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Acute allograft rejection in patients undergoing renal transplantation is diagnosed through histopathological analysis of renal graft biopsies, which can be used to quantify elementary lesions. However, quantification of elementary lesions requires considerable expertise, time, and effort. Using a 2-stage classification strategy, we sought to examine the effectiveness of deep learning in detecting and classifying glomeruli into 4 groups, namely normal, abnormal, sclerotic, and glomerulitis, as a potential biopsy triage system focused on transplant rejection. We used the U-Net model to build a glomeruli detection model using 137 kidney biopsy slides obtained from 80 kidney transplant patients. The median age of the patients was 52 (19-74) years, with 65% being men and 35% women. MobileNetV2 and VGG16 models were compared using a 2-stage classification strategy. In the first classification step, the models classified glomeruli into sclerotic and nonsclerotic glomeruli. In the second classification step, the nonsclerotic glomeruli from the first step were classified as normal, abnormal, or glomerulitis. The U-Net model achieved satisfactory detection (Dice coefficient = 0.90), and the MobileNetV2 model was the best for the 2 classification steps, with F1 scores of 0.85, 0.91, 0.98, and 0.92 for normal, abnormal, sclerotic, and glomerulitis, respectively. The 2-stage classification strategy identifies sclerotic glomeruli and abnormal glomeruli relative to permeable glomeruli and quantifies glomerulitis with significant accuracy while avoiding bias from abnormal glomeruli that do not have glomerulitis, providing valuable diagnostic information., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jun Ki Kim reports financial support was provided by Asan Medical Center. Jun Ki Kim reports a relationship with Asan Medical Center that includes: employment. Jun Ki Kim has patent pending to Asan medical center. Non applicable., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: With current immunosuppressive regimens, BK polyomavirus-associated nephropathy (BKPyVAN) is still a matter of concern. Stratification of patients at risk for allograft loss is of uttermost importance to guide treatment choice and assess prognosis. In 2018, the Banff working group proposed a classification scheme for the prognosis of BKPyVAN, but external application on independent cohorts is yet to be performed. We investigated how the 2018 Banff classification would perform in a multicenter cohort comprising 50 cases of biopsy-proven BKPyVAN compared to previously published classification systems., Methods: We analyzed consecutive BKPyVAN cases from two Dutch university hospitals between 2002 and 2013, retrieved clinical data, and scored all biopsies according to the Banff 2018 classification, and as a comparison, 4 previously proposed BKPyVAN classification systems. We used estimated glomerular filtration rate trajectories and death-censored graft survival as primary endpoints., Results: The 2018 Banff classification did not associate with estimated glomerular filtration rate decline or graft failure and performed only slightly better than the 4 previously proposed classifiers. Anti-human leukocyte antigen donor-specific antibodies (DSAs), especially in combination with ongoing biopsy-proven BKPyVAN on follow-up, did correlate with graft function and survival. Patients who were DSA+/BKPyVAN+ on follow-up had more inflammation at the baseline biopsy, which by itself was not associated with graft outcomes., Conclusions: Neither the 2018 Banff BKPyVAN classification nor previously published stratification systems could be applied to our multicenter patient cohort. Our data suggest that there might be a prognostic value for follow-up biopsies and DSA measurements to improve risk stratification after BKPyVAN, although prospective multicenter efforts with protocol measurements are needed to confirm this.

