HLA DSAs, including their C1q-binding ability. After adjusting for clinical and histological parameters, post-treatment C1q-binding anti-HLA DSA was an independent and significant determinant of allograft loss (adjusted hazard ratio 2.57 (95% confidence interval 1.29-5.12). In 101 patients without post-treatment C1q-binding anti-HLA DSA there was a significantly improved glomerular filtration rate with significantly reduced glomerulitis, peritubular capillaritis, interstitial inflammation, tubulitis, C4d deposition, and endarteritis compared with 38 patients with posttreatment C1q-binding anti-HLA DSA. A conditional inference tree model identified five prognostic groups at the time of post-treatment evaluation based on glomerular filtration rate, presence of cg lesion and C1q-binding anti-HLA DSA (cross-validated accuracy: 0.77). Thus, circulating complement-binding anti-HLA DSAs are strong and independent predictors of allograft outcome after standard of care treatment in kidney recipients with ABMR., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

[This corrects the article DOI: 10.1371/journal.pmed.1002572.].

The presence of preexisting (memory) or de novo donor-specific HLA antibodies (DSAs) is a known barrier to successful long-term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA vary markedly between centers. A collaborative effort between the American Society for Histocompatibility and Immunogenetics and the American Society of Transplantation provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as kidney, liver, heart, and lung transplantation. The goals were to perform a critical review of biologically driven, state-of-the-art, clinical diagnostics literature and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the Sensitization in Transplantation: Assessment of Risk (STAR) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, and highlighted gaps in knowledge are intended to spur research that will inform the next STAR Working Group meeting in 2019., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are recognized as a major barrier to patients' access to organ transplantation and the major cause of graft failure. The capacity of circulating anti-HLA DSAs to activate complement has been suggested as a potential biomarker for optimizing graft allocation and improving the rate of successful transplantations., Methods and Findings: To address the clinical relevance of complement-activating anti-HLA DSAs across all solid organ transplant patients, we performed a meta-analysis of their association with transplant outcome through a systematic review, from inception to January 31, 2018. The primary outcome was allograft loss, and the secondary outcome was allograft rejection. A comprehensive search strategy was conducted through several databases (Medline, Embase, Cochrane, and Scopus). A total of 5,861 eligible citations were identified. A total of 37 studies were included in the meta-analysis. Studies reported on 7,936 patients, including kidney (n = 5,991), liver (n = 1,459), heart (n = 370), and lung recipients (n = 116). Solid organ transplant recipients with circulating complement-activating anti-HLA DSAs experienced an increased risk of allograft loss (pooled HR 3.09; 95% CI 2.55-3.74, P = 0.001; I2 = 29.3%), and allograft rejection (pooled HR 3.75; 95% CI: 2.05-6.87, P = 0.001; I2 = 69.8%) compared to patients without complement-activating anti-HLA DSAs. The association between circulating complement-activating anti-HLA DSAs and allograft failure was consistent across all subgroups and sensitivity analyses. Limitations of the study are the observational and retrospective design of almost all included studies, the higher proportion of kidney recipients compared to other solid organ transplant recipients, and the inclusion of fewer studies investigating allograft rejection., Conclusions: In this study, we found that circulating complement-activating anti-HLA DSAs had a significant deleterious impact on solid organ transplant survival and risk of rejection. The detection of complement-activating anti-HLA DSAs may add value at an individual patient level for noninvasive biomarker-guided risk stratification., Trial Registration: National Clinical Trial protocol ID: NCT03438058., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: AMJ declares Speaker Bureau with Honoraria for ThermoFisher-One Lambda Corporation. ThermoFisher-One Lambda Corporation is involved in the manufacture of C1q anti-HLA antibody test. JK has received research grants and/or research support from Novartis, CareDx, and TransMedics.

