Publications by authors named "Jean-Paul Duong van Huyen"

84 Publications

[Pathology of heart transplantation: Where are we now?]

Ann Pathol 2021 Feb 4;41(1):38-49. Epub 2021 Jan 4.

Service d'anatomie et cytologie pathologiques, hôpital Necker-Enfant malades, 149, rue de Sèvres, 75015 Paris, France; Université de Paris, Paris, France; Inserm UMRS U970, Paris Transplant Group, PARCC HEGP, Paris, France. Electronic address:

Pathology is still the gold standard for the diagnosis of rejection in heart transplantation. During the last decade, molecular pathology has emerged as a powerful tool for the understanding of the processes implicated in allograft rejection. Transcriptomic analysis of the allograft may also help the pathologist for diagnosis and accurate classification of rejection. This review will describe the recent advances and perspectives of molecular pathology in the field of heart transplantation.
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http://dx.doi.org/10.1016/j.annpat.2020.12.001DOI Listing
February 2021

[A protocol endomyocardial biopsy during follow-up of a cardiac transplanted patient].

Ann Pathol 2021 Feb 23;41(1):106-109. Epub 2020 Nov 23.

Service d'anatomie pathologique, hôpital européen Georges-Pompidou, Assistance Publique-Hôpitaux de Paris, 20, rue Leblanc, 75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2020.10.005DOI Listing
February 2021

[A protocol endomyocardial biopsy during follow-up of a cardiac transplanted patient (No. 2)].

Ann Pathol 2021 Feb 16;41(1):110-112. Epub 2020 Oct 16.

Service d'anatomie pathologique, hôpital européen Georges-Pompidou, AP-HP, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2020.09.009DOI Listing
February 2021

[A for-cause endomyocardial biopsy during follow-up of a cardiac transplanted patient].

Ann Pathol 2021 Feb 6;41(1):114-117. Epub 2020 Oct 6.

Service d'anatomie pathologique, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris, 20, rue Leblanc, 75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2020.09.005DOI Listing
February 2021

The XVth Banff Conference on Allograft Pathology the Banff Workshop Heart Report: Improving the diagnostic yield from endomyocardial biopsies and Quilty effect revisited.

Am J Transplant 2020 12 28;20(12):3308-3318. Epub 2020 Jun 28.

Department of Pathology, Stanford University, Stanford, California, USA.

The XVth Banff Conference on Allograft Pathology meeting was held on September 23-27, 2019, in Pittsburgh, Pennsylvania, USA. During this meeting, two main topics in cardiac transplant pathology were addressed: (a) Improvement of endomyocardial biopsy (EMB) accuracy for the diagnosis of rejection and other significant injury patterns, and (b) the orphaned lesion known as Quilty effect or nodular endocardial infiltrates. Molecular technologies have evolved in recent years, deciphering pathophysiology of cardiac rejection. Diagnostically, it is time to integrate the histopathology of EMBs and molecular data. The goal is to incorporate molecular pathology, performed on the same paraffin block as a companion test for histopathology, to yield more accurate and objective EMB interpretation. Application of digital image analysis from hematoxylin and eosin (H&E) stain to multiplex labeling is another means of extracting additional information from EMBs. New concepts have emerged exploring the multifaceted significance of myocardial injury, minimal rejection patterns supported by molecular profiles, and lesions of arteriolitis/vasculitis in the setting of T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR). The orphaned lesion known as Quilty effect or nodular endocardial infiltrates. A state-of-the-art session with historical aspects and current dilemmas was reviewed, and possible pathogenesis proposed, based on advances in immunology to explain conflicting data. The Quilty effect will be the subject of a multicenter project to explore whether it functions as a tertiary lymphoid organ.
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http://dx.doi.org/10.1111/ajt.16083DOI Listing
December 2020

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

Am J Transplant 2020 09 28;20(9):2318-2331. Epub 2020 May 28.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.

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.
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http://dx.doi.org/10.1111/ajt.15898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496245PMC
September 2020

Banff 2019 Meeting Report: Molecular diagnostics in solid organ transplantation-Consensus for the Banff Human Organ Transplant (B-HOT) gene panel and open source multicenter validation.

