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.
In this article, the Banff consortium presents the most updated version of the kidney, pancreas, and VCA transplant rejection classification and prospects for implementing intragraft molecular assessment. See the companion report on page 42.
The Banff working group on preimplantation biopsy was established to develop consensus criteria (best practice guidelines) for the interpretation of preimplantation kidney biopsies. Digitally scanned ...slides were used (i) to evaluate interobserver variability of histopathologic findings, comparing frozen sections with formalin‐fixed, paraffin‐embedded tissue of wedge and needle core biopsies, and (ii) to correlate consensus histopathologic findings with graft outcome in a cohort of biopsies from international medical centers. Intraclass correlations (ICCs) and univariable and multivariable statistical analyses were performed. Good to fair reproducibility was observed in semiquantitative scores for percentage of glomerulosclerosis, arterial intimal fibrosis and interstitial fibrosis on frozen wedge biopsies. Evaluation of frozen wedge and core biopsies was comparable for number of glomeruli, but needle biopsies showed worse ICCs for glomerulosclerosis, interstitial fibrosis and tubular atrophy. A consensus evaluation form is provided to help standardize the reporting of histopathologic lesions in donor biopsies. It should be recognized that histologic parameters may not correlate with graft outcome in studies based on organs deemed to be acceptable after careful clinical assessment. Significant limitations remain in the assessment of implantation biopsies.
The Banff preimplantation biopsy working group reports the results of histopathological digital evaluation of preimplantation kidney biopsies by expert renal pathologists, provides a consensus form to help standardize reporting of donor biopsies, and reiterates the advantages and limitations of using pathology to predict graft outcomes.
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.
The Banff consortium presents revisions to the diagnostic criteria for T cell– and antibody‐mediated kidney transplant rejection, including specific criteria for chronic active T cell–mediated rejection, plus prospects for integrative endpoints in clinical trials. See related articles on pages 321, 364, and 377.
The 12th Banff Conference on Allograft Pathology was held in Comandatuba, Brazil, from August 19–23, 2013, and was preceded by a 2‐day Latin American Symposium on Transplant Immunobiology and ...Immunopathology. The meeting was highlighted by the presentation of the findings of several working groups formed at the 2009 and 2011 Banff meetings to: (1) establish consensus criteria for diagnosing antibody‐mediated rejection (ABMR) in the presence and absence of detectable C4d deposition; (2) develop consensus definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score), associated with improved inter‐observer agreement and correlation with clinical, molecular and serological data; (3) determine whether isolated lesions of intimal arteritis (“isolated v”) represent acute rejection similar to intimal arteritis in the presence of tubulointerstitial inflammation; (4) compare different methodologies for evaluating interstitial fibrosis and for performing/evaluating implantation biopsies of renal allografts with regard to reproducibility and prediction of subsequent graft function; and (5) define clinically and prognostically significant morphologic criteria for subclassifying polyoma virus nephropathy. The key outcome of the 2013 conference is defining criteria for diagnosis of C4d‐negative ABMR and respective modification of the Banff classification. In addition, three new Banff Working Groups were initiated.
The 2013 Banff Transplant Conference defines revised, consensus criteria for acute/active and chronic, active antibody‐mediated rejection in renal allograft biopsies, criteria that include C4d‐negative antibody‐mediated rejection and antibody‐associated arterial lesions. Also see comprehensive review by Djamali et al on page 255.
The updated Banff classification allows for the diagnosis of antibody‐mediated rejection (AMR) in the absence of peritubular capillary C4d staining. Our objective was to quantify allograft loss risk ...in patients with consistently C4d‐negative AMR (n = 51) compared with C4d‐positive AMR patients (n = 156) and matched control subjects without AMR. All first‐year posttransplant biopsy results from January 2004 through June 2014 were reviewed and correlated with the presence of donor‐specific antibody (DSA). C4d‐negative AMR patients were not different from C4d‐positive AMR patients on any baseline characteristics, including immunologic risk factors (panel reactive antibody, prior transplant, HLA mismatch, donor type, DSA class, and anti‐HLA/ABO‐incompatibility). C4d‐positive AMR patients were significantly more likely to have a clinical presentation (85.3% vs. 54.9%, p < 0.001), and those patients presented substantially earlier posttransplantation (median 14 interquartile range 8–32 days vs. 46 interquartile range 20–191, p < 0.001) and were three times more common (7.8% vs 2.5%). One‐ and 2‐year post–AMR‐defining biopsy graft survival in C4d‐negative AMR patients was 93.4% and 90.2% versus 86.8% and 82.6% in C4d‐positive AMR patients, respectively (p = 0.4). C4d‐negative AMR was associated with a 2.56‐fold (95% confidence interval, 1.08–6.05, p = 0.033) increased risk of graft loss compared with AMR‐free matched controls. No clinical characteristics were identified that reliably distinguished C4d‐negative from C4d‐positive AMR. However, both phenotypes are associated with increased graft loss and thus warrant consideration for intervention.
