Conference Organizing Committee - BANFF BOARD
2017 BANFF-CST Meeting, Scientific Committee - Executive Committee
Website : 2017 BANFF-SCT, March 27-31, 2017 | Barcelona, Spain
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).
Molecular Assessment of Microcirculation Injury in Formalin-Fixed Human Cardiac Allograft Biopsies With Antibody-Mediated Rejection.
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.
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.
Value of Donor-Specific Anti-HLA Antibody Monitoring and Characterization for Risk Stratification of Kidney Allograft Loss
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.
The purpose of the present review is to describe how we improve the model for risk stratification of transplant outcomes in kidney transplantation by incorporating the novel insights of donor-specific anti-HLA antibody (DSA) characteristics. The detection of anti-HLA DSA is widely used for the assessment of pre- and posttransplant risks of rejection and allograft loss; however, not all anti-HLA DSA carry the same risk for transplant outcomes. These antibodies have been shown to cause a wide spectrum of effects on allografts, ranging from the absence of injury to indolent or full-blown acute antibody-mediated rejection. Consequently, the presence of circulating anti-HLA DSA does not provide a sufficient level of accuracy for the risk stratification of allograft outcomes. Enhancing the predictive performance of anti-HLA DSA is currently one of the most pressing unmet needs for facilitating individualized treatment choices that may improve outcomes. Recent advancements in the assessment of anti-HLA DSA properties, including their strength, complement-binding capacity, and IgG subclass composition, significantly improved the risk stratification model to predict allograft injury and failure. Although risk stratification based on anti-HLA DSA properties appears promising, further specific studies that address immunological risk stratification in large and unselected populations are required to define the benefits and cost-effectiveness of such comprehensive assessment prior to clinical implementation.
Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection
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.
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.
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; P<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 (P<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.
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.
On December 14th, 2016, Phil Halloran received the award of Doctor Honoris Causa in Paris.
The movie tells the story of renal transplantation and its most famous contributors.
The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology.
A. Loupy, M. Haas, K. Solez, L. Racusen, D. Glotz, D. Seron, B. J. Nankivell, R. B. Colvin, M. Afrouzian, E. Akalin, N. Alachkar, S. Bagnasco, J. U. Becker, L. Cornell, C. Drachenberg, D. Dragun, H. de Kort, I. W. Gibson, E. S. Kraus C. Lefaucheur, C. Legendre, H. Liapis, T. Muthukumar, V. Nickeleit, B. Orandi, W. Park, M. Rabant, P. Randhawa, E. F. Reed, C. Roufosse, S. V. Seshan, B. Sis, H. K. Singh, C. Schinstock, A. Tambur, A. Zeevi, M. Mengel.
The XIII Banff meeting, held in conjunction the Canadian Society of Transplantation in Vancouver, Canada, reviewed the clinical impact of updates of C4d-negative antibody-mediated rejection (ABMR) from the 2013 meeting, reports from active Banff Working Groups, the relationships of donor-specific antibody tests (anti-HLA and non-HLA) with transplant histopathology, and questions of molecular transplant diagnostics. The use of transcriptome gene sets, their resultant diagnostic classifiers, or common key genes to supplement the diagnosis and classification of rejection requires further consensus agreement and validation in biopsies. Newly introduced concepts include the i-IFTA score, comprising inflammation within areas of fibrosis and atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active T cell-mediated rejection (TCMR) or chronic ABMR. The pattern of mixed TCMR and ABMR was increasingly recognized. This report also includes improved definitions of TCMR and ABMR in pancreas transplants with specification of vascular lesions and prospects for defining a vascularized composite allograft rejection classification. The goal of the Banff process is ongoing integration of advances in histologic, serologic, and molecular diagnostic techniques to produce a consensus-based reporting system that offers precise composite scores, accurate routine diagnostics, and applicability to next-generation clinical trials.