Am J Transplant 2020 09 27;20(9):2305-2317. Epub 2020 Jun 27.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

This meeting report from the XV Banff conference describes the creation of a multiorgan transplant gene panel by the Banff Molecular Diagnostics Working Group (MDWG). This Banff Human Organ Transplant (B-HOT) panel is the culmination of previous work by the MDWG to identify a broadly useful gene panel based on whole transcriptome technology. A data-driven process distilled a gene list from peer-reviewed comprehensive microarray studies that discovered and validated their use in kidney, liver, heart, and lung transplant biopsies. These were supplemented by genes that define relevant cellular pathways and cell types plus 12 reference genes used for normalization. The 770 gene B-HOT panel includes the most pertinent genes related to rejection, tolerance, viral infections, and innate and adaptive immune responses. This commercially available panel uses the NanoString platform, which can quantitate transcripts from formalin-fixed paraffin-embedded samples. The B-HOT panel will facilitate multicenter collaborative clinical research using archival samples and permit the development of an open source large database of standardized analyses, thereby expediting clinical validation studies. The MDWG believes that a pathogenesis and pathway based molecular approach will be valuable for investigators and promote therapeutic decision-making and clinical trials.
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http://dx.doi.org/10.1111/ajt.16059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496585PMC
September 2020

1-Methyluric Acid Nephropathy.

Kidney Int Rep 2020 May 22;5(5):737-741. Epub 2020 Feb 22.

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S 1155, Assistance Publique des Hôpitaux de Paris Service des Explorations Fonctionnelles Multidisciplinaires, Hôpital Tenon, Paris, France.

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http://dx.doi.org/10.1016/j.ekir.2020.02.1026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210604PMC
May 2020

Identification and Characterization of Trajectories of Cardiac Allograft Vasculopathy After Heart Transplantation: A Population-Based Study.

Circulation 2020 Jun 4;141(24):1954-1967. Epub 2020 May 4.

Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (R.L., J.K.P., J.K.).

Background: Cardiac allograft vasculopathy (CAV) is a major contributor of heart transplant recipient mortality. Little is known about the prototypes of CAV trajectories at the population level. We aimed to identify the different evolutionary profiles of CAV and to determine the respective contribution of immune and nonimmune factors in CAV development.

Methods: Heart transplant recipients were from 4 academic centers (Pitié-Salpêtrière and Georges Pompidou Hospital, Paris, Katholieke Universiteit Leuven, and Cedars-Sinai, Los Angeles; 2004-2016). Patients underwent prospective, protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical, histological, and immunologic parameters. The main outcome was a prediction for CAV trajectory. We identified CAV trajectories by using unsupervised latent class mixed models. We then identified the independent predictive variables of the CAV trajectories and their association with mortality.

Results: A total of 1301 patients were included (815 and 486 in the European and US cohorts, respectively). The median follow-up after transplantation was 6.6 (interquartile range, 4-9.1) years with 4710 coronary angiographies analyzed. We identified 4 distinct profiles of CAV trajectories over 10 years. The 4 trajectories were characterized by (1) patients without CAV at 1 year and nonprogression over time (56.3%), (2) patients without CAV at 1 year and late-onset slow CAV progression (7.6%), (3) patients with mild CAV at 1 year and mild progression over time (23.1%), and (4) patients with mild CAV at 1 year and accelerated progression (13.0%). This model showed good discrimination (0.92). Among candidate predictors assessed, 6 early independent predictors of these trajectories were identified: donor age (<0.001), donor male sex (<0.001), donor tobacco consumption (=0.001), recipient dyslipidemia (=0.009), class II anti-human leukocyte antigen donor-specific antibodies (=0.004), and acute cellular rejection ≥2R (=0.028). The 4 CAV trajectories manifested consistently in the US independent cohort with similar discrimination (0.97) and in different clinical scenarios, and showed gradients for overall-cause mortality (<0.001).

Conclusions: In a large multicenter and highly phenotyped prospective cohort of heart transplant recipients, we identified 4 CAV trajectories and their respective independent predictive variables. Our results provide the basis for a trajectory-based assessment of patients undergoing heart transplantation for early risk stratification, patient monitoring, and clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04117152.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044924DOI Listing
June 2020

Severe and progressive neuronal loss in myelomeningocele begins before 16 weeks of pregnancy.

Am J Obstet Gynecol 2020 08 10;223(2):256.e1-256.e9. Epub 2020 Apr 10.

Department of Obstetrics and Maternal-Fetal Medicine, Necker-Enfants Malades Hospital, AP-HP and Paris Descartes University; EHU FETUS, Université de Paris and IMAGINE Institute. Electronic address:

Background: Despite undisputable benefits, midtrimester prenatal surgery is not a cure for myelomeningocele (MMC): residual intracranial and motor deficits leading to lifelong handicap question the timing of prenatal surgery. Indeed, the timing and intensity of intrauterine spinal cord injury remains ill defined.

Objective: We aimed to describe the natural history of neuronal loss in MMC in utero based on postmortem pathology.

