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Dynamic prediction of renal survival among deeply phenotyped kidney transplant recipients using artificial intelligence: an observational, international, multicohort study

10/27/2021

 
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For individuals with end-stage renal disease, kidney transplantation is the best treatment, in terms of quality and quantity of life and costs for society. Considering the organ shortage worldwide, the allograft failure is a real burden in chronic kidney disease, contributing to the growing number of the seven million individuals with end-stage renal disease. For these reasons, health agencies such as the Food and Drug Administation and the European Medicines Agency, have emphasized the need for developing a prediction model that would accurately predict the risk of allograft failure, which would allow clinicians to continuously enhance their prognostic judgements, and adapt the patient monitoring and management.

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COVID-19-related medical research: a meta-research and critical appraisal

1/12/2021

 
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As with many fields, science has been put to the test by the coronavirus pandemic. An international team of researchers, led by French scientists, has demonstrated novel scientific practices around Covid-19. Under the pressure of the number of cases and the urgent need to understand the virus, many research groups have shared results, sometimes to the expense of high scientific standards.

During the first wave of the Covid-19 epidemic, medical research saw a historic number of studies on the coronavirus published in a short period of time. An international consortium of experts in medical methodology undertook the major challenge of evaluating the Covid-19 research during this first wave.

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Assessment of the Utility of Kidney Histology as a Basis for Discarding Organs in the US

12/15/2020

 
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New research indicates that analyses of kidney biopsies from deceased donors don’t provide meaningful information beyond standard assessments of donor and recipient characteristics. In addition, the study revealed that relying on these analyses has prompted the discard of many potentially suitable organs for transplantation in the United States. The findings appear in JASN.

Despite a critical scarcity of organs available for transplantation, thousands of deceased donor kidneys are discarded each year in the United States. 


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The Banff 2019 Kidney Meeting Reports

9/20/2020

 
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. 

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Statistical performance of 16 posttransplant risk scores in a contemporary cohort of heart transplant recipients

7/28/2020

 
Accurate risk stratification of early heart transplant failure is required to avoid futile transplants and rationalize donor selection. We aimed to evaluate the statistical performance of existing risk scores on a contemporary cohort of heart transplant recipients.

After an exhaustive search, we identified 16 relevant risk scores. From the UNOS database, we selected all first noncombined adult heart transplants performed between 2014 and 2017 for validation. The primary endpoint was death or retransplant during the first year posttransplant.

​For all scores, we analyzed their association with outcomes, sensitivity, specificity, likelihood ratios, and discrimination (concordance index and overlap of individual scores). The cohort included 9396 patients. All scores were significantly associated with the primary outcome (P < .001 for all scores). Their likelihood ratios, both negative and positive, were poor. The discriminative performance of all scores was limited, with concordance index ranging from 0.544 to 0.646 (median 0.594) and an important overlap of individual scores between patients with or without the primary endpoint. Subgroup analyses revealed important variation in discrimination according to donor age, recipient age, and the type of assist device used at transplant.

Our findings raise concerns about the use of currently available scores in the clinical field.

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A considerable decline in the number of organ transplants since the start of the COVID-19 pandemic in France and the US

5/12/2020

 
​​A French-American study conducted by researchers from the Paris Transplant Group (University of Paris, Inserm and AP-HP) just published in The Lancet reveals a more than 90% drop in the number of organ procurement and transplants during the COVID-19 pandemic in France. The trend, which is also continuing across the Atlantic, poses a life-threatening risk to the thousands of people waiting for transplants in France and the United States.
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Identification and characterization of trajectories of cardiac allograft vasculopathy after heart transplantation

5/4/2020

 
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Every year, tens of thousands of deaths are due to end-stage heart failure in Europe and in the US combined. Heart transplantation is the ultimate treatment, but its number is dramatically limited due to the shortage of organs in those countries. 
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​In the same time, the chances of survival beyond one year after transplantation have remained unchanged in recent years, despite significant progress in immunosuppressive therapy and patient care.
One of the most common reasons for long-term graft failure and patient death is an accelerated form of coronary artery disease called cardiac allograft vasculopathy. It is a frequent complication that affects up to half of patients within 10 years following heart transplantation. Yet, until now, little has been known about the different evolutive profiles of cardiac allograft vasculopathy and their risk factors.