Inflammation in fibrosis areas (i-IF/TA) of kidney allografts is associated with allograft loss; however, its diagnostic significance remains to be determined. We investigated the clinicohistologic phenotype and determinants of i-IF/TA in a prospective cohort of 1539 kidney recipients undergoing evaluation of i-IF/TA and tubulitis in atrophic tubules (t-IF/TA) on protocol allograft biopsies performed at 1 year posttransplantation. We considered donor, recipient, and transplant characteristics, immunosuppression, and histological diagnoses in 2260 indication biopsies performed within the first year posttransplantation. Nine hundred forty-six (61.5%) patients presented interstitial fibrosis/tubular atrophy (IF/TA Banff grade > 0) at 1 year posttransplant, among whom 394 (41.6%) showed i-IF/TA. i-IF/TA correlated with concurrent t-IF/TA (P < .001), interstitial inflammation (P < .001), tubulitis (P < .001), total inflammation (P < .001), peritubular capillaritis (P < .001), interstitial fibrosis (P < .001), and tubular atrophy (P = .02). The independent determinants of i-IF/TA were previous T cell-mediated rejection (TCMR) (P < .001), BK virus nephropathy (P = .007), steroid therapy (P = .039), calcineurin inhibitor therapy (P = .011), inosine-5'-monophosphate dehydrogenase inhibitor therapy (P = .011), HLA-B mismatches (P = .012), and HLA-DR mismatches (P = .044). TCMR patients with i-IF/TA on posttreatment biopsy (N = 83/136, 61.0%) exhibited accelerated progression of IF/TA over time (P = .01) and decreased 8-year allograft survival (70.8% vs 83.5%, P = .038) compared to those without posttreatment i-IF/TA. Our results support that i-IF/TA may represent a manifestation of chronic active TCMR., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Complement-activating anti-HLA donor-specific antibodies (DSAs) are associated with impaired kidney transplant outcome; however, whether these antibodies induce a specific rejection phenotype and influence response to therapy remains undetermined. We prospectively screened 931 kidney recipients for complement-activating DSAs and used histopathology, immunostaining, and allograft gene expression to assess rejection phenotypes. Effector cells were evaluated using in vitro human cell cultures. Additionally, we assessed the effect of complement inhibition on kidney allograft rejection phenotype and the clinical response to complement inhibition in 116 independent kidney recipients with DSAs at transplant receiving rejection prophylaxis with eculizumab or standard of care (plasma exchange and intravenous Ig) at ten international centers. The histomolecular rejection phenotype associated with complement-activating DSA was characterized by complement deposition and accumulation of natural killer cells and monocytes/macrophages in capillaries and increased expression of five biologically relevant genes ( CXCL11 , CCL4 , MS4A7 , MS4A6A , and FCGR3A ) indicative of endothelial activation, IFN γ response, CD16-mediated natural killer cell activation, and monocyte/macrophage activation. Compared with standard of care, eculizumab specifically abrogated this histomolecular rejection phenotype and associated with a decreased 3-month rejection incidence rate in patients with complement-activating DSAs (56%; 95% confidence interval [95% CI], 38% to 74% versus 19%; 95% CI, 8% to 35%; P =0.001) but not in those with noncomplement-activating DSAs (9%; 95% CI, 2% to 25% versus 13%; 95% CI, 2% to 40%; P =0.65). In conclusion, circulating complement-activating anti-HLA DSAs are associated with a specific histomolecular kidney allograft rejection phenotype that can be abrogated by complement inhibition., (Copyright © 2018 by the American Society of Nephrology.)

No tool is available for the early assessment of response to antibody-mediated rejection (ABMR) therapies in kidney allograft recipients. This study was designed to define a dynamic composite prognostic ABMR score to predict kidney allograft survival, integrating the disease characteristics at diagnosis and the response to treatment. Among 1978 kidney recipients who underwent transplant between 2008 and 2014, we included 278 patients diagnosed with active ABMR and receiving standard treatment, including plasma exchange, intravenous Ig, and rituximab. Patients were prospectively assessed at diagnosis and after treatment for clinical data, histologic characteristics (allograft biopsy specimen), and donor-specific anti-HLA antibodies (DSA). The dynamic ABMR prediction model included GFR ( P <0.001) and presence of interstitial fibrosis/tubular atrophy ( P =0.003) at diagnosis and changes in GFR ( P <0.001), peritubular capillaritis Banff score ( P =0.002), and DSA mean fluorescence intensity ( P <0.001) after treatment. Overall, this model showed good calibration and discrimination (C-statistic=0.84). The ABMR prognostic score derived from the prediction model identified three risk strata with 6-year kidney allograft survival rates of 6.0% (high-risk group, n =40), 44.9% (intermediate-risk group, n =36), and 84.4% (low-risk group, n =202), and it provided greater net clinical benefit to patients than did considering them all to have the same level of risk of allograft loss. The performance of the ABMR prognostic score was validated in an independent cohort of 202 kidney recipients with ABMR (C-statistic=0.79). The ABMR prognostic score could be used to inform therapeutic decisions in clinical practice and for the design of clinical trials., (Copyright © 2018 by the American Society of Nephrology.)

