Rôle pronostic des anticorps anti-HLA en transplantation rénale : approches en population

Background : The alloimmune response induced by transplantation from a donor who differs genetically from the kidney recipient has always been the major obstacle to graft success. The present work aimed to improve characterization of kidney-allograft rejection phenotypes and identify how each one is associated with anti-HLA antibodies. We also sought to determine whether characteristics of these antibodies i.e., their levels or complementbinding ability, might play a role in kidney allograft failure. Finally, we evaluated the clinical relevance of indolent forms of ABMR and the clinical relevance of new genes expression technologies to stratify the kidney recipients at risk for failure. Methods : We used a population-based approach in precisely phenotyped cohorts of kidney recipients. The design of our study, which is based on the concomitant evaluation of immunologic and histologic data, permits a precise connection of circulating anti-HLA antibodies with a phenotype of graft injury. Findings : We identified four distinct patterns of kidney allograft rejection: T cell-mediated vascular rejection (9%), antibody-mediated vascular rejection (21%), not included in international classifications, T cell- (46%) and antibody-mediated rejection without vasculitis (24%). Risk of graft loss was 9.07 times (95CI 3.6-19.7) higher in antibody-mediated vascular rejection than in T-cell mediated rejections (p<0.0001). Patients with post-transplant complement-binding DSA had more severe graft injury phenotype with higher inflammation and increased deposition of complement fraction C4d. They have the poorest graft survival with 3.7 fold increased risk of graft loss (95CI 1.9-7.2). Subclinical ABMR is a truncated for of rejection associated with risk of kidney allograft failure. Gene expression assessment in kidney allografts with early ABMR improves classification of individuals at risk for kidney allograft loss. Conclusion : This work addresses the unmet need of the deleterious impact of anti-HLA antibodies and the improvement of risk stratification in kidney transplantation. Recognition of distinct phenotypes could lead to the development of new treatment strategies. Gene expression assessment appears useful to evaluate disease activity, disease state and prediction of failure.Contexte : La réponse allo-immune induite par la transplantation à partir d'un donneur génétiquement différent est un obstacle majeur au succès de la greffe. Notre objectif est de caractériser les différents phénotypes de rejet d'allogreffe rénale et d'identifier la façon dont chacun est associé aux anticorps anti-HLA. Nous avons également évalué l’impact de certaines propriétés de ces anticorps, comme leur intensité ou leur capacité à fixer le complément, sur l'échec des allogreffes rénales. Pour finir, nous avons étudié l’impact pronostic des formes indolentes de rejets ainsi que l’apport des nouvelles technologies d’analyses transcriptomique des biopsies de patients transplantés. Méthodes : Nous avons utilisé une approche en population, basée sur l’étude de larges cohortes de receveurs de greffes rénales. L’étude concomitante des données immunologiques et histologiques, nous a permis de corréler les caractéristiques des anticorps anti-HLA circulants aux phénotypes lésionnels. Résultats : Nous avons identifié et caractérisé 4 types distincts de rejet : les rejets vasculaires médiés par les lymphocytes T (9%) et par les anticorps (21%), non reconnus par les classifications internationales, et les rejets cellulaires (46%) et humoraux sans vascularite (24%). Le risque de perte de greffons est le plus important dans les cas de rejet vasculaire médié par anticorps. Les anticorps dirigés contre le donneur (DSA) fixant le complément induisent un phénotype histologique plus sévère, dominé par des lésions inflammatoires et plus de dépôts de la fraction C4d du complément dans les greffons. En leur présence, le risque de perte de greffons est augmenté de 3,7 fois (IC95 1,9-7,2). Les formes indolentes de rejet médié par les anticorps sont également associées à un risque accru de perte du greffon. L’utilisation d’approches moléculaires permet d’améliorer la stratification du risque au sein du groupe des patients présentant des rejets humoraux. Conclusion : Ce travail répond à un besoin clinique pressant dans le domaine de la transplantation, celui de déterminer l’impact clinique des anticorps anti-HLA et d’améliorer la stratification du risque immunologique en se basant sur leurs propriétés et l’utilisation de nouvelles technologies pour mieux caractériser l’activité et le stade des rejets humoraux

