Generating automated kidney transplant biopsy reports combining molecular measurements with ensembles of machine learning classifiers.

We previously reported a system for assessing rejection in kidney transplant biopsies using microarray-based gene expression data, the Molecular Microscope® Diagnostic System (MMDx). The present study was designed to optimize the accuracy and stability of MMDx diagnoses by replacing single machine learning classifiers with ensembles of diverse classifier methods. We also examined the use of automated report sign-outs and the agreement between multiple human interpreters of the molecular results. Ensembles generated diagnoses that were both more accurate than the best individual classifiers, and nearly as stable as the best, consistent with expectations from the machine learning literature. Human experts had ≈93% agreement (balanced accuracy) signing out the reports, and random forest-based automated sign-outs showed similar levels of agreement with the human experts (92% and 94% for predicting the expert MMDx sign-outs for T cell-mediated (TCMR) and antibody-mediated rejection (ABMR), respectively). In most cases disagreements, whether between experts or between experts and automated sign-outs, were in biopsies near diagnostic thresholds. Considerable disagreement with histology persisted. The balanced accuracies of MMDx sign-outs for histology diagnoses of TCMR and ABMR were 73% and 78%, respectively. Disagreement with histology is largely due to the known noise in histology assessments (ClinicalTrials.gov NCT01299168).

The bridge between transplantation and regenerative medicine: Beginning a new Banff classification of tissue engineering pathology.

The science of regenerative medicine is arguably older than transplantation-the first major textbook was published in 1901-and a major regenerative medicine meeting took place in 1988, three years before the first Banff transplant pathology meeting. However, the subject of regenerative medicine/tissue engineering pathology has never received focused attention. Defining and classifying tissue engineering pathology is long overdue. In the next decades, the field of transplantation will enlarge at least tenfold, through a hybrid of tissue engineering combined with existing approaches to lessening the organ shortage. Gradually, transplantation pathologists will become tissue-(re-) engineering pathologists with enhanced skill sets to address concerns involving the use of bioengineered organs. We outline ways of categorizing abnormalities in tissue-engineered organs through traditional light microscopy or other modalities including biomarkers. We propose creating a new Banff classification of tissue engineering pathology to standardize and assess de novo bioengineered solid organs transplantable success in vivo. We recommend constructing a framework for a classification of tissue engineering pathology now with interdisciplinary consensus discussions to further develop and finalize the classification at future Banff Transplant Pathology meetings, in collaboration with the human cell atlas project. A possible nosology of pathologic abnormalities in tissue-engineered organs is suggested.

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology.

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.

The Revised (2013) Banff Classification for Antibody-Mediated Rejection of Renal Allografts: Update, Difficulties, and Future Considerations.

The Banff 2013 classification (Banff 2013) for antibody-mediated rejection (ABMR) in renal allografts represents the first major revision of the original Banff classification for ABMR that was published in 2003. The main impetus for this revision was the need to include C4d-negative ABMR, although this revised classification contains a number of additional features based on findings reported from 2007 to 2013. Since its publication, several studies have examined the validity of different aspects of Banff 2013 and compared it to earlier (2003, 2007) versions of the Banff ABMR classification. Recent evidence, albeit limited, indicates that Banff 2013 represents an improvement over the previous versions, enhancing our ability to accurately diagnose cases of acute/active and chronic active ABMR on renal allograft biopsy. Molecular studies appear to justify the threshold value of glomerulitis plus peritubular capillaritis score ≥2 required by Banff 2013 for the diagnosis of C4d-negative ABMR; however, other aspects of the classification, including its overall interobserver reproducibility, the clinical significance of the category of C4d staining without evidence of rejection, and whether surrogate markers might potentially substitute for the requirement for the presence of donor-specific antibodies, require additional investigation.

Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants.