Antibody-mediated rejection (AMR) of solid organ transplants is characterized by the activation and injury of the allograft endothelium. Histological and transcriptomic studies have associated microvascular inflammation and endothelial lesions with the severity of rejection and poor graft outcomes. The allograft endothelium forms the physical barrier between the donor organ and the recipient; this position directly exposes the endothelium to alloimmune responses. However, endothelial cells are not just victims and can actively participate in the pathogenesis of rejection. In healthy tissues, the endothelium plays a major role in vascular and immune homeostasis. Organ transplantation, however, subjects the endothelium to an environment of inflammation, alloreactive lymphocytes, donor-specific antibodies, and potentially complement activation. As a result, endothelial cells become activated and have modified interactions with the cellular effectors of allograft damage: lymphocytes, natural killer, and myeloid cells. Activated endothelial cells participate in leukocyte adhesion and recruitment, lymphocyte activation and differentiation, as well as the secretion of cytokines and chemokines. Ultimately, highly activated endothelial cells promote pro-inflammatory alloresponses and become accomplices to AMR.

Immunosuppressive treatment is a prerequisite for both organ transplantation and tolerance of the allograft. However, long-term immunosuppression has been associated with a higher incidence of malignancies and infections. Immunosuppressors mainly target circulating immune cells and little is known of their "off-target" effects, such as their impact on endothelial cells (ECs). In chronic antibody-mediated rejection (AMR), the allograft endothelium is a target of damage, histologically detected as transplant glomerulopathy, and which correlates with poor graft survival. Under inflammatory conditions, EC expression of HLA class II antigens can lead to CD4 + -T lymphocyte alloactivation and selective expansion of pro-inflammatory Th17 and pro-tolerance Treg subsets. This response can be modified and preactivation of the EC by HLA-DR antibody binding promoted a proinflammatory Th17 response. However, whether or not immunosuppressors alter EC immunogenicity has not been examined. In alloimmunized patients with AMR, cyclosporine A (CsA) and mycophenolic acid (MPA) are often combined with intravenous immunoglobulins (IVIgs). This study reports changes in the microvascular EC phenotype and function after treatment with CsA, MPA, or IVIg. Both CsA and MPA decreased HLA-DR and increased CD54 expression, whereas IVIg increased HLA-DR expression. Interleukin 6 secretion was reduced by all three immunomodulators. Preincubation of ECs with CsA or MPA limited, while IVIg amplified, Treg expansion. Because CsA, MPA, and IVIg are known for their ability to act upon leukocytes, we confirmed that ECs maintained their immunoregulatory role when allogeneic leukocytes were pretreated with CsA, MPA, or IVIg. The results reveal that individual immunosuppressors, used in the induction and maintenance of renal allograft tolerance, had direct and distinct effects on ECs. Results of experiments associating IVIg with either CsA or MPA underlined the differences observed using individual immunosuppressors. Paradoxically, CsA or MPA may increase EC mediated inflammatory responses and long-term exposure may contribute to limitation of allograft tolerance. In contrast, IVIg interaction with the endothelium may mediate some of its immunosuppressive effects through promotion of Treg expansion, contributing to the maintenance of allograft tolerance.