Rôle pronostic des anticorps anti-HLA en transplantation rénale (approches en population)

Contexte : La réponse allo-immune induite par la transplantation à partir d'un donneur génétiquement différent est un obstacle majeur au succès de la greffe. Notre objectif est de caractériser les différents phénotypes de rejet d'allogreffe rénale et d'identifier la façon dont chacun est associé aux anticorps anti-HLA. Nous avons également évalué l impact de certaines propriétés de ces anticorps, comme leur intensité ou leur capacité à fixer le complément, sur l'échec des allogreffes rénales. Pour finir, nous avons étudié l impact pronostic des formes indolentes de rejets ainsi que l apport des nouvelles technologies d analyses transcriptomique des biopsies de patients transplantés. Méthodes : Nous avons utilisé une approche en population, basée sur l étude de larges cohortes de receveurs de greffes rénales. L étude concomitante des données immunologiques et histologiques, nous a permis de corréler les caractéristiques des anticorps anti-HLA circulants aux phénotypes lésionnels. Résultats : Nous avons identifié et caractérisé 4 types distincts de rejet : les rejets vasculaires médiés par les lymphocytes T (9%) et par les anticorps (21%), non reconnus par les classifications internationales, et les rejets cellulaires (46%) et humoraux sans vascularite (24%). Le risque de perte de greffons est le plus important dans les cas de rejet vasculaire médié par anticorps. Les anticorps dirigés contre le donneur (DSA) fixant le complément induisent un phénotype histologique plus sévère, dominé par des lésions inflammatoires et plus de dépôts de la fraction C4d du complément dans les greffons. En leur présence, le risque de perte de greffons est augmenté de 3,7 fois (IC95 1,9-7,2). Les formes indolentes de rejet médié par les anticorps sont également associées à un risque accru de perte du greffon. L utilisation d approches moléculaires permet d améliorer la stratification du risque au sein du groupe des patients présentant des rejets humoraux. Conclusion : Ce travail répond à un besoin clinique pressant dans le domaine de la transplantation, celui de déterminer l impact clinique des anticorps anti-HLA et d améliorer la stratification du risque immunologique en se basant sur leurs propriétés et l utilisation de nouvelles technologies pour mieux caractériser l activité et le stade des rejets humoraux.Background : The alloimmune response induced by transplantation from a donor who differs genetically from the kidney recipient has always been the major obstacle to graft success. The present work aimed to improve characterization of kidney-allograft rejection phenotypes and identify how each one is associated with anti-HLA antibodies. We also sought to determine whether characteristics of these antibodies i.e., their levels or complementbinding ability, might play a role in kidney allograft failure. Finally, we evaluated the clinical relevance of indolent forms of ABMR and the clinical relevance of new genes expression technologies to stratify the kidney recipients at risk for failure. Methods : We used a population-based approach in precisely phenotyped cohorts of kidney recipients. The design of our study, which is based on the concomitant evaluation of immunologic and histologic data, permits a precise connection of circulating anti-HLA antibodies with a phenotype of graft injury. Findings : We identified four distinct patterns of kidney allograft rejection: T cell-mediated vascular rejection (9%), antibody-mediated vascular rejection (21%), not included in international classifications, T cell- (46%) and antibody-mediated rejection without vasculitis (24%). Risk of graft loss was 9.07 times (95CI 3.6-19.7) higher in antibody-mediated vascular rejection than in T-cell mediated rejections (p<0.0001). Patients with post-transplant complement-binding DSA had more severe graft injury phenotype with higher inflammation and increased deposition of complement fraction C4d. They have the poorest graft survival with 3.7 fold increased risk of graft loss (95CI 1.9-7.2). Subclinical ABMR is a truncated for of rejection associated with risk of kidney allograft failure. Gene expression assessment in kidney allografts with early ABMR improves classification of individuals at risk for kidney allograft loss. Conclusion : This work addresses the unmet need of the deleterious impact of anti-HLA antibodies and the improvement of risk stratification in kidney transplantation. Recognition of distinct phenotypes could lead to the development of new treatment strategies. Gene expression assessment appears useful to evaluate disease activity, disease state and prediction of failure.PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Immunosuppressant drugs and quality-of-life outcomes in kidney transplant recipients: An international cohort study (EU-TRAIN)