Figure 1: Molecular lesions and their corresponding histologic lesions in T cell–mediated rejection and antibody‐mediated rejection in kidney allografts. cg, glomerular double contours; cv, vascular fibrous intimal thickening; i, inflammation; ptc, peritubular capillaritis; ti, total inflammation; v, intimal arteritis.
2016 American Transplant Congress (ATC)
June 11-15, 2016 in Boston, MA
Sunday June 12, 2016
1/ Complement-Binding Donor-Specific Anti-HLA Antibodies Are Associated with Severe Kidney Allograft Arteriosclerosis
Concurrent Session: Novel Markers of Long Term Kidney Transplant Outcomes (2:30 PM-4:00 PM)
Ballroom A - 2:30 pm
A. Loupy, D. Viglietti, J. Duong Van Huyen, D. Glotz, C. Legendre, A. Zeevi, C. Lefaucheur. Necker Hospital, Paris, France; Saint-Louis Hospital, Paris, France; University of Pittsburgh Medical Center, Pittsburgh
The role of circulating donor-specific anti-HLA antibodies (DSA) in the development of accelerated arteriosclerosis have been recently reported in kidney transplant recipients. This study investigated the characteristics of DSA that are associated with the severity of allograft arteriosclerosis.
We enrolled 744 consecutive kidney transplantation performed between January 1, 2004 and January 1, 2010 at Necker Hospital (Paris, France), with systematic assessment of injury phenotype and arteriosclerotic lesions using the vascular fibrous intimal thickening (cv) Banff score on allograft biopsies performed at one year after transplantation. We assessed circulating DSA and their characteristics (specificity, HLA class, mean fluorescence intensity [MFI] and C1q-binding) at six months after transplantation.
We identified 281 patients with cv0 score, 213 patients with cv1 score, 189 patients with cv2 score and 61 patients with cv3 score. The distribution of DSA according to cv score was the following: 47/281 (17%) in cv0 patients, 39/213 (18%) in cv1 patients, 63/189 (33%) in cv2 patients and 28/61 (46%) in cv3 patients. Immunodominant DSA (iDSA) MFI level was positively correlated with the severity of arteriosclerosis (Spearman's rho=0.23, p=0.002), with a mean MFI of 3204.0±3725.2 in cv0 patients, 3760±3598 in cv1 patients, 4892±4676 in cv2 patients and 5541±3892 in cv3 patients. C1q-binding DSA prevalence increased with the severity of allograft arteriosclerosis: 8/281 (3%) in cv0 patients, 6/213 (3%) in cv1 patients, 25/189 (13%) in cv2 patients and 9/61 (15%) in cv3 patients (p<0.001). Patients with C1q-binding iDSA had a higher cv score compared with patients with non-C1q-binding DSA (1.7±1.0 versus 1.3±1.1, respectively, p=0.01). The C1q-binding capacity of DSA was associated with increased microvascular inflammation (p<0.001) and C4d deposition in peritubular capillaries or arteries (p<0.001).
This study shows a biological gradient between DSA MFI level and the severity of allograft arteriosclerosis. The complement-binding capacity of DSA is associated with an increased severity of arteriosclerosis and complement deposition in allograft.
M. Racapé, A. Loupy, J. Reeve, J. Venner, R. Guillemain, L. Hidalgo, C. Lefaucheur, X. Jouven, P. Bruneval, J. Duong Van Huyen, P. Halloran.
The XIIIth Banff Conference on Allograft Pathology: The Banff 2015 Heart Meeting Report: Improving Antibody-Mediated Rejection Diagnostics: Strengths, Unmet Needs, and Future Directions.
Bruneval P, Angelini A, Miller D, Potena L, Loupy A, Zeevi A, Reed EF, Dragun D, Reinsmoen N, Smith RN, West L, Tebutt S, Thum T, Haas M, Mengel M, Revelo P, Fedrigo M, Duong Van Huyen JP, Berry GJ.