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Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study

3/3/2020

 
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The first universal algorithm for predicting the risk of kidney transplant loss, named iBox, has been developed, validated and just made public by teams from Europe and the US.

​The iBox is designed for clinicians to personalize and improve patient follow-up. The iBox could also accelerate the development of new immunosuppressive treatments by reducing the duration of clinical trials and defining a valid surrogate endpoint.
Chronic kidney disease affects 1 out of 10 people worldwide and is steadily increasing. When it reaches end-stage renal disease and endangers the lives of patients, dialysis or transplantation is required. ​

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Disparities in Acceptance of Deceased Donor Kidneys Between the United States and France and Estimated Effects of Increased US Acceptance

8/26/2019

 
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New publication in JAMA Internal Medicine: The first international analysis of renal transplant patient data shows that a change in allocation criteria in the United States could benefit patients on the waiting list. Thousands more kidneys could be transplanted each year if the United States used, as France does, kidneys from older donors.
Nearly 5,000 people in the United States and 3,500 in Europe die each year waiting for a kidney transplant. Yet, over the same period, in the United States, more than 3,500 available kidneys were discarded. The Journal of the American Medical Association (JAMA) Internal Medicine today published our results, obtained with the help of an international team, that compared the use of kidneys available in the United States and France between 2004 and 2014. ​
Using a new approach based on validated analytical methods and computer simulations, this work revealed that French transplant centres are much more likely to transplant kidneys from older donors than their American counterparts, and that this effectively increases the number of patients transplanted. 

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

3/14/2019

 
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New research conducted by the Paris Translational Research Center for Organ Transplantation team could help clinicians determine which patients will have a disease that usually occurs after a kidney transplant and which are at high risk of transplant failure. The results are published today in the prestigious Journal of the American Society of Nephrology (JASN).

Transplant glomerulopathy was first described and characterized 50 years ago. It is a disease associated with the loss of a kidney transplant and common after a transplant. It affects the functional units (i. e. glomeruli) of the transplanted kidney. There is currently no treatment for this heterogeneous disease.

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Antibody-Mediated Rejection of Solid-Organ Allografts

9/20/2018

 
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End-stage organ diseases are responsible for millions of deaths worldwide each year. Organ transplantation has become the treatment of choice, but despite the 120,000 new organ transplantations performed each year, only 1 million persons worldwide have functioning solid-organ transplants1 because of the lack of improvement in long-term allograft survival over the past few decades and the limited organ supply.

HLA incompatibility between donors and recipients who are not genetically identical has been identified as the main barrier to successful transplantation, mostly because of antibody-mediated rejection, a form of allograft rejection triggered by the production of antibodies directed mainly toward donor (nonself) HLA molecules. ​
This review focuses on current standards for the management of antibody-mediated rejection in transplant recipients and identifies future directions for improving diagnostics and moving toward tailored therapeutics. Such advances require the development of pathogenesis-based approaches that combine precise characterization of the biologic properties of antibodies, noninvasive biomarkers, and allograft gene-expression profiling, which will set the stage for bringing antibody-mediated rejection into the era of precision medicine.

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Complement-activating donor-specific anti-HLA antibodies and solid organ transplant survival: A systematic review and meta-analysis

5/25/2018

 
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 findingsTo 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.
ConclusionsIn 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.
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Cit: Antoine Bouquegneau et al.  PLoS Med. 2018 May 25;15(5):e1002572. PMID: 30052664

Complement-binding anti-HLA antibodies are independent predictors of response to treatment in kidney recipients with antibody-mediated rejection

5/22/2018

 
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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.
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Denis Viglietti et al.
Kidney Int. 2018 Oct;94(4):773-787.
PMID: 29801667

Banff Lung Report 2017

2/5/2018

 
​The Lung session of the 2017 14th Banff Foundation for Allograft Pathology Conference, Barcelona focused on the multiple aspects of antibody-mediated rejec-tion (AMR) in lung transplantation.