The key lesions in antibody-mediated kidney transplant rejection (ABMR) are microcirculation inflammation (peritubular capillaritis and/or glomerulitis lesions, abbreviated "pg") and glomerular double contours (cg lesions). We used these features to explore subphenotypes in 164 indication biopsies with ABMR-related diagnoses: 137 ABMR (109 pure and 28 mixed with T cell-mediated rejection [TCMR]) and 27 transplant glomerulopathy (TG), identified from prospective multicenter studies. The lesions indicated three ABMR subphenotypes: pgABMR, cgABMR, and pgcgABMR. Principal component analysis confirmed these subphenotypes and showed that TG can be reclassified as pgcgABMR (n = 17) or cgABMR (n = 10). ABMR-related biopsies included 45 pgABMR, 90 pgcgABMR, and 25 cgABMR, with four unclassifiable. Dominating all time intervals was the subphenotype pgcgABMR. The pgABMR subphenotype presented earliest (median <2 years), frequently mixed with TCMR, and was most associated with nonadherence. The cgABMR subphenotype presented late (median 9 years). Subphenotypes differed in their molecular changes, with pgABMR having the most histologic-molecular discrepancies (i.e. potential errors). Donor-specific antibody (DSA) was not identified in 29% of pgcgABMR and 46% of cgABMR, but failure rates and molecular findings were similar to cases where DSA was known to be positive. Thus, ABMR presents distinct subphenotypes, early pg-dominant, late cg-dominant, and combined pgcg phenotype, differing in time, molecular features, accompanying TCMR, HLA antibody, and probability of nonadherence.

Optimizing rejection readouts in a corneal allograft transplantation model.

PURPOSE: To evaluate the feasibility of anterior segment spectral domain optic coherence tomography (ASOCT) as rejection readout in a keratoplasty mouse model and to compare ASOCT against the current standard (i.e., a clinical score system). Furthermore, to compare both approaches with respect to intra- and inter-individual observer variability and to calculate a critical point that distinguishes between rejection and non-rejection in ASOCT analysis. METHODS: Allogeneic penetrating keratoplasties (PKs) were performed using C3H/He donor mice and BALB/c recipient mice; syngeneic transplantations served as controls using BALB/c donors and recipients. Corneal graft rejection was determined with a clinical score. ASOCT was used to determine the central thickness of the corneal grafts in the same animals. The rejection status was corroborated with histopathological examination. RESULTS: The median survival time (MST) of the corneal allografts in the wild-type BALB/c mice was 12 days. Allogeneic transplantation led to a 100% rejection rate, whereas signs of rejection after syngeneic transplantation appeared in up to 20% of the mice. Central corneal thickness (CCT) determination via customized software revealed a direct correlation with the clinical score. Receiver operating curve (ROC) analysis confirmed CCT as a valid surrogate for rejection. Calculation of the area under the curve (AUC) revealed a value of 0.88 with an optimal cut-off at 267 pixels. CONCLUSIONS: An increase in the CCT during acute allogeneic corneal graft rejection significantly correlated with the clinical surrogate parameter "corneal opacity." ASOCT not only generates source data, but also analysis of the ASOCT data shows lower readout variability and fewer interpreter variations than the clinical score commonly used to define the time point of graft rejection in mice.

Impact of the Banff 2013 classification on the diagnosis of suspicious versus conclusive late antibody-mediated rejection in allografts without acute dysfunction.

BACKGROUND: The Banff classification is used worldwide to characterize pathological findings in renal allograft biopsies. During the 11th Banff meeting, relevant changes were introduced in the diagnostic criteria for Category 2 antibody-mediated rejection (ABMR). Here, we assess the effect of these changes on the diagnosis of late chronic ABMR. METHODS: Seventy-three indication renal graft biopsies (chronic dysfunction, proteinuria and/or the presence of de novo donor-specific antibodies) from 68 kidney transplant recipients initially classified following the Banff 2009 criteria were reviewed and reclassified as per the new Banff 2013 criteria. RESULTS: The diagnostic category changed in 18% of the study biopsies with Banff 2013. The reclassification mainly involved Category 2 cases, from which 23.5% of the biopsies from older patients with worse graft function were overlooked by Banff 2009. ABMR was ruled out in 13% of cases under the Banff 2009 criteria. A significant number of the study samples were conclusively diagnosed as ABMR (40% as per Banff 2009 and 74% as per Banff 2013; P = 0.006), because of the inclusion of microvascular inflammation and the acceptance of some ultrastructural diagnostic criteria. However, when following the criteria of the new classification, samples with histological signs of chronic ABMR, in which human leucocyte antigen donor-specific antibodies are not detected or ultrastructural studies are not performed, may be inadequately characterized. CONCLUSIONS: The Banff 2013 classification helps in making a diagnosis of late ABMR, identifying cases, decreasing the percentage of suspected ABMR and making more conclusive diagnoses.