The 13th Banff Conference on Allograft Pathology was held in Vancouver, British Columbia, Canada from October 5 to 10, 2015. The cardiac session was devoted to current diagnostic issues in heart transplantation with a focus on antibody-mediated rejection (AMR) and small vessel arteriopathy. Specific topics included the strengths and limitations of the current rejection grading system, the central role of microvascular injury in AMR and approaches to semiquantitative assessment of histopathologic and immunophenotypic indicators, the role of AMR in the development of cardiac allograft vasculopathy, the important role of serologic antibody detection in the management of transplant recipients, and the potential application of new molecular approaches to the elucidation of the pathophysiology of AMR and potential for improving the current diagnostic system. Herein we summarize the key points from the presentations, the comprehensive, open and wide-ranging multidisciplinary discussion that was generated, and considerations for future endeavors.
Figure 3: Spectrum of cardiac allograft vasculopathy (from epicardial arteries to myocardial capillaries). (A) Allograft epicardial coronary artery showing intimal and adventitial inflammation (hematoxylin and eosin [H&E], ×100). (B) Allograft epicardial coronary artery showing intimal fibrosis with shallow fibrin thrombus at the luminal aspect and some entrapped fibrin deeper in the intimal wall (arrows) (H&E, ×20). (C) Allograft epicardial coronary artery with less intimal thickening but dramatic adventitial lymphoid aggregate (asterisk) (H&E, ×20). (D) Allograft epicardial coronary artery showing advanced narrowing with a slit‐like lumen; there is very little outward remodeling of the vessel wall (H&E, ×40). (E) Allograft endomyocardial biopsy photomicrograph after computer‐assisted image analysis for capillary density. This case showed reduced capillaries (CD34 stain, ×200) (MVD, microvascular density). (F) Allograft endomyocardial biopsy photomicrograph after computer‐assisted image analysis for capillary density. This case showed preserved capillary density (CD34 stain, ×200). (G) and (H) Electron photomicrographs of allograft myocardium showing an interstitial capillary with basement membrane multilayering (arrows) (original ×4000 and ×10 000).
Conference Organizing Committee
2015 BAnff/CST Meeting, Organizing Corporation (MOC)
Alexandre Loupy, chair
Cinthia Beskox Drachenberg
W. Dean Wallace
Linda C cendales
2015 BANFF/CST, October 5-10, 2016 | Vancouver, BC
Kidney allograft rejection can occur in clinically stable patients, but long-term significance is unknown. We determined whether early recognition of subclinical rejection has long-term consequences for kidney allograft survival in an observational prospective cohort study of 1307 consecutive nonselected patients who underwent ABO-compatible, complement-dependent cytotoxicity-negative crossmatch kidney transplantation in Paris (2000-2010). Participants underwent prospective screening biopsies at 1 year post-transplant, with concurrent evaluations of graft complement deposition and circulating anti-HLA antibodies. The main analysis included 1001 patients. Three distinct groups of patients were identified at the 1-year screening: 727 (73%) patients without rejection, 132 (13%) patients with subclinical T cell-mediated rejection (TCMR), and 142 (14%) patients with subclinical antibody-mediated rejection (ABMR). Patients with subclinical ABMR had the poorest graft survival at 8 years post-transplant (56%) compared with subclinical TCMR (88%) and nonrejection (90%) groups (P<0.001). In a multivariate Cox model, subclinical ABMR at 1 year was independently associated with a 3.5-fold increase in graft loss (95% confidence interval, 2.1 to 5.7) along with eGFR and proteinuria (P<0.001). Subclinical ABMR was associated with more rapid progression to transplant glomerulopathy. Of patients with subclinical TCMR at 1 year, only those who further developed de novo donor-specific antibodies and transplant glomerulopathy showed higher risk of graft loss compared with patients without rejection. Our findings suggest that subclinical TCMR and subclinical ABMR have distinct effects on long-term graft loss. Subclinical ABMR detected at the 1-year screening biopsy carries a prognostic value independent of initial donor-specific antibody status, previous immunologic events, current eGFR, and proteinuria.