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)., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Antibody-mediated rejection (ABMR) is the leading cause of kidney graft loss worldwide. Criteria for acute humoral rejection (currently labeled active humoral rejection) established by the 2007 Banff classification are highly specific but lack sensitivity. Modifications to the Banff classification were introduced for its 2013 and 2017 versions in order to identify more cases of this entity., Purpose: We intend to demonstrate that, compared to its 2007 version, the 2017 Banff classification bears an improved capacity for graft loss prediction when histologic criteria for active ABMR are met., Patients and Methods: Single-center retrospective cohort study. A random sample of 201 kidney recipients who underwent a graft biopsy since January 2004 was analyzed. Patients were classified as ever developing histologic characteristics of acute ABMR (2007 Banff) or not and renal survival between groups was compared. The same patients were then classified as ever developing histologic characteristics of active ABMR (2017 Banff) or not and renal survival was again compared. Presence of circulating donor-specific antibodies (DSA) was not taken into consideration., Results: Patients were followed for a median 13.9 ± 7.9 years, during which grafts were biopsied on 537 occasions (2.7 ± 1.6 biopsies per graft). Baseline eGFR was 73.26 ± 17.6 ml/min and baseline creatinine 1.14 ± 0.25 mg/dl. Graft loss occurred in 38 recipients (18.9%) mainly due to ABMR (60.5%). Acute ABMR (2007 Banff) was identified in 11 recipients (5.5%) and graft survival did not differ between groups with and without active ABMR occurrence (log-rank p = 0.939). Active ABMR (2017 Banff) was found in 59 recipients (29%) and graft survival was better from the second post-transplant year onward in the group of patients without active ABMR occurrence (log-rank p = 0.001). Moderate microvascular inflammation was present in 89.6% of the 48 additional patients with active ABMR., Conclusion: The 2017 Banff classification identifies more patients who develop active ABMR and stratifies graft loss risk better than the 2007 version., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Kidney transplantation is considered the ideal treatment for end-stage renal disease. Acute rejection can influence graft survival. The aim of this study was to propose a classification system for acute rejection based on factor analysis., Materials and Methods: Data were collected from kidney transplant recipients with acute rejection diagnosis based on standard histological variables, the presence of peritubular eosinophils, and immunolabeling for lysozyme and myeloperoxidase in kidney tissue. Factor analysis was employed for data reduction and generation of a new case classification, with orthogonal rotation as a strategy to simplify factors, and principal component analysis was used as an extraction method., Results: Seventy-nine kidney biopsies were obtained from 74 patients. The total population was divided into humoral rejection (39.2%), cellular rejection (34.1%), and mixed acute rejection (26.7%). No significant differences were found between the three groups in clinical and biochemical variables. We extracted 4 factors using factor analysis. The 1st factor was characterized by the presence of capillaritis, plasma cells infiltration, tubulitis, and inflammation. The 2nd factor included positivity for lysozyme and myeloperoxidase, while the 3rd factor included the presence of eosinophils and glomerulitis. The 4th component consisted of the presence of C4d and endarteritis. The cases belonging to the 3rd factor showed the greatest increase in serum creatinine. The cases belonging to the 4th factor exhibited greater urinary excretion of proteins., Conclusions: This proposal of classification of acute rejection could contribute to evaluate the prognosis of kidney transplant recipients.

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., (© 2017 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© 2016 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.)

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., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

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.

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., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Bronchoscopy remains a pivotal diagnostic and therapeutic intervention in pediatric patients undergoing lung transplantation (LTx). Whether performed as part of a surveillance protocol or if clinically indicated, fibre-optic bronchoscopy allows direct visualization of the transplanted allograft, and in particular, an assessment of the patency of the bronchial anastomosis (or tracheal anastomosis following heart-lung transplantation). Additionally, bronchoscopy facilitates differentiation of infective processes from rejection episodes through collection and subsequent assessment of bronchoalveolar lavage (BAL) and transbronchial biopsy (TBBx) samples. Indeed, the diagnostic criteria for the grading of acute cellular rejection is dependent upon the histopathological assessment of biopsy samples collected at the time of bronchoscopy. Typically, performed in an out-patient setting, bronchoscopy is generally a safe procedure, although complications related to hemorrhage and pneumothorax are occasionally seen. Airway complications, including stenosis, malacia, and dehiscence are diagnosed at bronchoscopy, and subsequent management including balloon dilatation, laser therapy and stent insertion can also be performed bronchoscopically. Finally, bronchoscopy has been and continues to be an important research tool allowing a better understanding of the immuno-biology of the lung allograft through the collection and analysis of collected BAL and TBBx samples. Whilst new investigational tools continue to evolve, the simple visualization and collection of samples within the lung allograft by bronchoscopy remains the gold standard in the evaluation of the lung allograft. This review describes the use and experience of bronchoscopy following lung transplantation in the pediatric setting., (© 2015 Wiley Periodicals, Inc.)