Introduction: Patient-Reported Outcomes (PRO) integrate a wide range of holistic dimensions that arenot captured within clinical outcomes. Particularly, from induction treatment to maintenance therapy, patient quality-of-life (QoL) of kidney transplant recipients have been sparsely investigated in international settings.Methods: In a prospective, multi-centric cohort study, including nine transplant centers in four countries, we explored the QoL during the year following transplantation using validated elicitation instruments (EQ-5D-3L index with VAS) in a population of kidney transplant patients receiving immunosuppressive therapies. Calcineurin inhibitors (tacrolimus and ciclosporin), IMPD inhibitor (mycophenolate mofetil), and mTOR inhibitors (everolimus and sirolimus) were the standard-of-care (SOC) medications, together with tapering glucocorticoid therapy. We used EQ-5D and VAS data as QoL measures alongside descriptive statistics at inclusion, per country and hospital center. We computed the proportions of patients with different immunosuppressive therapy patterns, and using bivariate and multivariate analyses, assessed the variations of EQ-5D and VAS between baseline (i.e., inclusion Month 0) and follow up visits (Month 12).Results: Among 542 kidney transplant patients included and followed from November 2018 to June 2021, 491 filled at least one QoL questionnaire at least at baseline (Month 0). The majority of patients in all countries received tacrolimus and mycophenolate mofetil, ranging from 90.0% in Switzerland and Spain to 95.8% in Germany. At M12, a significant proportion of patients switched immunosuppressive drugs, with proportion varying from 20% in Germany to 40% in Spain and Switzerland. At visit M12, patients who kept SOC therapy had higher EQ-5D (by 8 percentage points, p &lt; 0.05) and VAS (by 4 percentage points, p &lt; 0.1) scores than switchers. VAS scores were generally lower than EQ-5D (mean 0.68 [0.5–0.8] vs. 0.85 [0.8–1]).Discussion: Although overall a positive trend in QoL was observed, the formal analyses did not show any significant improvements in EQ-5D scores or VAS. Only when the effect of a therapy use was separated from the effect of switching, the VAS score was significantly worse for switchers during the follow up period, irrespective of the therapy type. If adjusted for patient characteristics and medical history (e.g., gender, BMI, eGRF, history of diabetes), VAS and EQ-5D delivered sound PRO measures for QoL assessments during the year following renal transplantation