Study Design: Pathology findings were analyzed in 186 cases of myelomeningocele with lesion level between S1 and T1. Using a case-control, cross-sectional design, we investigated the timewise progression and topographic extension of neuronal loss between 13 and 39 weeks. Motor neurons were counted on histology at several spinal levels in 54 isolated MMC meeting quality criteria for cell counting. These were expressed as observed-to-expected ratios, after matching for gestational age and spinal level with 41 controls.

Results: Chiari II malformation increased from 30.7% to 91.6% after 16 weeks. The exposed spinal cord displayed early, severe, and progressive neuronal loss: the observed-to-expected count dropped from 17% to ≤2% after 16 weeks. Neuronal loss extended beyond the lesion to the upper levels: in cases <16 weeks, the observed-to-expected motor neuron count was 60% in the adjacent spinal cord, decreasing at a rate of 16% per week. Progressive loss was also found in the upper thoracic cord, but in much smaller proportions. The observed-over-expected ratio of motor neurons was not correlated with the level of myelomeningocele.

Conclusions: Significant neuronal loss is present ≤16 weeks in the exposed cord and progressively extends cranially. Earlier prenatal repair (<16 weeks) could prevent Chiari II malformation in 69.3% of cases, rescue the 17% remaining motor neurons in the exposed cord, and prevent the extension to the upper spinal cord.
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http://dx.doi.org/10.1016/j.ajog.2020.02.052DOI Listing
August 2020

Reverse transcriptase multiplex ligation-dependent probe amplification in endomyocardial biopsies for the diagnosis of cardiac allograft rejection.

J Heart Lung Transplant 2020 02 26;39(2):115-124. Epub 2019 Nov 26.

Paris Translational Research Centre for Organ Transplantation, INSERM, UMR-S970, Paris, France; Pathology department, Hôpital Necker, Assistance Publique - Hôpitaux de Paris and Paris Descartes University, Paris, France; Pathology department, Nantes University, Nantes, France. Electronic address:

Background: Molecular biology has emerged as a potential companion to histology for the diagnosis of rejection after heart transplantation. Reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) is a technique of targeted gene expression analysis suitable for formalin-fixed paraffin-embedded (FFPE) biopsies. Our aim was to assess RT-MLPA for the diagnosis of allograft rejection in heart transplantation.

Methods: We performed a cross-sectional, case-control, multicenter study. After the selection of a 14-transcript panel (endothelial burden, Natural killer cells, interferon-γ pathway, effector T-cells, and antigen presentation), RT-MLPA was applied to 183 FFPE endomyocardial biopsies (EMB), randomized into a training (n = 113) and a validation (n = 70) series. A two-step class prediction analysis was developed (Linear prediction score-LPS1: rejection vs non-rejection; LPS2: antibody-mediated rejection [AMR] vs acute cellular rejection [ACR]). A study of the agreement between pathology and RT-MLPA was performed.

Results: Overall, 48 ACR, 82 AMR, 5 mixed rejection, and 48 non-rejection EMBs were analyzed. Three molecular clusters were delineated by unsupervised hierarchical analysis (molecular non-rejection, ACR, and AMR). AMR was characterized by the high expression of CCL4, GNLY, FCGR3, CXCL11 and ACR by the high expression of CCL18 and ADAMdec. RT-MLPA and histopathology agreed in the final diagnosis in 82.2%, 67.7%, and 76.8% of the EMB in the test, validation, and overall cohort, respectively. Disagreement cases were more common in the case of histologic low-grade rejection and early post-transplant EMB.

Conclusions: RT-MLPA is a suitable technique for targeted gene expression analysis on FFPE EMB with a good overall agreement with the histologic diagnosis of heart allograft rejection.
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http://dx.doi.org/10.1016/j.healun.2019.11.010DOI Listing
February 2020

[Erratum to "A better characterization of kidney allograft rejection infiltrates using in situ multiplex immunofluorescence" [Nephrol. Ther. 15S (2019) S43-S52]].

Nephrol Ther 2019 12;15(7):553

Laboratoire d'anatomie et cytologie pathologiques, hôpital Necker-enfants malades, 149, rue de Sèvres, 75015 Paris, France; Inserm, U1151, institut Necker-enfants-malades, 149, rue de Sèvres, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris cité, 12, rue de l'École-de-Médecine, 75006 Paris, France; Paris translational research center for organ transplantation, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.nephro.2019.11.001DOI Listing
December 2019

Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants.

Nat Commun 2019 11 25;10(1):5350. Epub 2019 Nov 25.

CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France.

Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of β2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection.
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http://dx.doi.org/10.1038/s41467-019-13113-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877588PMC
November 2019

In situ multiplex immunofluorescence analysis of the inflammatory burden in kidney allograft rejection: A new tool to characterize the alloimmune response.

Am J Transplant 2020 04 11;20(4):942-953. Epub 2019 Dec 11.

Department of Pathology, Necker Hospital, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.

The exact composition of leukocyte infiltration during kidney allograft rejection is difficult to comprehend and visualize on the same biopsy slide. Using an innovative technology of multiplex immunofluorescence (mIF), we were able to detect simultaneously NK cells, macrophages, and T cells and to determine their intra- or extravascular localization using an endothelial marker. Twenty antibody-mediated rejection (ABMR), 20 T cell-mediated rejection (TCMR), and five normal biopsies were labeled, with automatic leukocyte quantification and localization. This method was compared to a classic NKp46 immunohistochemistry (IHC) with manual quantification and to mRNA quantification. mIF automatic quantification was strongly correlated to IHC (r = .91, P < .001) and to mRNA expression levels (r > .46, P < .021). T cells and macrophages were the 2 predominant populations involved in rejection (48.0 ± 4.4% and 49.3 ± 4.4%, respectively, in ABMR; 51.8 ± 6.0% and 45.3 ± 5.8% in TCMR). NK cells constituted a rare population in both ABMR (2.7 ± 0.7%) and TCMR (2.9 ± 0.6%). The intravascular compartment was mainly composed of T cells, including during ABMR, in peritubular and glomerular capillaries. However, NK cell and macrophage densities were significantly higher during ABMR in glomerular and peritubular capillaries. To conclude, this study demonstrates the feasibility and utility of mIF imaging to study and better understand the kidney allograft rejection process.
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http://dx.doi.org/10.1111/ajt.15699DOI Listing
April 2020

Non-HLA agonistic anti-angiotensin II type 1 receptor antibodies induce a distinctive phenotype of antibody-mediated rejection in kidney transplant recipients.

Kidney Int 2019 07 15;96(1):189-201. Epub 2019 Mar 15.

Clinic for Nephrology and Critical Care Medicine, Campus Virchow-Klinikum, Charité Universitätsmedizin Berlin, Germany; Center for Cardiovascular Research, Medical Faculty of the Charité Berlin, Berlin, Germany.

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.
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http://dx.doi.org/10.1016/j.kint.2019.01.030DOI Listing
July 2019

In situ multiplex immunofluorescence analysis of the inflammatory burden in kidney allograft rejection: A new tool to characterize the alloimmune response.

Nephrol Ther 2019 04;15 Suppl 1:S43-S52

Université Paris Descartes, Sorbonne Paris Cité, 12, rue de l'École-de-Médecine, 75006 Paris, France; Inserm, UMR-S970, 20, rue Leblanc, 75015 Paris, France; Laboratoire d'anatomie et cytologie pathologiques, hôpital européen Georges-Pompidou, 20 rue Leblanc, 75015 Paris, France.

Background: The exact composition and localization of the inflammatory burden during allograft rejection is difficult to analyse on the same biopsy slide. We tested the feasibility of detecting four distinct markers in a same paraffin-embedded tissue section from human kidney allograft rejection by using an innovative process of multiplex immunofluorescence. Methods: Kidney allograft biopsies from 20 antibody-mediated rejection, 20 T cell-mediated rejection and five non rejection were labelled against NKp46, CD163, CD3, and CD34 respectively for NK cells, macrophages, T cells and endothelial cells. Images were scanned and cells were automatically quantified and their extra- or intravascular location determined. Conventional immunohistochemistry against NKp46 with manual quantification and real time quantitative polymerase chain reaction for evaluation of the relative messenger ribonucleic acid (mRNA) expression levels of NK, T cell and macrophage transcripts were simultaneously performed. Results: Multiplex immunofluorescence cell quantification was strongly correlated to manual quantification by immunohistochemistry (r = 0.91, P < 0.001) and to mRNA expression levels (r > 0.46, P < 0.021). T cells and macrophages were the two predominant populations involved in rejection (48.0 ± 4.4% and 49.3 ± 4.4% in antibody-mediated rejection; 51.8 ± 6.0% and 45.3 ± 5.8% in T cell-mediated rejection respectively) despite an important heterogeneity in the composition of the inflammatory burden. NK cells constituted a rare population for both T cell-mediated rejection (2.9 ± 0.6%) and antibody-mediated rejection (2.7 ± 0.7%). The intravascular compartment was mainly composed of T cells, including during antibody-mediated rejection. However, NK cells and macrophages densities were significantly higher in capillaries during antibody-mediated rejection. Conclusion: Multiplex immunofluorescence staining is a reliable technology allowing studying the exact composition and localization of the inflammatory burden during kidney allograft rejection..
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http://dx.doi.org/10.1016/j.nephro.2019.03.008DOI Listing
April 2019

Archetype Analysis Identifies Distinct Profiles in Renal Transplant Recipients with Transplant Glomerulopathy Associated with Allograft Survival.