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., (© 2015 Steunstichting ESOT.)

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., (© 2015 Asian Pacific Society of Nephrology.)

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., (© 2015 Asian Pacific Society of Nephrology.)

Background: International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) coding for cytomegalovirus (CMV) has been used as a proxy for active CMV infection or disease occurring in the inpatient setting in retrospective studies of kidney transplant recipients using large amounts of administrative data. However, the accuracy of inpatient CMV coding has not been determined., Methods: We identified 393 kidney transplant recipients who were readmitted to Barnes-Jewish Hospital in St. Louis, Missouri from January 1, 2007 to December 31, 2011 to determine the accuracy of the ICD-9-CM diagnosis code for CMV (078.5) in identifying active CMV infection or disease (asymptomatic viremia, CMV syndrome, or tissue-invasive CMV disease) in the inpatient setting, using microbiological, histopathologic, or ophthalmologic evidence for CMV as the gold standard., Results: The sensitivity and positive predictive value of CMV coding in identifying active CMV infection or disease were 0.77 and 0.71, respectively. The specificity and negative predictive value were both 0.98. The sensitivity of CMV coding in identifying CMV syndrome or tissue-invasive CMV disease was 0.93., Conclusions: CMV coding had good accuracy in identifying active CMV infection or disease among readmitted kidney transplant recipients in our hospital. Further validation studies of CMV coding in other hospitals are needed to obtain more generalizable estimates of the accuracy of CMV coding., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Heart transplantation is currently the definitive gold standard surgical approach in the treatment of refractory heart failure. However, the shortage of donors limits the achievement of a greater number of heart transplants, in which the use of mechanical circulatory support devices is increasing. With well-established indications and contraindications, as well as diagnosis and treatment of rejection through defined protocols of immunosuppression, the outcomes of heart transplantation are very favorable. Among early complications that can impact survival are primary graft failure, right ventricular dysfunction, rejection, and infections, whereas late complications include cardiac allograft vasculopathy and neoplasms. Despite the difficulties for heart transplantation, in particular, the shortage of donors and high mortality while on the waiting list, in Brazil, there is a great potential for both increasing effective donors and using circulatory assist devices, which can positively impact the number and outcomes of heart transplants.

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., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Humoral immune responses during heart transplantation may result in antibody-mediated rejection (AMR), which is now taken into account on endomyocardial biopsy (EMB) specimens and ranked according to the pathologic AMR (pAMR) grades of the International Society for Heart and Lung Transplantation classification. This classification might benefit from new immunohistological markers and validation by others biomarkers, namely donor-specific antibodies (DSA)., Methods: From the 293 protocol EMBs performed in 113 patients in our institution during a 1-year period for this prospective study, 280 EMB specimens were available with both histology and immunohistochemistry. C4d and labeling of intravascular cells by cluster of differentiation (CD) 68 were performed on paraffin sections. Available sera (n = 150) concomitant of EMB specimens were tested for the presence of DSA. All of the pAMR+ EMB specimens, along with a set of randomized pAMR0 EMB specimens, were immunolabeled for mammalian target of rapamycin (mTOR) effectors, phosphorylated 70 S6-kinase (p70S6K) and phosphorylated S6 ribosomal protein (pS6RP)., Results: AMR was diagnosed in 37 EMB specimens (13.2%): 1 pAMR1(I+), 27 pAMR1(H+), and 9 pAMR2. The proportion of DSA-positive EMB varied according to the pAMR grade, with pAMR0, pAMR1(H+), and pAMR2 EMB presenting 17.6%, 77.3%, and 100% of DSA-positivity, respectively. Among the 30 pAMR+ specimens with available DSA testing and the 30 pAMR0 randomized specimens, mTOR pathway immunohistochemistry showed endothelial cell positivity for p70S6K in 17 pAMR+ EMB specimens (56.7%) and in 1 pAMR0 EMB specimen (3.3%). pS6RP was detected in 8 pAMR+ EMB specimens (26.7%) and in 1 pAMR0 EMB specimen (3.3%)., Conclusions: p70S6K and pS6RP immunohistochemistry afford new markers of AMR on EMB specimens because their expression is correlated with microcirculation inflammation and DSA. The correlation of DSA with pAMR grade suggests that this grading system is valid., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