Tissue Compartment Analysis for Biomarker Discovery by Gene Expression Profiling

BACKGROUND:Although high throughput technologies for gene profiling are reliable tools, sample/tissue heterogeneity limits their outcomes when applied to identify molecular markers. Indeed, inter-sample differences in cell composition contribute to scatter the data, preventing detection of small but relevant changes in gene expression level. To date, attempts to circumvent this difficulty were based on isolation of the different cell structures constituting biological samples. As an alternate approach, we developed a tissue compartment analysis (TCA) method to assess the cell composition of tissue samples, and applied it to standardize data and to identify biomarkers. METHODOLOGY/PRINCIPAL FINDINGS:TCA is based on the comparison of mRNA expression levels of specific markers of the different constitutive structures in pure isolated structures, on the one hand, and in the whole sample on the other. TCA method was here developed with human kidney samples, as an example of highly heterogeneous organ. It was validated by comparison of the data with those obtained by histo-morphometry. TCA demonstrated the extreme variety of composition of kidney samples, with abundance of specific structures varying from 5 to 95% of the whole sample. TCA permitted to accurately standardize gene expression level amongst >100 kidney biopsies, and to identify otherwise imperceptible molecular disease markers. CONCLUSIONS/SIGNIFICANCE:Because TCA does not require specific preparation of sample, it can be applied to all existing tissue or cDNA libraries or to published data sets, inasmuch specific operational compartments markers are available. In human, where the small size of tissue samples collected in clinical practice accounts for high structural diversity, TCA is well suited for the identification of molecular markers of diseases, and the follow up of identified markers in single patients for diagnosis/prognosis and evaluation of therapy efficiency. In laboratory animals, TCA will interestingly be applied to central nervous system where tissue heterogeneity is a limiting factor

Assessment of the Utility of Kidney Histology as a Basis for Discarding Organs in the United States: A Comparison of International Transplant Practices and Outcomes.

peer reviewedBACKGROUND: 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

Race-free estimated glomerular filtration rate equation in kidney transplant recipients:development and validation study

OBJECTIVE: To compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients.DESIGN: Development and validation study SETTING: 17 cohorts in Europe, the United States, and Australia (14 transplant centres, three clinical trials).PARTICIPANTS: 15 489 adults (3622 in development cohort (Necker, Saint Louis, and Toulouse hospitals, France), 11 867 in multiple external validation cohorts) who received kidney transplants between 1 January 2000 and 1 January 2021.MAIN OUTCOME MEASURE: The main outcome measure was GFR, measured according to local practice. Performance of the GFR equations was assessed using P 30 (proportion of estimated GFR (eGFR) within 30% of measured GFR (mGFR)) and correct classification (agreement between eGFR and mGFR according to GFR stages). The race-free equation, based on creatinine level, age, and sex, was developed using additive and multiplicative linear regressions, and its performance was compared with the three current main GFR equations: Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation, and race-free CKD-EPI 2021 equation. RESULTS: The study included 15 489 participants, with 50 464 mGFR and eGFR values. The mean GFR was 53.18 mL/min/1.73m 2 (SD 17.23) in the development cohort and 55.90 mL/min/1.73m 2 (19.69) in the external validation cohorts. Among the current GFR equations, the race-free CKD-EPI 2021 equation showed the lowest performance compared with the MDRD and CKD-EPI 2009 equations. When race was included in the kidney recipient specific GFR equation, performance did not increase. The race-free kidney recipient specific GFR equation showed significantly improved performance compared with the race-free CKD-EPI 2021 equation and performed well in the external validation cohorts (P 30 ranging from 73.0% to 91.3%). The race-free kidney recipient specific GFR equation performed well in several subpopulations of kidney transplant recipients stratified by race (P 30 73.0-91.3%), sex (72.7-91.4%), age (70.3-92.0%), body mass index (64.5-100%), donor type (58.5-92.9%), donor age (68.3-94.3%), treatment (78.5-85.2%), creatinine level (72.8-91.3%), GFR measurement method (73.0-91.3%), and timing of GFR measurement post-transplant (72.9-95.5%). An online application was developed that estimates GFR based on recipient's creatinine level, age, and sex (https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/). CONCLUSION: A new race-free kidney recipient specific GFR equation was developed and validated using multiple, large, international cohorts of kidney transplant recipients. The equation showed high accuracy and outperformed the race-free CKD-EPI 2021 equation that was developed in individuals with native kidneys.TRIAL REGISTRATION: ClinicalTrials.gov NCT05229939.</p

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

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

Clinical relevance of anti-HLA antibodies in kidney transplantation : population approaches