J Am Soc Nephrol 2019 04 14;30(4):625-639. Epub 2019 Mar 14.

Paris Translational Research Center for Organ Transplantation, Institut national de la santé et de la recherche médicale, Unité mixte de recherche-S970, Paris, France;

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.
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http://dx.doi.org/10.1681/ASN.2018070777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442337PMC
April 2019

Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens.

J Am Soc Nephrol 2019 04 8;30(4):692-709. Epub 2019 Mar 8.

Paris Descartes, Sorbonne Paris Cité University, Paris, France;

Background: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.

Methods: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.

Results: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.

Conclusions: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that cell-based assays are needed to improve risk assessments before transplant.
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http://dx.doi.org/10.1681/ASN.2018080868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442343PMC
April 2019

Response to treatment and long-term outcomes in kidney transplant recipients with acute T cell-mediated rejection.

Am J Transplant 2019 07 15;19(7):1972-1988. Epub 2019 Mar 15.

Paris Translational Research Center for Organ Transplantation, INSERM, UMR-S970, Paris, France.

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.
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http://dx.doi.org/10.1111/ajt.15299DOI Listing
July 2019

Antibody-mediated rejection in pediatric small bowel transplantation: Capillaritis is a major determinant of C4d positivity in intestinal transplant biopsies.

Am J Transplant 2018 09 24;18(9):2250-2260. Epub 2018 Mar 24.

Pathology Department, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.

The diagnostic criteria for antibody-mediated rejection (ABMR) after small bowel transplantation (SBT) are not clearly defined, although the presence of donor-specific antibodies (DSAs) has been reported to be deleterious for graft survival. We aimed to determine the incidence and prognostic value of DSAs and C4d in pediatric SBT and to identify the histopathologic features associated with C4d positivity. We studied all intestinal biopsies (IBx) obtained in the first year posttransplantation (N = 345) in a prospective cohort of 23 children. DSAs and their capacity to fix C1q were identified by using Luminex technology. Eighteen patients (78%) had DSAs, and 9 had the capacity to fix C1q. Seventy-eight IBx (22.6%) were C4d positive. The independent determinants of C4d positivity were capillaritis grades 2 and 3 (odds ratio [OR] 4.02, P = .047 and OR 5.17, P = .003, respectively), mucosal erosion/ulceration (OR 2.8, P = .019), lamina propria inflammation grades 1 and 2/3 (OR 1.95, P = .043 and OR 3.1, P = .016, respectively), and chorion edema (OR 2.16, P = .028). Complement-fixing DSAs and repeated C4d-positive IBx were associated with poor outcome (P = .021 and P = .001, respectively). Our results support that capillaritis should be considered as a feature of ABMR in SBT and identify C1q-fixing DSAs and repeated C4d positivity as potential markers of poor outcome.
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http://dx.doi.org/10.1111/ajt.14685DOI Listing
September 2018

Dynamic Prognostic Score to Predict Kidney Allograft Survival in Patients with Antibody-Mediated Rejection.

J Am Soc Nephrol 2018 02 18;29(2):606-619. Epub 2017 Dec 18.

Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S970, Paris, France;

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 (<0.001) and presence of interstitial fibrosis/tubular atrophy (=0.003) at diagnosis and changes in GFR (<0.001), peritubular capillaritis Banff score (=0.002), and DSA mean fluorescence intensity (<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, =40), 44.9% (intermediate-risk group, =36), and 84.4% (low-risk group, =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.
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http://dx.doi.org/10.1681/ASN.2017070749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791064PMC
February 2018

Isolated v-lesion in kidney transplant recipients: Characteristics, association with DSA, and histological follow-up.

Am J Transplant 2018 04 12;18(4):972-981. Epub 2018 Jan 12.