This study shows kidney transplant recipients with c4d‐negative antibody‐mediated rejection (AMR) are indistinguishable from c4d‐positive AMR recipients in terms of baseline demographic and transplant characteristics, but c4d‐negative AMR presents significantly later posttransplant and is more likely to be subclinical, and both groups have worse graft survival than AMR‐free matched controls.
Subclinical antibody‐mediated rejection (AMR) has been described in renal allograft recipients with stable serum creatinine (SCr), however whether this leads to development of chronic allograft ...nephropathy (CAN) remains unknown.
We retrospectively reviewed data from 83 patients who received HLA‐incompatible renal allografts following desensitization to remove donor‐specific antibodies (DSA). Ten patients had an allograft biopsy showing subclinical AMR stable SCr, neutrophil margination in peritubular capillaries (PTC), diffuse PTC C4d, positive DSA during the first year post‐transplantation; 3 patients were treated with plasmapheresis and intravenous immunoglobulin. Three patients had a subsequent rise in SCr and an associated biopsy with AMR; 5 others showed diagnostic or possible subclinical AMR on a later protocol biopsy. One graft was lost, while remaining patients have normal or mildly elevated
SCr 8–45 months post‐transplantation. However, the mean increase in CAN score (cg + ci + ct + cv) from those biopsies showing subclinical AMR to follow‐up biopsies 335 ± 248 (SD) days later was significantly greater (3.5 ± 2.5 versus 1.0 ± 2.0, p = 0.01) than that in 24 recipients of HLA‐incompatible grafts with no AMR over a similar interval (360 ± 117 days), suggesting that subclinical AMR may contribute to development of CAN.
Ten of 83 patients receiving an HLA‐incompatible renal allograft following desensitization had a protocol biopsy showing histologic and immunohistologic changes of acute antibody‐mediated rejection (AMR); follow‐up biopsies of these grafts taken a mean of ∼1 year later showed significantly more chronic change, including glomerulopathy, than biopsies of 24 HLA‐incompatible grafts with no history of AMR over a similar interval.
Unlike antibody‐mediated rejection (AMR) with clinical features, it remains unclear whether subclinical AMR should be treated, as its effect on allograft loss is unknown. It is also uncertain if ...AMR's effect is homogeneous across donor (deceased/live) and (HLA/ABO) antibody types. We compared 219 patients with AMR (77 subclinical, 142 clinical) to controls matched on HLA/ABO‐compatibility, donor type, prior transplant, panel reactive antibody (PRA), age and year. One and 5‐year graft survival in subclinical AMR was 95.9% and 75.7%, compared to 96.8% and 88.4% in matched controls (p = 0.0097). Subclinical AMR was independently associated with a 2.15‐fold increased risk of graft loss (95% CI: 1.19–3.91; p = 0.012) compared to matched controls, but not different from clinical AMR (p = 0.13). Fifty three point two percent of subclinical AMR patients were treated with plasmapheresis within 3 days of their AMR‐defining biopsy. Treated subclinical AMR patients had no difference in graft loss compared to matched controls (HR 1.73; 95% CI: 0.73–4.05; p = 0.21), but untreated subclinical AMR patients did (HR 3.34; 95% CI: 1.37–8.11; p = 0.008). AMR's effect on graft loss was heterogeneous when stratified by compatible deceased donor (HR = 4.73; 95% CI: 1.57–14.26; p = 0.006), HLA‐incompatible deceased donor (HR = 2.39; 95% CI: 1.10–5.19; p = 0.028), compatible live donor (no AMR patients experienced graft loss), ABO‐incompatible live donor (HR = 6.13; 95% CI: 0.55–67.70; p = 0.14) and HLA‐incompatible live donor (HR = 6.29; 95% CI: 3.81–10.39; p < 0.001) transplant. Subclinical AMR substantially increases graft loss, and treatment seems warranted.