​Multidimensional approaches for AMR diagnosis, including classification, histological and immunohistochemical analysis, and donor- specific antibody (DSA) characterization with their current strengths and limitations were reviewed in view of recent research.

The group also discussed the role of tissue gene expression analysis in the context of unmet needs in lung transplantation. The current best practice for monitoring of AMR and the therapeutic approach are summarized and highlighted in this report.

The working group reached consensus of the major gaps in current knowledge and focused on the unanswered questions regard-ing pulmonary AMR. An important outcome of the meeting was agreement on the need for future collaborative research projects to address these gaps in the field of lung transplantation.

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

1/31/2018

 
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Abstract: 
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.
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Denis Viglietti et al.
J Am Soc Nephrol. 2018 Feb;29(2):606-619.
PMID: 29255058

The Banff 2017 Kidney Meeting Report

12/15/2017

 
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​REVISED DIAGNOSTIC CRITERIA FOR CHRONIC ACTIVE T CELL–MEDIATED REJECTION, ANTIBODY‐MEDIATED REJECTION, AND PROSPECTS FOR INTEGRATIVE ENDPOINTS FOR NEXT‐GENERATION CLINICAL TRIALS
​The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i-IFTA) and its relationship to T cell-mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody-mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i-IFTA is associated with reduced graft survival. Furthermore, these groups presented that i-IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i-IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor-specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next-generation clinical trials.

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

11/9/2017

 
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Abstract
Halloran PF, Potena L, Van Huyen JD, Bruneval P, Leone O, Kim DH, Jouven X, Reeve J, Loupy A.

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.
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.
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.
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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J Heart Lung Transplant. 2017 Nov;36(11):1192-1200
PMID:28662985

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

10/31/2017

 
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Carmen Lefaucheur et al
Am J Transplant.
 2018 Feb;18(2):377-390.
PMID: 29086461
​Abstract
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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Complement-Activating Anti-HLA Antibodies in Kidney Transplantation: Allograft Gene Expression Profiling and Response to Treatment

10/17/2017

 
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Carmen Lefaucheur et al
JASN February 2018, 29 (2) 620-635
PMID: 29042454
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Abstract
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, IFNγ 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.

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

9/7/2017

 
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Abstract
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.

Authors: Gosset C, Viglietti D, Rabant M, Vérine J, Aubert O, Glotz D, Legendre C, Taupin JL, Duong Van-Huyen JP, Loupy A, Lefaucheur C.
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Kidney Int. 2017 Sep;92(3):729-742.
PMID: 28554738 ​

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

6/1/2017

 
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Olivier Aubert et al.
JASN 
June 2017, 28 (6) 1912-1923. 
​PMID: 28255002
Abstract
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 IFNγ-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 m2) 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.
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Real Time Central Assessment of Kidney Transplant Indication Biopsies by Microarrays: The INTERCOMEX Study

4/27/2017

 
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​Am J Transplant. 2017 Nov;17(11):2851-2862.
PMID: 28449409 
Abstract
Halloran PF, Reeve J, Akalin E, Aubert O, Bohmig GA, Brennan D, Bromberg J, Einecke G, Eskandary F, Gosset C, Duong Van Huyen JP, Gupta G, Lefaucheur C, Malone A, Mannon RB, Seron D, Sellares J, Weir M, Loupy A.