Pathology department, Tenon Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Isolated v-lesion (IvL) represents a rare and challenging situation in renal allograft biopsies because it is unknown whether IvL truly represents rejection, antibody- or T cell-mediated, or not. This multicentric retrospective study describes the clinicopathological features of IvL with an emphasis on the donor-specific antibody (DSA) status, histological follow-up, and graft survival. Inclusion criteria were the presence of v-lesion with minimal interstitial (i ≤ 1) and microvascular inflammation (g + ptc≤1). C4d-positive biopsies were excluded. We retrospectively found 33 IvL biopsies in 33 patients, mainly performed in the early posttransplantation period (median time 27 days) and clinically indicated in 66.7%. A minority of recipients (5/33, 15.2%) had DSA at the time of biopsy. IvL was treated by anti-rejection therapy in 21 cases (63.6%), whereas 12 (36.4%) were untreated. Seventy percent of untreated patients and 66% of treated patients showed favorable histological evolution on subsequent biopsy. Kidney graft survival in IvL was significantly higher than in a matched cohort of antibody-mediated rejection with arteritis. In conclusion, IvL is not primarily antibody-mediated and may show a favorable evolution. The heterogeneity of IvL pathophysiology on early biopsies should prompt DSA testing as well as close clinical and histological follow-up in all patients with IvL.
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http://dx.doi.org/10.1111/ajt.14617DOI Listing
April 2018

Endothelial chimerism and vascular sequestration protect pancreatic islet grafts from antibody-mediated rejection.

J Clin Invest 2018 01 20;128(1):219-232. Epub 2017 Nov 20.

French National Institute of Health and Medical Research (INSERM) Unit 1111, Lyon, France.

Humoral rejection is the most common cause of solid organ transplant failure. Here, we evaluated a cohort of 49 patients who were successfully grafted with allogenic islets and determined that the appearance of donor-specific anti-HLA antibodies (DSAs) did not accelerate the rate of islet graft attrition, suggesting resistance to humoral rejection. Murine DSAs bound to allogeneic targets expressed by islet cells and induced their destruction in vitro; however, passive transfer of the same DSAs did not affect islet graft survival in murine models. Live imaging revealed that DSAs were sequestrated in the circulation of the recipients and failed to reach the endocrine cells of grafted islets. We used murine heart transplantation models to confirm that endothelial cells were the only accessible targets for DSAs, which induced the development of typical microvascular lesions in allogeneic transplants. In contrast, the vasculature of DSA-exposed allogeneic islet grafts was devoid of lesions because sprouting of recipient capillaries reestablished blood flow in grafted islets. Thus, we conclude that endothelial chimerism combined with vascular sequestration of DSAs protects islet grafts from humoral rejection. The reduced immunoglobulin concentrations in the interstitial tissue, confirmed in patients, may have important implications for biotherapies such as vaccines and monoclonal antibodies.
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http://dx.doi.org/10.1172/JCI93542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749508PMC
January 2018

T cell-mediated rejection is a major determinant of inflammation in scarred areas in kidney allografts.

Am J Transplant 2018 02 21;18(2):377-390. Epub 2017 Nov 21.

Paris Translational Research Center for Organ Transplantation, INSERM, UMR-S970, Paris, France.

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.
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http://dx.doi.org/10.1111/ajt.14565DOI Listing
February 2018

Complement-Activating Anti-HLA Antibodies in Kidney Transplantation: Allograft Gene Expression Profiling and Response to Treatment.

J Am Soc Nephrol 2018 02 17;29(2):620-635. Epub 2017 Oct 17.

Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche-S970, Paris, France.

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 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 (, , , , and ) indicative of endothelial activation, IFN 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%; =0.001) but not in those with noncomplement-activating DSAs (9%; 95% CI, 2% to 25% versus 13%; 95% CI, 2% to 40%; =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.
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http://dx.doi.org/10.1681/ASN.2017050589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791056PMC
February 2018

Building a tissue-based molecular diagnostic system in heart transplant rejection: The heart Molecular Microscope Diagnostic (MMDx) System.

J Heart Lung Transplant 2017 Nov 29;36(11):1192-1200. Epub 2017 May 29.

Paris Translational Research Centre for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale , UMR-S970, Paris, France.

Background: The emergence of molecular systems offers opportunities for improving the assessment of rejection in heart transplant biopsy specimens. The present study developed a microarray-based system for assessing heart transplant endomyocardial biopsy (EMB) specimens.

Methods: We analyzed 331 protocol or for-cause EMB specimens from 221 subjects in 3 centers (Edmonton, Bologna, and Paris). Unsupervised principal component analysis (PCA) and archetype analysis used rejection-associated transcripts (RATs) shown in kidney transplants to be associated with antibody-mediated rejection (ABMR) or T cell-mediated rejection (TCMR), or both. To compare EMB specimens to kidney biopsy specimens, rejection status in both was simplified to TCMR, ABMR, or no rejection.