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., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (Copyright © 2012 S. Karger AG, Basel.)

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.

Purpose of Review: In spite of impressive improvements in short-term outcomes for intestine transplant recipients, late allograft loss continues to plague the field. Attention has mostly been focused on T-cell-mediated cellular mechanisms of allograft rejection to explain these losses; however, as in other forms of solid-organ transplantation, especially kidney and heart, antibody-mediated mechanisms of acute and chronic allograft injury are increasingly being implicated. In this review, the mechanisms of B-cell- and humoral-mediated allograft injury will be briefly discussed along with the limited evidence that exist for invoking antibody-mediated rejection (AMR) as important in intestine transplantation., Recent Findings: The presence of donor-specific antibody has been reported to increase the incidence and severity of intestine allograft rejection and to worsen the overall prognosis for graft and patient. C4d staining in intestine biopsies is unreliable, and currently it is not possible to diagnose AMR with certainty in intestine transplantation. Treatment of presumed AMR in intestine recipients is purely anecdotal at this time., Summary: Further basic and clinical research needs to be conducted to more confidently diagnose and treat AMR in intestinal transplantation.

Purpose of Review: The review will discuss the current pathological criteria for the diagnosis and classification of antibody-mediated rejection (AMR) in the cardiac allograft., Recent Findings: Until recently, the diagnosis of AMR required clinical dysfunction, presence of donor specific antibodies and pathological alterations. The concept of asymptomatic AMR and its adverse long-term outcomes created, in part the need to reevaluate diagnostic criteria. The results of a recent consensus meeting sponsored by International Society For Heart And Lung Transplantation are discussed., Summary: The diagnosis of AMR rests on histopathological and immunophenotypic findings. These provide the basis for a new grading scheme.

Purpose of Review: This review discusses recent findings that are changing and expanding the spectrum of pathologic changes associated with antibodies directed against renal allografts., Recent Findings: This review focuses on four lesions: subclinical antibody-mediated rejection (AMR), C4d-negative AMR, intimal arteritis, and arterial intimal fibrosis. A number of studies have identified morphologic lesions of AMR in protocol biopsies of normally functioning renal allografts, particularly in sensitized recipients, that correlate with subsequent development of chronic changes in the graft, including transplant glomerulopathy. These same studies as well as molecular studies of indication biopsies of conventional renal allografts have noted evidence of microvascular injury, which, in the presence of donor-specific antibodies (DSAs) but the absence of C4d deposition in peritubular capillaries, is associated with development of transplant glomerulopathy and graft loss. Finally, recent studies suggest that intimal arteritis, previously felt to represent a lesion of cell-mediated rejection, and bland arterial intimal fibrosis, resembling arteriosclerosis, may in some cases be manifestations of DSA-induced graft injury., Summary: Incorporation of these newly recognized lesions of AMR into a working diagnostic schema with sufficient sensitivity and specificity to minimize undertreatment and overtreatment of patients is an important challenge currently faced by renal pathologists and transplant clinicians.