​The authors conducted a prospective trial to assess the feasibility of real time central molecular assessment of kidney transplant biopsy samples from 10 North American or European centers. Biopsy samples taken 1 day to 34 years posttransplantation were stabilized in RNAlater, sent via courier overnight at ambient temperature to the central laboratory, and processed (29 h workflow) using microarrays to assess T cell- and antibody-mediated rejection (TCMR and ABMR, respectively). Of 538 biopsy samples submitted, 519 (96%) were sufficient for microarray analysis (average length, 3 mm). Automated reports were generated without knowledge of histology and HLA antibody, with diagnoses assigned based on Molecular Microscope Diagnostic System (MMDx) classifier algorithms and signed out by one observer. Agreement between MMDx and histology (balanced accuracy) was 77% for TCMR, 77% for ABMR, and 76% for no rejection. A classification tree derived to provide automated sign-outs predicted the observer sign-outs with >90% accuracy. In 451 biopsy samples where feedback was obtained, clinicians indicated that MMDx more frequently agreed with clinical judgment (87%) than did histology (80%) (p = 0.0042). In 81% of feedback forms, clinicians reported that MMDx increased confidence in management compared with conventional assessment alone. The authors conclude that real time central molecular assessment is feasible and offers a useful new dimension in biopsy interpretation. ClinicalTrials.gov NCT#01299168.

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Timing of anti-donor antibody responses affects the survival of kidney transplants

3/2/2017

 
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Kidney rejection initiated by antibodies that were present before transplantation is linked with a better outcome that rejection due to antibodies that arise after transplantation
New research provides insights on transplant recipients’ antibody responses against donor kidneys and how the timing of those responses can have important implications. The findings appear in an upcoming issue of the Journal of the American Society of Nephrology (JASN).
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Molecular Assessment of Microcirculation Injury in Formalin-Fixed Human Cardiac Allograft Biopsies With Antibody-Mediated Rejection.

2/17/2017

 
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Am J Transplant. 2017 Feb;17(2):496-505.
PMID: 27401781

Abstract
B. Afzali, E. Chapman,  M. Racapé, B. Adam,  P. Bruneval, F. Gil, D. Kim, L. Hidalgo, P. Campbell, B. Sis, J. P. Duong Van Huyen, M. Mengel.
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Precise diagnosis of antibody-mediated rejection (AMR) in cardiac allograft endomyocardial biopsies (EMBs) remains challenging. This study assessed molecular diagnostics in human EMBs with AMR. A set of 34 endothelial, natural killer cell and inflammatory genes was quantified in 106 formalin-fixed, paraffin-embedded EMBs classified according to 2013 International Society for Heart and Lung Transplantation (ISHLT) criteria. The gene set expression was compared between ISHLT diagnoses and correlated with donor-specific antibody (DSA), endothelial injury by electron microscopy (EM) and prognosis. Findings were validated in an independent set of 57 EMBs. In the training set (n = 106), AMR cases (n = 70) showed higher gene set expression than acute cellular rejection (ACR; n = 21, p < 0.001) and controls (n = 15, p < 0.0001). Anti-HLA DSA positivity was associated with higher gene set expression (p = 0.01). Endothelial injury by electron microscopy strongly correlated with gene set expression, specifically in AMR cases (r = 0.62, p = 0.002). Receiver operating characteristic curve analysis for diagnosing AMR showed greater accuracy with gene set expression (area under the curve [AUC] = 79.88) than with DSA (AUC = 70.47) and C4d (AUC = 70.71). In AMR patients (n = 17) with sequential biopsies, increasing gene set expression was associated with inferior prognosis (p = 0.034). These findings were confirmed in the validation set. In conclusion, biopsy-based molecular assessment of antibody-mediated microcirculation injury has the potential to improve diagnosis of AMR in human cardiac transplants.

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Value of Donor-Specific Anti-HLA Antibody Monitoring and Characterization for Risk Stratification of Kidney Allograft Loss

1/31/2017

 
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Denis Viglietti et al.
J Am Soc Nephrol. 2017 Feb;28(2):702-715.
PMID: 27493255

Abstract
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.
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