Dynamic prediction of renal survival among deeply phenotyped kidney transplant recipients using artificial intelligence: an observational, international, multicohort study
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.
Statistical performance of 16 posttransplant risk scores in a contemporary cohort of heart transplant recipients
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.
A considerable decline in the number of organ transplants since the start of the COVID-19 pandemic in France and the US
Identification and characterization of trajectories of cardiac allograft vasculopathy after heart transplantation
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.
Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study
Disparities in Acceptance of Deceased Donor Kidneys Between the United States and France and Estimated Effects of Increased US Acceptance
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.
Archetype Analysis Identifies Distinct Profiles in Renal Transplant Recipients with Transplant Glomerulopathy Associated with Allograft Survival
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.
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.
Complement-activating donor-specific anti-HLA antibodies and solid organ transplant survival: A systematic review and meta-analysis
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.
Complement-binding anti-HLA antibodies are independent predictors of response to treatment in kidney recipients with antibody-mediated rejection
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.
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.
Dynamic Prognostic Score to Predict Kidney Allograft Survival in Patients with Antibody-Mediated Rejection
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.
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.
Building a tissue-based molecular diagnostic system in heart transplant rejection: The heart Molecular Microscope Diagnostic (MMDx) System.
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.
T cell-mediated rejection is a major determinant of inflammation in scarred areas in kidney allografts.
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.
Complement-Activating Anti-HLA Antibodies in Kidney Transplantation: Allograft Gene Expression Profiling and Response to Treatment
Paris Transplant Group
Our global aim is to accelerate the translation of immunological and gene expression discoveries into the clinical field by filling the gap between basic science and applied biomedical researches.
Jean Luc Taupin
Jean Paul Duong Van Huyen
Jean Philippe Empana