Current views on chronic rejection after lung transplantation.

Chronic lung allograft dysfunction (CLAD) was recently introduced as an overarching term mainly to classify patients with chronic rejection after lung transplantation, although other conditions may also qualify for CLAD. Initially, only the development of a persistent and obstructive pulmonary function defect, clinically identified as bronchiolitis obliterans syndrome (BOS), was considered as chronic rejection, if no other cause could be identified. It became clear in recent years that some patients do not qualify for this definition, although they developed a chronic and persistent decrease in FEV1 , without another identifiable cause. As the pulmonary function decline in these patients was rather restrictive, this was called restrictive allograft syndrome (RAS). In the present review, we will further elaborate on these two CLAD phenotypes, with specific attention to the diagnostic criteria, the role of pathology and imaging, the risk factors, outcome, and the possible treatment options.

The impact of C4d-negative acute antibody-mediated rejection on short-term prognosis among kidney transplant recipients.

AIM: We aimed to investigate the clinical and pathological features of C4d-negative acute antibody-mediated rejection (aAMR), and examined the impact of C4d-negative aAMR on short-term prognosis. METHODS: From 2005 to 2011, 626 kidney transplantations were performed in our institution and related hospitals. We excluded 174 ABO-incompatible transplantations, and analysed clinical and pathological data from the remaining 452 until December 2013. RESULTS: During the follow-up period, 39 patients underwent aAMR. We divided them into two groups. According to C4d positivity in each patient's first AMR, we divided the cohort into a C4d-positive aAMR group and a C4d-negative aAMR group, using the new Banff 2013 classification. We compared each aAMR patient's features to controls. Clinical and pathological characteristics were similar in both groups and the short-term outcomes of the two groups were similar, but both were worse than control. CONCLUSION: C4d-negative aAMR resembles C4d-positive aAMR in terms of clinical and pathological features, and that C4d positivity has no influence on short-term outcome.

Banff 2013 update: Pearls and pitfalls in transplant renal pathology.

The pathological classification of rejection in renal allografts (Banff classification) has undergone substantial evolution for more than 20 years, and has been the diagnostic gold standard in clinical practice. The 2013 updated Banff classification encompasses a revised scheme of antibody-mediated rejection (ABMR) that consists of donor-specific antibody (DSA) positivity, characteristic histological manifestations for both acute and chronic ABMR, and DSA-induced endothelial cell injury which is represented by either C4d positivity, microvascular inflammation or expression of activated endothelial gene transcripts. Other modified criteria include a C4d positivity threshold, and histological definition of transplant glomerulitis and transplant glomerulopathy. Morphologically, glomerulonephritis, either recurrent or de novo, can be challenging to differentiate from ABMR-mediated transplant glomerulitis. Endothelial arteritis by itself does not warrant the diagnosis of acute T-cell mediated rejection; ABMR should also be considered based on the DSA test results. With regard to polyomavirus BK-associated nephropathy, immunohistochemical examination using anti-simian virus (SV) 40 antibody can be a promising method to assess the quantitative viral load of polyomavirus BK and graft survival. In summary, the 2013 updated Banff classification strictly defines ABMR with histopathological and serological criteria irrespective of C4d positivity. Inclusion of gene expression data relevant to ABMR highlights that the Banff criteria have entered the era of 'Seeing the Unseen' schemes, reflecting recent advances in understanding the molecular events in allograft injury.

Molecular classifiers for acute kidney transplant rejection in peripheral blood by whole genome gene expression profiling.

There are no minimally invasive diagnostic metrics for acute kidney transplant rejection (AR), especially in the setting of the common confounding diagnosis, acute dysfunction with no rejection (ADNR). Thus, though kidney transplant biopsies remain the gold standard, they are invasive, have substantial risks, sampling error issues and significant costs and are not suitable for serial monitoring. Global gene expression profiles of 148 peripheral blood samples from transplant patients with excellent function and normal histology (TX; n = 46), AR (n = 63) and ADNR (n = 39), from two independent cohorts were analyzed with DNA microarrays. We applied a new normalization tool, frozen robust multi-array analysis, particularly suitable for clinical diagnostics, multiple prediction tools to discover, refine and validate robust molecular classifiers and we tested a novel one-by-one analysis strategy to model the real clinical application of this test. Multiple three-way classifier tools identified 200 highest value probesets with sensitivity, specificity, positive predictive value, negative predictive value and area under the curve for the validation cohort ranging from 82% to 100%, 76% to 95%, 76% to 95%, 79% to 100%, 84% to 100% and 0.817 to 0.968, respectively. We conclude that peripheral blood gene expression profiling can be used as a minimally invasive tool to accurately reveal TX, AR and ADNR in the setting of acute kidney transplant dysfunction.