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., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

A classification schema for grading Polyomavirus nephropathy was proposed at the 2009 Banff allograft meeting. The schema included 3 stages of Polyomavirus nephropathy: early (stage A), florid (stage B), and late sclerosing (stage C). Grading categories for histologic viral load levels were also proposed. To examine the applicability and the interobserver agreement of the proposed Polyomavirus nephropathy grading schema, we evaluated 24 renal allograft biopsies with confirmed Polyomavirus nephropathy by histology and SV40. Four renal pathologists independently scored the Polyomavirus nephropathy stage (A, B, or C), without knowledge of the clinical history. Viral load was scored as a percent of tubules exhibiting viral replication, using either a 3-tier viral load score (1: ≤1%; 2: >1%-10%; 3: >10%) or a 4-tier score (1: ≤1%; 2: >1%-≤5%; 3: >5%-15%; 4: >15%). The κ score for the Polyomavirus nephropathy stage was 0.47 (95% confidence interval, 0.35-0.60; P < .001). There was a substantial agreement using both the 3-tier and the 4-tier scoring for the viral load (Kendall concordance coefficients, 0.72 and 0.76, respectively; P < .001 for both). A better complete agreement was found using the 3-tier viral load score. In this first attempt to evaluate the interobserver reproducibility of the proposed Polyomavirus nephropathy classifying schema, we demonstrated moderate κ agreement in assessing the Polyomavirus nephropathy stage and a substantial agreement in scoring the viral load level. The proposed grading schema can be applied in routine allograft biopsy practice for grading the Polyomavirus nephropathy stage and the viral load level., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to assess, at the European level and using digital technology, the inter-pathologist reproducibility of the ISHLT 2004 system and to compare it with the 1990 system We also assessed the reproducibility of the morphologic criteria for diagnosis of antibody-mediated rejection detailed in the 2004 grading system., Methods: The hematoxylin-eosin-stained sections of 20 sets of endomyocardial biopsies were pre-selected and graded by two pathologists (A.A. and M.B.) and digitized using a telepathology digital pathology system (Aperio ImageScope System; for details refer to http://aperio.com/). Their diagnoses were considered the index diagnoses, which covered all grades of acute cellular rejection (ACR), early ischemic lesions, Quilty lesions, late ischemic lesions and (in the 2005 system) antibody-mediated rejection (AMR). Eighteen pathologists from 16 heart transplant centers in 7 European countries participated in the study. Inter-observer reproducibility was assessed using Fleiss's kappa and Krippendorff's alpha statistics., Results: The combined kappa value of all grades diagnosed by all 18 pathologists was 0.31 for the 1990 grading system and 0.39 for the 2005 grading system, with alpha statistics at 0.57 and 0.55, respectively. Kappa values by grade for 1990/2005, respectively, were: 0 = 0.52/0.51; 1A/1R = 0.24/0.36; 1B = 0.15; 2 = 0.13; 3A/2R = 0.29/0.29; 3B/3R = 0.13/0.23; and 4 = 0.18. For the 2 cases of AMR, 6 of 18 pathologists correctly suspected AMR on the hematoxylin-eosin slides, whereas, in each of 17 of the 18 AMR-negative cases a small percentage of pathologists (range 5% to 33%) overinterpreted the findings as suggestive for AMR., Conclusions: Reproducibility studies of cardiac biopsies by pathologists in different centers at the international level were feasible using digitized slides rather than conventional histology glass slides. There was a small improvement in interobserver agreement between pathologists of different European centers when moving from the 1990 ISHLT classification to the "new" 2005 ISHLT classification. Morphologic suspicion of AMR in the 2004 system on hematoxylin-eosin-stained slides only was poor, highlighting the need for better standardization of morphologic criteria for AMR. Ongoing educational programs are needed to ensure standardization of diagnosis of both acute cellular and antibody-mediated rejection., (2011 International Society for Heart and Lung Transplantation. All rights reserved.)