Rejection is one of the major causes of late cardiac allograft failure and at present can only be diagnosed by invasive endomyocardial biopsies. We sought to determine whether microRNA profiling could serve as a non-invasive biomarker of cardiac allograft rejection.
We included 113 heart transplant recipients from four referral French institutions (test cohort, n = 60, validation cohort, n = 53). In the test cohort, we compared patients with acute biopsy-proven allograft rejection (n = 30) to matched control patients without rejection (n = 30), by assessing microRNAs expression in the heart allograft tissue and patients concomitant serum using RNA extraction and qPCR analysis. Fourteen miRNAs were selected on the basis of their implication in allograft rejection, endothelial activation, and inflammation and tissue specificity.
We identified seven miRNAs that were differentially expressed between normal and rejecting heart allografts: miR-10a, miR-21, miR-31, miR-92a, miR-142-3p miR-155, and miR-451 (P < 0.0001 for all comparisons). Four out of seven miRNAs also showed differential serological expression (miR-10a, miR-31, miR-92a, and miR-155) with strong correlation with their tissular expression. The receiver-operating characteristic analysis showed that these four circulating miRNAs strongly discriminated patients with allograft rejection from patients without rejection: miR-10a (AUC = 0.975), miR-31 (AUC = 0.932), miR-92a (AUC = 0.989), and miR-155 (AUC = 0.998, P < 0.0001 for all comparisons). We confirmed in the external validation set that these four miRNAs highly discriminated patients with rejection from those without. The discrimination capability of the four miRNAs remained significant when stratified by rejection diagnosis (T-cell-mediated rejection or antibody-mediated rejection) and time post-transplant.
This study demonstrates that a differential expression of miRNA occurs in rejecting allograft patients, not only at the tissue level but also in the serum, suggesting their potential relevance as non-invasive biomarkers in heart transplant rejection.
Molecular Microscope Strategy to Improve Risk Stratification in Early Antibody-Mediated Kidney Allograft Rejection
Antibody-mediated rejection (ABMR) is the leading cause of kidney allograft loss. We investigated whether the addition of gene expression measurements to conventional methods could serve as a molecular microscope to identify kidneys with ABMR that are at high risk for failure. We studied 939 consecutive kidney recipients at Necker Hospital (2004–2010; principal cohort) and 321 kidney recipients at Saint LouisHospital (2006–2010; validation cohort) and assessed patients with ABMR in the first 1 year post-transplant. In addition to conventional features, we assessed microarray-based gene expression in transplant biopsy specimens using relevant molecular measurements: the ABMRMolecular
Score and endothelial donor-specific antibody-selective transcript set. The main outcomes were kidney transplant loss and progression to chronic transplant injury. We identified 74 patientswith ABMR in the principal cohort and 54 patients with ABMR in the validation cohort. Conventional features independently associated with failure were donor age and humoral histologic score (g+ptc+v+cg+C4d). Adjusting for conventional features, ABMR Molecular Score (hazard ratio [HR], 2.22; 95% confidence interval [95% CI], 1.37 to 3.58; P=0.001) and endothelial donor-specific antibody-selective transcripts (HR, 3.02; 95% CI, 1.00 to 9.16; P,0.05) independently associated with an increased risk of graft loss. The results were replicated in the independent validation group. Adding a gene expression assessment to a traditional risk model improved the stratification of patients at risk for graft failure (continuous net reclassification improvement, 1.01; 95% CI, 0.57 to 1.46; P,0.001; integrated discrimination improvement, 0.16; P,0.001). Compared with conventional assessment, the addition of gene expression measurement in kidney transplants with ABMR improves stratification of patients at high risk for graft loss.