Evaluation of molecular profiles in calcineurin inhibitor toxicity post-kidney transplant: input to chronic allograft dysfunction.

The molecular basis of calcineurin inhibitor toxicity (CNIT) in kidney transplantation (KT) and its contribution to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA) were evaluated by: (1) identifying specific CNIT molecular pathways that associate with allograft injury (cross-sectional study) and (2) assessing the contribution of the identified CNIT signature in the progression to CAD with IF/TA (longitudinal study). Kidney biopsies from well-selected transplant recipients with histological diagnosis of CNIT (n = 14), acute rejection (n = 13) and CAD with IF/TA (n = 10) were evaluated. Normal allografts (n = 18) were used as controls. To test CNIT contribution to CAD progression, an independent set of biopsies (n = 122) from 61 KT patients collected at 3 and ~12 months post-KT (range = 9-18) were evaluated. Patients were classified based on 2-year post-KT graft function and histological findings as progressors (n = 30) or nonprogressors to CAD (n = 31). Molecular signatures characterizing CNIT samples were identified. Patients classified as progressors showed an overlap of 7% and 22% with the CNIT signature at 3 and at ~12 months post-KT, respectively, while the overlap was <1% and 1% in nonprogressor patients, showing CNIT at the molecular level as a nonimmunological factor involved in the progression to CAD.

Diagnosis and classification of kidney transplant rejection using machine learning-assisted surface-enhanced Raman spectroscopy using a single drop of serum.

The quest to reduce kidney transplant rejection has emphasized the urgent requirement for the development of non-invasive, precise diagnostic technologies. These technologies aim to detect antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR), which are asymptomatic and pose a risk of potential kidney damage. The protocols for managing rejection caused by ABMR and TCMR differ, and diagnosis has traditionally relied on invasive biopsy procedures. Therefore, a convergence system using a nano-sensing chip, Raman spectroscopy, and AI technology was introduced to facilitate diagnosis using serum samples obtained from patients with no major abnormality, ABMR, and TCMR after kidney transplantation. Tissue biopsy and Banff score analysis were performed across the groups for validation, and 5 µL of serum obtained at the same time was added onto the Au-ZnO nanorod-based Surface-Enhanced Raman Scattering sensing chip to obtain Raman spectroscopy signals. The accuracy of machine learning algorithms for principal component-linear discriminant analysis and principal component-partial least squares discriminant analysis was 93.53% and 98.82%, respectively. The collagen (an indicative of kidney injury), creatinine, and amino acid-derived signals (markers of kidney function) contributed to this accuracy; however, the high accuracy was primarily due to the ability of the system to analyze a broad spectrum of various biomarkers.

A four-year pathology review of the near total face transplant.

In December of 2008, our institution performed a near total face transplant. The patient was monitored for signs of rejection assessed by paired skin and mucosa biopsies. The results of histological review of 120 biopsies collected during the first 4 years posttransplant are discussed. All biopsies were stained with hematoxylin and eosin, periodic acid-Schiff, immunohistochemical and TUNEL assays and graded using the Banff 2007 classification. Grade III rejection was diagnosed clinically at weeks 45 and 66, posttransplant; week 45 was determined as folliculitis while the erythema episode at week 66 confirmed an acute rejection (AR) that required hospitalization. The mucosa frequently showed interface inflammation without clinical signs of rejection and was not present in skin biopsies. In all, 34 of the 45 mucosal biopsies (75%) showed these interface changes. Clinical symptoms concurred with skin pathology in two grade III rejections. The mucosa showed histologic signs of rejection more frequently, which may indicate: increased mucosal sensitivity to rejection, a different type or subtype of AR that is specific to the mucosa, or a nonspecific process such as a drug effect. With more data and world experience, the diagnosis of face transplant rejection will be better defined and the Banff classification enhanced.