Background: The acceptance and implementation of the International Society for Heart and Lung Transplantation's most recently adopted grading system (ISHLT-2004), which supplanted the ISHLT-1990 system for diagnosing cardiac allograft rejection, are unknown., Methods: We performed an online survey of pathologists at cardiac transplant centers in the United States and Canada to determine how cardiac transplant rejection is reported. The survey consisted of a series of questions related to biopsy volume, the rejection grading system used, and reasons why that grading system was used., Results: Survey responses were obtained from 96 of 122 centers in the United States and Canada. Eighty-seven percent of respondents reported adopting the ISHLT-2004 grading system, either exclusively or in combination with other grading systems. Overall, 45% of respondents use only the ISHLT-2004 grading system, 40% issue reports containing both the ISHLT-2004 and the ISHLT-1990 grading systems, 12% use only the ISHLT-1990 system, and 3% use either the ISHLT-2004 or the ISHLT-1990 system in combination with an older scoring system. The primary reasons for not using the ISHLT-2004 grading system exclusively were (1) the perceived preference of cardiologists and cardiac surgeons at that particular center (77%) and (2) a belief that the ISHLT-2004 grading system is not as informative as the ISHLT-1990 grading system (62%)., Conclusions: There is appreciable variability in the system(s) used for reporting rejection among North American cardiac transplant centers. Understanding the reasons behind this variability will be crucial for the optimization of future grading systems for cardiac allograft rejection., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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.

Biopsy of the transplanted kidney plays an important role in the care and treatment of patients after kidney transplantation. Today the renal biopsy is a standard procedure which is performed early after renal transplantation in the case of a primary non-functioning graft or a significant rise in serum creatinine. On the other hand, a kidney biopsy is performed if an acute or creeping rise in serum creatinine or acute onset of proteinuria or erythrocyturia is observed during follow-up. Furthermore, zero biopsies or intraoperative biopsies of the graft are important in order to obtain information about the initial quality of the graft. This is particularly important in view of the shortage of donor organs and the resulting necessity to accept increasingly marginal organs, such as for example in the ESP program. In addition, an increasing number of transplant centres perform protocol biopsies, i.e. biopsies that are not based on clinical indication, but are performed at a certain time point after transplantation to detect subclinical rejections as well as histological alterations pointing to chronic allograft damage. Additionally, there is much scientific interest in protocol biopsies.

Lung transplantation is the ultimate therapeutical approach for the treatment of both children and adults with terminal congenital or acquired lung disease. In contrast to survival rates during the first year following transplantation, the long-term survival for patients after lung transplantation has not significantly improved in the past. In addition to other complications, acute cellular rejection constitutes a major cause for diminished function of pulmonary grafts, and can, among other factors, be causative for chronic rejection (bronchiolitis obliterans syndrome, BOS). In 2006, the International Society for Heart and Lung Transplantation (ISHLT) provided a revised version of the grading system for acute and chronic rejection of pulmonary grafts.

Liver allograft pathology continues to play an important role in the diagnosis and management of complications in the course of liver transplantation. This article summarizes important patterns of liver damage and also considers new aspects of transplant pathology from the literature. In the context of transplant rejection, late cellular rejection has aroused new interest. Histopathological changes in late rejection differ from acute cellular rejection and there seem to be similarities to de novo autoimmune hepatitis and idiopathic post-transplant hepatitis. Central perivenulitis is a typical change in late cellular rejection and should be differentiated from central toxic necrosis. Other important areas of transplant pathology include vascular and biliary changes resulting from surgical complications or as sequelae of immunosuppressive therapy. Furthermore, disease recurrence plays an important role and combined patterns of disease poses a challenge for the pathologist.