In this matched cohort study of 219 kidney transplant recipients with early antibody‐mediated rejection (AMR) according to 2013 Banff criteria, those with subclinical rejection were found to have higher rates of graft loss than AMR‐free matched controls, with a heterogeneous magnitude of effect based on donor (deceased/live) and antibody (HLA/ABO) types.
The Open Computing Cluster for Advanced data Manipulation (OCCAM) is a multipurpose flexible HPC cluster designed and operated by a collaboration between the University of Torino and the Sezione di ...Torino of the Istituto Nazionale di Fisica Nucleare. It is aimed at providing a flexible, reconfigurable and extendable infrastructure to cater to a wide range of different scientific computing use cases, including ones from solid-state chemistry, high-energy physics, computer science, big data analytics, computational biology, genomics and many others. Furthermore, it will serve as a platform for R&D activities on computational technologies themselves, with topics ranging from GPU acceleration to Cloud Computing technologies. A heterogeneous and reconfigurable system like this poses a number of challenges related to the frequency at which heterogeneous hardware resources might change their availability and shareability status, which in turn affect methods and means to allocate, manage, optimize, bill, monitor VMs, containers, virtual farms, jobs, interactive bare-metal sessions, etc. This work describes some of the use cases that prompted the design and construction of the HPC cluster, its architecture and resource provisioning model, along with a first characterization of its performance by some synthetic benchmark tools and a few realistic use-case tests.
Biopsies of ABO‐incompatible and positive crossmatch (HLA‐incompatible) renal allografts were retrospectively examined to compare results of C4d and C3d staining, and the correlation between such ...staining and histologic findings suggestive of antibody‐mediated rejection (AMR). A total of 75 biopsies (55 protocol, 17 for graft dysfunction, 3 for other indications) of 24 ABO‐incompatible grafts and 244 biopsies (103 protocol, 129 for graft dysfunction, 12 for other indications) of 66 HLA‐incompatible grafts were examined; all were stained for C4d and ∼40% for C3d.
In ABO‐incompatible grafts, 80% of protocol biopsies and 59% performed for graft dysfunction showed C4d staining in peritubular capillaries (PTC); this staining was not correlated with neutrophil margination in PTC. In HLA‐incompatible grafts, PTC C4d was present in 26% of protocol biopsies and 60% of biopsies for graft dysfunction; 92% of biopsies with >1+ (0–4+ scale), diffuse PTC C4d had ≥1+ margination and/or thrombotic microangiopathy (TMA), compared with 12% of C4d‐negative biopsies. C3d was somewhat more predictive of margination than C4d in ABO‐incompatible, but not HLA‐incompatible, grafts. In summary, while PTC C4d deposition indicates probable AMR in biopsies of HLA‐incompatible grafts, including protocol biopsies, there is no histologic evidence that C4d deposition is correlated with injury in most ABO‐incompatible grafts.
This retrospective biopsy study showed that ABO incompatible kidney biopsies were 25% positive for C4d staining in protocol biopsies and 60% positive in biopsies for graft dysfunction, but unlike HLA antibodies C4d deposition in most ABO incompatible grafts was not correlated with histologic injury. See also editorial by Sis, Kaplan, and Halloran in this issue on page 1753.
In the ideal limit of infinite resources, multi-tenant applications are able to scale in/out on a Cloud driven only by their functional requirements. While a large Public Cloud may be a reasonable ...approximation of this condition, small scientific computing centres usually work in a saturated regime. In this case, an advanced resource allocation policy is needed in order to optimize the use of the data centre. The general topic of advanced resource scheduling is addressed by several components of the EU-funded INDIGO-DataCloud project. In this contribution, we describe the FairShare Scheduler Service (FaSS) for OpenNebula (ONE). The service must satisfy resource requests according to an algorithm which prioritizes tasks according to an initial weight and to the historical resource usage of the project. The software was designed to be less intrusive as possible in the ONE code. We keep the original ONE scheduler implementation to match requests to available resources, but the queue of pending jobs to be processed is the one ordered according to priorities as delivered by the FaSS. The FaSS implementation is still being finalized and in this contribution we describe the functional and design requirements the module should satisfy, as well as its high-level architecture.
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