Contexte : La réponse allo-immune induite par la transplantation à partir d'un donneur génétiquement différent est un obstacle majeur au succès de la greffe. Notre objectif est de caractériser les différents phénotypes de rejet d'allogreffe rénale et d'identifier la façon dont chacun est associé aux anticorps anti-HLA. Nous avons également évalué l’impact de certaines propriétés de ces anticorps, comme leur intensité ou leur capacité à fixer le complément, sur l'échec des allogreffes rénales. Pour finir, nous avons étudié l’impact pronostic des formes indolentes de rejets ainsi que l’apport des nouvelles technologies d’analyses transcriptomique des biopsies de patients transplantés. Méthodes : Nous avons utilisé une approche en population, basée sur l’étude de larges cohortes de receveurs de greffes rénales. L’étude concomitante des données immunologiques et histologiques, nous a permis de corréler les caractéristiques des anticorps anti-HLA circulants aux phénotypes lésionnels. Résultats : Nous avons identifié et caractérisé 4 types distincts de rejet : les rejets vasculaires médiés par les lymphocytes T (9%) et par les anticorps (21%), non reconnus par les classifications internationales, et les rejets cellulaires (46%) et humoraux sans vascularite (24%). Le risque de perte de greffons est le plus important dans les cas de rejet vasculaire médié par anticorps. Les anticorps dirigés contre le donneur (DSA) fixant le complément induisent un phénotype histologique plus sévère, dominé par des lésions inflammatoires et plus de dépôts de la fraction C4d du complément dans les greffons. En leur présence, le risque de perte de greffons est augmenté de 3,7 fois (IC95 1,9-7,2). Les formes indolentes de rejet médié par les anticorps sont également associées à un risque accru de perte du greffon. L’utilisation d’approches moléculaires permet d’améliorer la stratification du risque au sein du groupe des patients présentant des rejets humoraux. Conclusion : Ce travail répond à un besoin clinique pressant dans le domaine de la transplantation, celui de déterminer l’impact clinique des anticorps anti-HLA et d’améliorer la stratification du risque immunologique en se basant sur leurs propriétés et l’utilisation de nouvelles technologies pour mieux caractériser l’activité et le stade des rejets humoraux.Background : The alloimmune response induced by transplantation from a donor who differs genetically from the kidney recipient has always been the major obstacle to graft success. The present work aimed to improve characterization of kidney-allograft rejection phenotypes and identify how each one is associated with anti-HLA antibodies. We also sought to determine whether characteristics of these antibodies i.e., their levels or complementbinding ability, might play a role in kidney allograft failure. Finally, we evaluated the clinical relevance of indolent forms of ABMR and the clinical relevance of new genes expression technologies to stratify the kidney recipients at risk for failure. Methods : We used a population-based approach in precisely phenotyped cohorts of kidney recipients. The design of our study, which is based on the concomitant evaluation of immunologic and histologic data, permits a precise connection of circulating anti-HLA antibodies with a phenotype of graft injury. Findings : We identified four distinct patterns of kidney allograft rejection: T cell-mediated vascular rejection (9%), antibody-mediated vascular rejection (21%), not included in international classifications, T cell- (46%) and antibody-mediated rejection without vasculitis (24%). Risk of graft loss was 9.07 times (95CI 3.6-19.7) higher in antibody-mediated vascular rejection than in T-cell mediated rejections (p<0.0001). Patients with post-transplant complement-binding DSA had more severe graft injury phenotype with higher inflammation and increased deposition of complement fraction C4d. They have the poorest graft survival with 3.7 fold increased risk of graft loss (95CI 1.9-7.2). Subclinical ABMR is a truncated for of rejection associated with risk of kidney allograft failure. Gene expression assessment in kidney allografts with early ABMR improves classification of individuals at risk for kidney allograft loss. Conclusion : This work addresses the unmet need of the deleterious impact of anti-HLA antibodies and the improvement of risk stratification in kidney transplantation. Recognition of distinct phenotypes could lead to the development of new treatment strategies. Gene expression assessment appears useful to evaluate disease activity, disease state and prediction of failure