Molecular diagnosis of T cell-mediated rejection in human kidney transplant biopsies.

Histologic diagnosis of T cell-mediated rejection is flawed by subjective assessments, nonspecific lesions and arbitrary rules. This study developed a molecular test for T cell-mediated rejection. We used microarray results from 403 kidney transplant biopsies to derive a classifier assigning T cell-mediated rejection scores to all biopsies, and compared these with histologic assessments. The score correlated with histologic lesions of T cell-mediated rejection (infiltrate, tubulitis). The accuracy of the classifier for the histology diagnoses was 89%. Very high and low molecular scores corresponded with unanimity among three pathologists on the presence or absence of T cell-mediated rejection, respectively. The molecular score had low sensitivity (50%) and positive predictive value (62%) for the histology diagnoses. However, histology showed similar disagreement between pathologists--only 45-56% sensitivity of one pathologist with diagnoses of T cell-mediated rejection by another. Discrepancies between molecular scores and histology were mostly when histology was ambiguous ("borderline") or unreliable, e.g. in cases with scarring or inflammation induced by tissue injury. Vasculitis (isolated v-lesion TCMR) was particularly discrepant, with most cases exhibiting low TCMR scores. We propose new rules to integrate molecular tests and histology into a precision diagnostic system that can reduce errors, ambiguity and interpathologist disagreement.

Pseudorejection and true rejection after kidney transplantation: classification and clinical significance.

OBJECTIVES: Multiple factors may result in an elevation in serum creatinine level after kidney transplantation, mimicking rejection. It is crucial to differentiate between a true rejection and other conditions inducing a 'pseudorejection', in order to avoid overtreatment, or worse, mistreatment. Our goal was to review and classify true rejections and pseudorejections and their clinical significance. MATERIAL AND METHODS: This was a retrospective review of articles published in the USA and Europe, from 1976 to the present. The sites from which information was retrieved included PubMed, Clinical Imaging, Histopathology, Archives of Surgery, JACS, the American Urological Association, Medline and Springer Link. The importance of the resistive index will also be emphasized. RESULTS: We reviewed 61 articles regarding the causes of renal graft dysfunction, which may be classified into true rejections and pseudorejections, the latter including the following 6 factors: hyperglycemia, ureteral obstruction, lymphocele, arterial stenosis, infection and recurrence of primary pathology. CONCLUSIONS: 'Pseudorejection' has been described only once, for the first time in 1976 in the USA, and there have been no other reports since then. Multiple factors, mainly hyperglycemia, may induce a pseudorejection, presenting with an elevation of serum creatinine level and leading the clinician to an erroneous diagnosis of true rejection initially, resulting in inappropriate management.

A computational pipeline for the development of multi-marker bio-signature panels and ensemble classifiers.

BACKGROUND: Biomarker panels derived separately from genomic and proteomic data and with a variety of computational methods have demonstrated promising classification performance in various diseases. An open question is how to create effective proteo-genomic panels. The framework of ensemble classifiers has been applied successfully in various analytical domains to combine classifiers so that the performance of the ensemble exceeds the performance of individual classifiers. Using blood-based diagnosis of acute renal allograft rejection as a case study, we address the following question in this paper: Can acute rejection classification performance be improved by combining individual genomic and proteomic classifiers in an ensemble? RESULTS: The first part of the paper presents a computational biomarker development pipeline for genomic and proteomic data. The pipeline begins with data acquisition (e.g., from bio-samples to microarray data), quality control, statistical analysis and mining of the data, and finally various forms of validation. The pipeline ensures that the various classifiers to be combined later in an ensemble are diverse and adequate for clinical use. Five mRNA genomic and five proteomic classifiers were developed independently using single time-point blood samples from 11 acute-rejection and 22 non-rejection renal transplant patients. The second part of the paper examines five ensembles ranging in size from two to 10 individual classifiers. Performance of ensembles is characterized by area under the curve (AUC), sensitivity, and specificity, as derived from the probability of acute rejection for individual classifiers in the ensemble in combination with one of two aggregation methods: (1) Average Probability or (2) Vote Threshold. One ensemble demonstrated superior performance and was able to improve sensitivity and AUC beyond the best values observed for any of the individual classifiers in the ensemble, while staying within the range of observed specificity. The Vote Threshold aggregation method achieved improved sensitivity for all 5 ensembles, but typically at the cost of decreased specificity. CONCLUSION: Proteo-genomic biomarker ensemble classifiers show promise in the diagnosis of acute renal allograft rejection and can improve classification performance beyond that of individual genomic or proteomic classifiers alone. Validation of our results in an international multicenter study is currently underway.