AbstractAnti-HLA antibodies hamper successful transplantation, and activation of the complement cascade is involved in antibody-mediated rejection. We investigated whether the complement-binding capacity of anti-HLA antibodies plays a role in kidney-allograft failure.
We enrolled patients who received kidney allografts at two transplantation centers in Paris between January 1, 2005, and January 1, 2011, in a population-based study.
Patients were screened for the presence of circulating donor-specific anti-HLA antibodies and their complement-binding capacity. Graft injury phenotype and the time to kidney-allograft loss were assessed.
The primary analysis included 1016 patients. Patients with complement-binding donor-specific anti-HLA antibodies after transplantation had the lowest 5-year rate of graft survival (54%), as compared with patients with non–complement-binding donor-specific anti-HLA antibodies (93%) and patients without donor-specific anti-HLA antibodies (94%) (P<0.001 for both comparisons). The presence of complement-binding donor-specific anti-HLA antibodies after transplantation was associated with a risk of graft loss that was more than quadrupled (hazard ratio, 4.78; 95% confidence interval [CI], 2.69 to 8.49) when adjusted for clinical, functional, histologic, and immunologic factors. These antibodies were also associated with an increased rate of antibody-mediated rejection, a more severe graft injury phenotype with more extensive microvascular inflammation, and increased deposition of complement fraction C4d within graft capillaries. Adding complement-binding donor specific anti-HLA antibodies to a traditional risk model improved the stratification of patients at risk for graft failure (continuous net reclassification improvement, 0.75; 95% CI, 0.54 to 0.97).
Assessment of the complement-binding capacity of donor-specific anti-HLA antibodies appears to be useful in identifying patients at high risk for kidney-allograft loss.
Rejection of allografts has always been the major obstacle to transplantation success. We aimed to improve characterisation of diff erent kidney-allograft rejection phenotypes, identify how each one is associated with anti-HLA antibodies, and investigate their distinct prognoses.
Patients who underwent ABO-compatible kidney transplantations in Necker Hospital and Saint-Louis Hospital (Paris, France) between Jan 1, 1998, and Dec 31, 2008, were included in our population-based study. We assessed patients who provided biopsy samples for acute allograft rejection, which was defi ned as the association of deterioration in function and histopathological lesions. The main outcome was kidney allograft loss—ie, return to dialysis. To investigate distinct rejection patterns, we retrospectively assessed rejection episodes with review of graft histology, C4d in allograft biopsies, and donor-specifi c anti-HLA antibodies.
2079 patients were included in the main analyses, of whom 302 (15%) had acute biopsy-proven rejection. We identified four distinct patterns of kidney allograft rejection: T cell-mediated vascular rejection (26 patients [9%]), antibody-mediated vascular rejection (64 [21%]), T cell-mediated rejection without vasculitis (139 [46%]), and antibody mediated rejection without vasculitis (73 [24%]). Risk of graft loss was 9.07 times (95 CI 3.62–19.7) higher in antibody-mediated vascular rejection than in T cell-mediated rejection without vasculitis (p<0.0001), compared with an increase of 2.93 times (1.1–7.9; P=0.0237) in antibody-mediated rejection without vasculitis and no significant rise in T cell-mediated vascular rejection (hazard ratio [HR] 1.5, 95% CI 0.33–7.6; p=0.60).
We have identified a type of kidney rejection not presently included in classifications: antibody mediated vascular rejection. Recognition of this distinct phenotype could lead to the development of new treatment strategies that could salvage many kidney allografts.
Mastering the risk of HLA antibodies in kidney transplantation: an algorithm based on pretransplant single-antigen flow bead techniques.