Results: The pattern of RAT expression was similar in EMB and kidney specimens, permitting use of RATs to assign scores and group ("cluster") membership to each EMB, independent of histology. Three clusters emerged in EMB specimens, similar to kidney specimens: TCMR, ABMR, and no rejection. This permitted each EMB specimen to be given 3 scores and assigned to 1 cluster by its highest score. There was significant agreement between molecular phenotype-archetype scores or clusters-and both histologic diagnoses and donor-specific antibody. Area under curve estimates for predicting histologic TCMR, ABMR, and no rejection by molecular assessment were lower in EMB specimens than in kidney specimens, reflecting more uncertainty in EMB specimens, particularly in histologic diagnosis of TCMR.

Conclusions: Rejection-associated transcripts can be used to estimate the probability of TCMR and ABMR in heart transplant specimens, providing a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines.
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http://dx.doi.org/10.1016/j.healun.2017.05.029DOI Listing
November 2017

Circulating donor-specific anti-HLA antibodies are a major factor in premature and accelerated allograft fibrosis.

Kidney Int 2017 09 26;92(3):729-742. Epub 2017 May 26.

Paris Translational Research Center for Organ Transplantation, Institut national de la santé et de la recherche médicale, Unité mixte de recherche-S970, Paris, France; Department of Nephrology and Kidney Transplantation, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

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.
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http://dx.doi.org/10.1016/j.kint.2017.03.033DOI Listing
September 2017

Antibody-Mediated Rejection Due to Preexisting versus Donor-Specific Antibodies in Kidney Allograft Recipients.

J Am Soc Nephrol 2017 Jun 2;28(6):1912-1923. Epub 2017 Mar 2.

Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada.

Antibody-mediated rejection (ABMR) can occur in patients with preexisting anti-HLA donor-specific antibodies (DSA) or in patients who develop 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 (=205). Overall, 103 (50%) patients had preexisting DSA and 102 (50%) had DSA. Compared with patients with preexisting DSA ABMR, patients with DSA ABMR displayed increased proteinuria, more transplant glomerulopathy lesions, and lower glomerulitis, but similar levels of peritubular capillaritis and C4d deposition. DSA ABMR was characterized by increased expression of IFN-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 DSA ABMR (63% versus 34% at 8 years after rejection, respectively; <0.001). After adjusting for clinical, histologic, and immunologic characteristics and treatment, we identified DSA ABMR (hazard ratio [HR], 1.82 compared with preexisting DSA ABMR; 95% confidence interval [95% CI], 1.07 to 3.08; =0.03); low eGFR (<30 ml/min per 1.73 m) at diagnosis (HR, 3.27; 95% CI, 1.48 to 7.23; <0.001); ≥0.30 g/g urine protein-to-creatinine ratio (HR, 2.44; 95% CI, 1.47 to 4.09; <0.001); and presence of cg lesions (HR, 2.25; 95% CI, 1.34 to 3.79; =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 DSA.
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http://dx.doi.org/10.1681/ASN.2016070797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461792PMC
June 2017

Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection.

Circulation 2017 Mar 1;135(10):917-935. Epub 2017 Feb 1.

From Paris Descartes University and Hôpital Necker, Assistance Publique-Hôpitaux de Paris, France (A.L., J.P.D.V.H., M.R.); Paris Translational Research Centre for Organ Transplantation, INSERM, UMR-S970, France (A.L., J.P.D.V.H., O.A., T.B., J.P.E., C.L., P.B., X.J.); Pathology Department, Necker Hospital, Paris, France (J.P.D.V.H.); Alberta Transplant Applied Genomics Centre; University of Alberta, Edmonton, AB, Canada (L.H., J.R., J.M.V., K.F., P.F.H.); Cardiology Department and Intensive Care (M.C.B.), Cardiology and Heart Transplant Department (R.G., X.J.), and Pathology Department (P.B.), Georges Pompidou Hospital, Paris, France; Pathology (P.R.) and Cardiac Surgery Departments (S.V., P.L.), La Pitié Salpétrière Hospital, Paris; Pathology (C.T.) and Thoracic and Cardiovascular Surgery Departments (S.P), Laennec Hospital, Nantes; Pathology (A.F.) and Cardiovascular Surgery Departments (A.G), Charles Nicolle Hospital, Rouen, France.

Background: Antibody-mediated rejection (AMR) contributes to heart allograft loss. However, an important knowledge gap remains in terms of the pathophysiology of AMR and how detection of immune activity, injury degree, and stage could be improved by intragraft gene expression profiling.