Addressing the causes of kidney allograft-accelerated aging is an important challenge for improving long-term transplant outcomes. Here we investigated the role of circulating donor-specific anti-HLA antibodies (HLA-DSAs) in the development and the progression of kidney allograft fibrosis with inclusion of traditional risk factors for allograft fibrosis. We prospectively enrolled 1539 consecutive kidney recipients transplanted in two centers and assessed interstitial fibrosis and tubular atrophy (IF/TA) in biopsies performed at one year post-transplantation. The HLA-DSAs and all traditional determinants of IF/TA were recorded at transplantation and within the first year post-transplantation, including histological diagnoses in 2260 "for cause" biopsies. This identified 498 (32%) patients with severe IF/TA (Banff IF/TA grade 2 or more). HLA-DSAs were significantly associated with severe IF/TA (adjusted odds ratio, 1.53; 95% confidence interval 1.16-2.01) after including 37 determinants. HLA-DSAs remained significantly associated with severe IF/TA in patients without antibody-mediated rejection (adjusted odds ratio 1.54; 1.11-2.14). HLA-DSAs were the primary contributor, being involved in 11% of cases, while T cell-mediated rejection, calcineurin-inhibitor toxicity, acute tubular necrosis, pyelonephritis, and BK virus-associated nephropathy were involved in 9%, 8%, 6%, 5%, and 4% of cases, respectively. One hundred fifty-four patients with HLA-DSA-associated severe IF/TA showed significantly increased microvascular inflammation, transplant glomerulopathy, C4d deposition in capillaries, and decreased allograft survival compared to 344 patients with severe IF/TA without HLA-DSAs. Three hundred seventy-eight patients with post-transplant HLA-DSAs exhibited significantly accelerated progression of IF/TA compared to 1161 patients without HLA-DSAs in the biopsies performed at one year post-transplant and beyond. Thus, circulating HLA-DSAs are major determinants of premature and accelerated allograft fibrosis acting independently of traditional risk factors and antibody-mediated rejection., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Antibody-mediated rejection (ABMR) can occur in patients with preexisting anti-HLA donor-specific antibodies (DSA) or in patients who develop de novo DSA. However, how these processes compare in terms of allograft injury and outcome has not been addressed. From a cohort of 771 kidney biopsy specimens from two North American and five European centers, we performed a systematic assessment of clinical and biologic parameters, histopathology, circulating DSA, and allograft gene expression for all patients with ABMR ( n =205). Overall, 103 (50%) patients had preexisting DSA and 102 (50%) had de novo DSA. Compared with patients with preexisting DSA ABMR, patients with de novo DSA ABMR displayed increased proteinuria, more transplant glomerulopathy lesions, and lower glomerulitis, but similar levels of peritubular capillaritis and C4d deposition. De novo DSA ABMR was characterized by increased expression of IFN γ -inducible, natural killer cell, and T cell transcripts, but less expression of AKI transcripts compared with preexisting DSA ABMR. The preexisting DSA ABMR had superior graft survival compared with the de novo DSA ABMR (63% versus 34% at 8 years after rejection, respectively; P <0.001). After adjusting for clinical, histologic, and immunologic characteristics and treatment, we identified de novo DSA ABMR (hazard ratio [HR], 1.82 compared with preexisting DSA ABMR; 95% confidence interval [95% CI], 1.07 to 3.08; P =0.03); low eGFR (<30 ml/min per 1.73 m 2 ) at diagnosis (HR, 3.27; 95% CI, 1.48 to 7.23; P <0.001); ≥0.30 g/g urine protein-to-creatinine ratio (HR, 2.44; 95% CI, 1.47 to 4.09; P <0.001); and presence of cg lesions (HR, 2.25; 95% CI, 1.34 to 3.79; P =0.002) as the main independent determinants of allograft loss. Our findings support the transplant of kidneys into highly sensitized patients and should encourage efforts to monitor patients for de novo DSA., (Copyright © 2017 by the American Society of Nephrology.)

The diagnosis system for allograft loss lacks accurate individual risk stratification on the basis of donor-specific anti-HLA antibody (anti-HLA DSA) characterization. We investigated whether systematic monitoring of DSA with extensive characterization increases performance in predicting kidney allograft loss. This prospective study included 851 kidney recipients transplanted between 2008 and 2010 who were systematically screened for DSA at transplant, 1 and 2 years post-transplant, and the time of post-transplant clinical events. We assessed DSA characteristics and performed systematic allograft biopsies at the time of post-transplant serum evaluation. At transplant, 110 (12.9%) patients had DSAs; post-transplant screening identified 186 (21.9%) DSA-positive patients. Post-transplant DSA monitoring improved the prediction of allograft loss when added to a model that included traditional determinants of allograft loss (increase in c statistic from 0.67; 95% confidence interval [95% CI], 0.62 to 0.73 to 0.72; 95% CI, 0.67 to 0.77). Addition of DSA IgG3 positivity or C1q binding capacity increased discrimination performance of the traditional model at transplant and post-transplant. Compared with DSA mean fluorescence intensity, DSA IgG3 positivity and C1q binding capacity adequately reclassified patients at lower or higher risk for allograft loss at transplant (category-free net reclassification index, 1.30; 95% CI, 0.94 to 1.67; P<0.001 and 0.93; 95% CI, 0.49 to 1.36; P<0.001, respectively) and post-transplant (category-free net reclassification index, 1.33; 95% CI, 1.03 to 1.62; P<0.001 and 0.95; 95% CI, 0.62 to 1.28; P<0.001, respectively). Thus, pre- and post-transplant DSA monitoring and characterization may improve individual risk stratification for kidney allograft loss., (Copyright © 2017 by the American Society of Nephrology.)