The utilization of sensitive techniques of detection of HLA antibodies to define and measure sensitization has greatly evolved in recent years. We present here an approach to minimize the risk of HLA antibodies in kidney transplantation based on the evaluation of graft accessibility of sensitized patients by calculated PRA (cPRA) and estimation of potential matched donors (PMD) using a national simulation software program. This study included all registered patients on our waiting list (WL) for deceased donor (DD) kidney transplants. All patients were screened by single-antigen flowbead (SAFB) techniques. Of the 502 registered patients, 174 (34.7%) were sensitized. Among these, 48.3% (84 pts) had a cPRA>85%. For 75.3% of sensitized patients (90 pts with cPRA≤85% and 41 pts with cPRA>85%), the flow of PMD was considered sufficient to allow a transplant avoiding all unacceptable antigens. The 41 patients with a cPRA>85% (48.8%) had a satisfactory donor flow in the framework of the national prioritization program for highly sensitized patients. Finally, 43 sensitized patients (24.7%) were deemed eligible for a strategy of higher immunological risk through desensitization protocols or transplantation against HLA-DSAs. This approach provides a logical and systematic strategy to rationalize the access of sensitized patients to kidney transplantation minimizing the risk of HLA antibodies.
JASN - PMID: 20634297
The clinical importance of preexisting HLA antibodies at the time of transplantation, identified by contemporary techniques, is not well understood. We conducted an observational study analyzing the association between preexisting donor-specific HLA antibodies (HLA-DSA) and incidence of acute antibody-mediated rejection (AMR) and survival of patients and grafts among 402 consecutive deceased-donor kidney transplant recipients. We detected HLA-DSA using Luminex single-antigen assays on the peak reactive and current sera. All patients had a negative lymphocytotoxic cross-match test on the day of transplantation. We found that 8-year graft survival was significantly worse (61%) among patients with preexisting HLA-DSA compared with both sensitized patients without HLA-DSA (93%) and nonsensitized patients (84%). Peak HLA-DSA Luminex mean fluorescence intensity (MFI) predicted AMR better than current HLA-DSA MFI (P = 0.028). As MFI of the highest ranked HLA-DSA detected on peak serum increased, graft survival decreased and the relative risk for AMR increased: Patients with MFI >6000 had >100-fold higher risk for AMR than patients with MFI <465 (relative risk 113; 95% confidence interval 31 to 414). The presence of HLA-DSA did not associate with patient survival. In conclusion, the risk for both AMR and graft loss directly correlates with peak HLA-DSA strength. Quantification of HLA antibodies allows stratification of immunologic risk, which should help guide selection of acceptable grafts for sensitized patients.
Comparison of combination Plasmapheresis/IVIg/anti-CD20 versus high-dose IVIg in the treatment of antibody-mediated rejection.
American Journal of Transplantation - PMID: 19422335
Different strategies appear to improve the success in treatment of antibody-mediated rejection (AMR), although no one best method has yet emerged. The objective of this study was to compare the efficacy of the combination of Plasmapheresis/intravenous immunoglobulin (IVIg)/anti-CD20-based regimes versus high-dose IVIg alone in the treatment of AMR. Group A (12 patients) was treated with high-dose IVIg between January 2000 and December 2003; group B (12 patients) was treated by Plasmapheresis/IVIg/anti-CD20 between January 2004 and December 2005. Graft survival at 36 months was 91.7% in group B versus 50% in group A (p = 0.02). Donor-specific human leukocyte antigens (DSA) levels detected by Luminex single antigen (Luminex SA) and ELISA, 3 months postrejection are significantly lower in group B than in group A: DSA ELISA class 2 score 6-8 (p = 0.02), DSA mean intensity of fluorescence (MFI) max (p = 0.009) and DSA mean MFI (p = 0.0004). The persistence of elevated DSA levels posttreatment is more frequent in patients with graft loss as compared to those with preserved renal function: score 6-8 on ELISA (p = 0.04); mean MFI (p = 0.00009) and MFImax (p = 0.018). We conclude that: (1) high dose IVIg alone is inferior to Plasmapheresis/IVIg/anti-CD20 as therapy for AMR and (2)DSA postrejection can be quantified using solid phase assays, showing that 3 months after AMR, DSA levels are higher in patients with graft loss.
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.