Methods: We prospectively monitored 617 heart transplant recipients referred from 4 French transplant centers (January 1, 2006-January 1, 2011) for AMR. We compared patients with AMR (n=55) with a matched control group of 55 patients without AMR. We characterized all patients using histopathology (ISHLT [International Society for Heart and Lung Transplantation] 2013 grades), immunostaining, and circulating anti-HLA donor-specific antibodies at the time of biopsy, together with systematic gene expression assessments of the allograft tissue, using microarrays. Effector cells were evaluated with in vitro human cell cultures. We studied a validation cohort of 98 heart recipients transplanted in Edmonton, AB, Canada, including 27 cases of AMR and 71 controls.

Results: A total of 240 heart transplant endomyocardial biopsies were assessed. AMR showed a distinct pattern of injury characterized by endothelial activation with microcirculatory inflammation by monocytes/macrophages and natural killer (NK) cells. We also observed selective changes in endothelial/angiogenesis and NK cell transcripts, including CD16A signaling and interferon-γ-inducible genes. The AMR-selective gene sets accurately discriminated patients with AMR from those without and included NK transcripts (area under the curve=0.87), endothelial activation transcripts (area under the curve=0.80), macrophage transcripts (area under the curve=0.86), and interferon-γ transcripts (area under the curve=0.84; <0.0001 for all comparisons). These 4 gene sets showed increased expression with increasing pathological AMR (pAMR) International Society for Heart and Lung Transplantation grade (<0.001) and association with donor-specific antibody levels. The unsupervised principal components analysis demonstrated a high proportion of molecularly inactive pAMR1(I+), and there was significant molecular overlap between pAMR1(H) and full-blown pAMR2/3 cases. Endothelial activation transcripts, interferon-γ, and NK transcripts showed association with chronic allograft vasculopathy. The molecular architecture and selective AMR transcripts, together with gene set discrimination capacity for AMR identified in the discovery set, were reproduced in the validation cohort.

Conclusions: Tissue-based measurements of specific pathogenesis-based transcripts reflecting NK burden, endothelial activation, macrophage burden, and interferon-γ effects accurately classify AMR and correlate with degree of injury and disease activity. This study illustrates the clinical potential of a tissue-based analysis of gene transcripts to refine diagnosis of heart transplant rejection.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022907DOI Listing
March 2017

Long-term Outcomes of Kidney Transplantation in Patients With High Levels of Preformed DSA: The Necker High-Risk Transplant Program.

Transplantation 2017 10;101(10):2440-2448

1 Department of Nephrology-Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, University Paris Descartes, Paris, France. 2 INSERM U1151, Paris, France. 3 Paris Translational Research Center for Organ Transplantation, INSERM U970, Paris, France. 4 Department of Immunology and Histocompatibility, Saint-Louis Hospital, Paris, France. 5 Department of Pathology, Necker Hospital, Paris, France. 6 Kidney Transplant Unit, Instituto de Medicina Integral, Recife, Brazil. 7 Department of Urology, Georges Pompidou European Hospital, Paris, France. 8 Department of Anesthesiology, Necker Hospital, Paris, France. 9 Centaure Foundation and Labex Transplantex, Necker Hospital, Paris, France.

Background: There is an increasing number of anti-HLA sensitized and highly sensitized renal transplant candidates on waiting lists, and the presence of donor-specific alloantibodies (DSAs) at the time of transplantation leads to acute and chronic antibody-mediated rejection (AMR). Acceptable short-term outcomes have been described, notably because of desensitization protocols, but mid- and long-term data are still required.

Methods: Our high immunologic risk program included 95 patients with high peak or day 0 DSA levels (mean fluorescence intensity [MFI] > 3000) with a complement-dependent cytotoxicity-negative crossmatch, who received a posttransplant desensitization protocol starting at day 0 with high-dose intravenous immunoglobulin, plasma exchanges, and eventually rituximab. Their characteristics were compared with a control group including 39 patients with a lower immunologic risk (MFI between 500 and 3000 at day 0) who received the same posttransplant desensitization.

Results: The median MFI of the immunodominant class I or II DSA in the peak or day 0 serum was 9421 (interquartile range, 4959-12 610). An AMR occurred during the first posttransplant year in 31 patients (32.6%), and at one year, the rate of chronic AMR was 39.5%. The 1-, 3-, 5- and 7-year death-censored allograft survival rates were 98%, 91%, 86%, and 78%, respectively, with concomitant recipient survival rates of 97%, 93%, 85%, and 79%, respectively.

Conclusions: These results suggest that DSA-sensitized patients with high MFI levels can receive transplantation across the HLA-barrier, with the use of an intensified posttransplant immunosuppressive therapy starting at day 0 combined with close clinical, immunologic, and histologic monitoring.
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http://dx.doi.org/10.1097/TP.0000000000001650DOI Listing
October 2017