Since the first heart transplantation in 1967, the procedure has become an established therapy in the treatment of terminal heart failure. Constant advances in the development of potent immunosuppressive drugs, as well as greater clinical experience and pathological diagnostics have improved patient survival dramatically. The first grading system for rejection was published in 1990 by the International Society for Heart and Lung Transplantation (ISHLT) and revised in 2004. The 2004 grading system comprises three grades of severity (1R, 2R, 3R), whereby the former grade 2 in the 1990 system has been incorporated in the new grade 1R. Recommendations are made for the histological diagnosis of acute antibody-mediated rejection using immunohistochemical staining against C4d and macrophages. To the present day, the pathological examination of endomyocardial biopsies remains the gold standard for post-transplant diagnostic procedures. Whether or not non-invasive diagnostic approaches (e.g. gene array profile analysis on leukocytes) can replace morphological investigations needs to be clarified in randomised, prospective clinical studies.

The diagnosis and treatment of anti-donor antibody-mediated rejection or humoral rejection (ABMR) is one of the main discussions at the moment in kidney transplantation. The search for histopathological markers that help us to diagnose ABMR has been more problematic, in contrast to the histological expression of cellular or tubulointerstitial rejection. Although the relationship between post-transplant anti-donor antibodies and the allograft's prognosis has been a topic of discussion for a long time, led in the main by P.Terasaki, it was not until the beginning of 1990s when P. Halloran studied the humoral mechanisms of rejection in greater depth. Feutch described the importance of C4d deposits as a marker that shows a humoral mechanism of allograft rejection in 1993. As a result of many studies carried out, the Banff consensus group established some diagnostic histopathological criteria of acute (ABMR) in 2003. These have been modified slightly in later meetings of the group. Furthermore, in 2005 this same working group looked at the physiopathological mechanisms causing chronic allograft failure in more detail and established the criteria defining chronic humoral rejection. In this review, we are trying to update any useful histopathological criteria for diagnosing acute and chronic ABMR.

A 43-year-old man had severe circumocular exanthema associated with chronic rejection 10 years after receiving a kidney transplant to treat end-stage renal failure. After the renal allograft was extracted, the exanthema diminished rapidly without any treatment. Donor-reactive immune cells seem to have cross-reacted with unknown pathogens on the skin and contributed to inflammation.

Introduction: The predictive potentialities of application of data mining algorithms to medical research are well known. In this article, we have applied to a transplant population classification trees to build predictive models of graft failure, evaluating the interactions between body mass index (BMI) and other risk factors. The decision trees have been widely used to represent classification rules in a population by a hierarchical sequential structure., Patients and Methods: We retrospectively studied 194 renal transplant patients with 5 years of follow-up (128 males, 66 females, mean age at time of transplant of 43.9 +/- 12.5 years). Exclusion criteria were: age < 18 years, multiorgan transplant, and retransplant. The BMI was calculated at the time of transplantation. In the classification algorithm, we considered the following parameters: age, sex, time on dialysis, donor type, donor age, HLA mismatches, delayed graft function (DGF), acute rejection episode (ARE), and chronic allograft nephropathy (CAN). The primary endpoint was graft loss within 5-years follow-up., Results: The classification algorithm produced a decision tree that allowed us to evaluate the interactions between ARE, DGF, CAN, and BMI on graft outcomes, producing a validation set with 88.2% sensitivity and 73.8% specificity. Our model was able to highlight that subjects at risk of graft loss experienced one or more events of ARE, developed DGF and CAN, or has a BMI > 24.8 kg/m(2) and CAN., Conclusions: The use of decision trees in clinical practice may be a suitable alternative to the traditional statistical methods, since it may allow one to analyze interactions between various risk factors beyond the previous knowledge., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Purpose of Review: To revisit the history and main defining characteristics of the Banff classification., Recent Findings: From small beginnings in 1991 the Banff classification of renal allograft pathology has grown to be the major standard setting force in renal transplant pathology and in international clinical trials of new antirejection agents. The meeting and classification has unique history, consensus generation mechanisms, funding, and tradition, and looks poised to continue for at least another 20 years. The Banff meetings also deal with setting standards for most other areas of solid organ transplantation and increasingly incorporate training courses and working groups so the activity never stops., Summary: The Banff meeting has gone from being just another meeting to becoming the embodiment of the global standard, The Banff Classification, by which we determine the presence of rejection and other important disease conditions in the transplanted organ. It is crucial for patient care and crucial for clinical trials of new therapies that it remains updated and modern, an important dynamic yardstick against which we measure clinical success.