Identification and classification of acute cardiac rejection by intragraft transcriptional profiling.

BACKGROUND: Treatment of acute rejection (AR) in heart transplantation relies on histopathological grading of endomyocardial biopsies according to International Society for Heart and Lung Transplantation guidelines. Intragraft gene expression profiling may be a way to complement histological evaluation. METHODS AND RESULTS: Transcriptional profiling was performed on 26 endomyocardial biopsies, and expression patterns were compared with the 1990 International Society for Heart and Lung Transplantation AR grades. Importantly, transcriptional profiles from settings with an equivalent AR grade appeared the same. In addition, grade 0 profiles could not be distinguished from 1A profiles, and grade 3A profiles could not be distinguished from 3B profiles. Comparing the AR groupings (0+1A, 1B, and 3A+3B), 0+1A showed more striking differences from 1B than from 3A+3B. When these findings were extrapolated to the 2005 revised guidelines, the combination of 1A and 1B into a single category (1R) appears to have brought together endomyocardial biopsies with different underlying processes that are not evident from histological evaluation. Grade 1B was associated with upregulated immune response genes, as 1 categorical distinction from grade 1A. Although grade 1B was distinct from the clinically relevant AR grades 3A and 3B, all of these grades shared a small number of overlapping pathways consistent with common physiological underpinnings. CONCLUSION: The gene expression similarities and differences identified here in different AR settings have the potential to revise the clinical perspective on acute graft rejection, pending the results of larger studies.

Banff 2011 Meeting report: new concepts in antibody-mediated rejection.

The 11th Banff meeting was held in Paris, France, from June 5 to 10, 2011, with a focus on refining diagnostic criteria for antibody-mediated rejection (ABMR). The major outcome was the acknowledgment of C4d-negative ABMR in kidney transplants. Diagnostic criteria for ABMR have also been revisited in other types of transplants. It was recognized that ABMR is associated with heterogeneous phenotypes even within the same type of transplant. This highlights the necessity of further refining the respective diagnostic criteria, and is of particular significance for the design of randomized clinical trials. A reliable phenotyping will allow for definition of robust end-points. To address this unmet need and to allow for an evidence-based refinement of the Banff classification, Banff Working Groups presented multicenter data regarding the reproducibility of features relevant to the diagnosis of ABMR. However, the consensus was that more data are necessary and further Banff Working Group activities were initiated. A new Banff working group was created to define diagnostic criteria for ABMR in kidneys independent of C4d. Results are expected to be presented at the 12th Banff meeting to be held in 2013 in Brazil. No change to the Banff classification occurred in 2011.

The Banff 2009 Working Proposal for polyomavirus nephropathy: a critical evaluation of its utility as a determinant of clinical outcome.

Clinical outcome in BK virus nephropathy (BKVN) was examined in relation to clinical and histologic parameters with reference to the Banff Working Proposal 2009, which emphasizes tubular injury and viral load. Seventy one patients were evaluated in three eras: (i) Era-I: No BKV PCR performed (n = 36), (ii) Era-II: PCR performed for rising creatinine (n = 24) and (iii) Era III: PCR performed for routine screening (n = 11). Six of seventy-one (8.4%) patients were classified as Class A, 46/71 (64.8%) as Class B and 19/71 (26.8%) as Class C. Banff class A never occurred in Era-I. It is a heterogeneous class that includes biopsies with inflammation that have hitherto been included in Class B. Higher inflammation, but not tubular injury, nor histologic viral load correlated with worse creatinine at 3 months. On long-term follow-up, class C associated with graft loss (hazard ratio 2.45, p = 0.03). Clearance of viremia was associated with better graft survival at 5 years (46.0% vs. 25.0%). Viruria clearance was infrequent (15.6%). In conclusion, the clinical utility of the Banff Working Proposal 2009 derives from scoring of fibrosis and not extent of tubular injury or viral cytopathic effect. The proposal is not superior to existing schemas that include assessment of inflammation, which is a well-known prognostic marker in other renal allograft diseases.