During solid organ transplantation, interactions between recipient and donor immune cells occur chiefly in the allograft microvasculature. All three HLA class II antigens, DR, DP and DQ, have been detected on renal EC with a markedly increased expression of HLA class II observed in renal allografts undergoing rejection. Recent studies of donor-specific antibodies (DSA) have exposed the prevalence of de novo DSA directed against HLA-DQ, as well as a strong association between these antibodies and allograft damage. The HLA-DQ molecule can be distinguished from the other class II antigens by its transcription, expression and peptide repertoire. The distinct intragraft expression and immunogenicity of HLA-DQ may contribute to the incidence of HLA-DQ DSA, as well as directing the DSA-mediated damage. The possibility of HLA class II antigen-specific signaling in EC may reveal different mechanisms of allograft damage that act in tandem with complement-dependent injury. This review addresses the features of the HLA-DQ heterodimer that may underlie the high incidence of HLA-DQ directed DSA and their association with allograft damage. We also consider existing data in hematopoietic stem cell transplantation concerning HLA directed DSA., (Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Antibody removal therapies are used for patients with antibody-mediated-rejection or those requiring desensitization to become transplantable. Accurate measurement of antibody levels prior to, and during treatment, are required to choose the best therapeutic approach, and to provide measure of treatment efficacy. Currently, the FDA does not regard solid-phase assays for HLA-antibody identification as a reliable surrogate-marker for treatment efficacy. Serum samples from 40 patients (58 assays; >2200 positive data points) undergoing antibody-removal-therapies were tested as sample-pairs, pre- and post-treatment. MFI values of IgG and C1q single-antigen-bead assays were compared with antibody titer values (serial dilutions). Antibody reduction was tracked and the differences in pre-to-post-treatment values were calculated as delta-reduction of antibody levels. Dynamic patterns of titration studies reduced effects of serum-inherent inhibitory factors (prozone-like); eliminated over-saturation limitations, and provided better estimation of antibody-binding strength compared with the other methods. Moreover, delta-reduction of antibody values using titration studies was significantly more uniform compared with either IgG or C1q tests. Analyzing antibody results using only C1q positive or only higher MFI values did not change the overall magnitude of results. Overall, titration studies provided better estimate of responsiveness to treatment and thus can serve as companion to monitoring efficacy of antibody-removal therapies., (Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: The review describes the current clinical relevance of circulating anti-human leukocyte antigen (anti-HLA) antibodies in kidney transplantation and discusses recent improvements in their characterization that provide new insights into the identification and management of important clinical outcomes., Recent Findings: Recent studies addressing the relationships between donor-specific anti-HLA antibody (HLA-DSA) properties (i.e., their strength, complement-binding capacity, and IgG subclass composition) and allograft injury and survival have highlighted their relevance in the prediction of antibody-mediated injury and allograft loss., Summary: Antibody-mediated rejection is the leading cause of kidney allograft loss. Although considerable experimental and clinical evidence suggests a causal effect of circulating HLA-DSAs in antibody-mediated rejection and allograft failure, HLA-DSAs induce a wide spectrum of injuries to the allograft that illustrate the need to delineate the characteristics of HLA-DSAs that confer pathogenesis. Current risk stratification is based on HLA-DSA characteristics, including antibody specificity, HLA class, and strength. Recently, the complement-binding capacity of HLA-DSAs has been recognized as a clinically relevant marker for predicting pathogenicity and allograft loss. Emerging data also support a role for HLA-DSA IgG subclass composition in discriminating distinct patterns of antibody-mediated injury. This progress in our understanding of HLA-DSA pathogenicity provides new tools to stratify individual immunological risks. However, specific prospective studies addressing immunological risk stratification in large and unselected populations are required to define the clinical benefit and cost-effectiveness of such a comprehensive assessment of HLA-DSAs before implementation in current clinical practice.