Kidney transplantation has become increasingly common in major health centres, making renal allograft evaluation through biopsy a common procedure. Early allograft dysfunction occurs in 30-50% of all transplants, while chronic graft failure is almost uniform at a rate of 2-4% a year. Allograft biopsy remains the gold standard for the diagnosis of graft dysfunction. Rejection, albeit the most important, is only one of many causes of allograft dysfunction. The widely accepted Banff classification has set criteria for the diagnosis of acute and chronic rejection. The major differential diagnoses are acute ischaemic injury, calcineurin inhibitor toxicity (acute and chronic), infections, including pyelonephritis and polyomavirus nephropathy, chronic obstruction/reflux, hypertension, and recurrent and de novo disease. In this review, there is an outline of the Banff criteria and their implications, the various causes of graft dysfunction, and a discussion on morphological guidelines towards the various diagnoses.

According to the Banff classification of renal allograft pathology, the category borderline changes defines changes insufficient for a diagnosis of acute rejection. The relationship between borderline changes and acute renal allograft rejection still remains unclear. The appropriate clinical management for patients showing such changes is controversial. One possible interpretation of the high incidence of subacute tubulitis is that these changes in the absence of graft dysfunction are of no consequence and that treatment with intensified immunosuppression is unnecessary and perhaps harmful. Another view, consistent with the high incidence of CAN in late protocol biopsy studies, is that immunosuppression has become so powerful, that rejection may not even be manifested by a rising serum creatinine. Borderline changes should be used as part of an algorithm, but not as the only criterion, for therapeutic decision making. Based on the weak evidence of existing studies, in our patients with clinical borderline rejection, we have to weigh the individual immunological risk against the potential side effects of increased immunosuppression. Even in the knowledge that a majority of patients with borderline infiltrates will not progress into rejection, in many transplant centers, borderline rejection is treated with additional steroids or augmentation of maintenance immunosuppression.

Background: Despite morphologic differences of lymphocytes aggregation between nonrejection (0 on the International Society for Heart and Lung Transplantation [ISHLT] scale) and moderate focal cellular rejection (1a, ISHLT), genetic and clinical differences have not been shown in Cardiac Allograft Rejection Gene Observation (CARGO) studies. Therefore, we sought to compare the expression of selected antigens associated with apoptosis in heart transplant recipients in the context of grade 0 versus grade 1a cellular rejection episodes. We assessed the expression of annexin V, a nonspecific apoptosis marker, Bcl-2 as opposed to antiapoptotic activity of Bcl-xL and Bcl-xL/S., Materials and Methods: We retrospectively examined 17 heart transplant patients (2 women and 15 men) of overall mean age of 46.2 +/- 13.9 years and body mass index of 25.7 +/- 3.2. Ten biopsies showed rejection grade 0 and the other 10, grade 1a on the ISHLT scale, comprising groups A and B, respectively. Endomyocardial biopsy specimens were processed using routine immunohistochemical methods. The expression of apoptotic molecules was assessed according to the IHC method: 0, the lack of expression; 1, trace; 2, distinct; and 3, strong. A correlation was analyzed between particular molecular expressions., Results: We observed a significant increase in Bcl-2 expression associated with rejection. The expression of other antigens did not show a significant tendency. No correlation was noted among group A, whereas in group B those were significant strong and negative correlations with Bcl-2 and Bcl-xL/S., Conclusion: Bcl-2 expression corresponded to the morphologic progression of graft rejection as opposed to Bcl-xL/S activity.