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Borderline T cell-mediated rejection is a diagnostic category of the Banff schema that uses a lower diagnostic threshold. Subclinical borderline T cell-mediated rejection detected by surveillance sampling is not entirely benign. Studies demonstrate increased rates of late rejection, progressive nephron loss, functional impairment, donor-specific antibody formation, and allograft failure. It can be conceptualized as a failure to control the cellular alloimmune response. Mixed results are reported for its treatment, and randomized controlled trials are needed.

Copyright © 2019 Aguado-Domínguez, Cabrera-Pérez, Suarez-Benjumea, AbadMolina, Núñez-Roldán and Aguilera., Currently, the diagnosis of kidney allograft rejection relies on individual histological assessments made by expert pathologists according to the Banff classification. In this study, we applied new Computer-Assisted System Technology (newCAST™) by Visiopharm® with the aim of identifying and quantifying the immune cells in inflammatory infiltrates. We searched for distinctive cellular profiles that could be assigned to each rejection category of the Banff schema: antibody-mediated rejection (active and chronic active), borderline, T cell-mediated rejection (TCMR), and mixed rejection. This study was performed with 49 biopsy samples, 42 from patients with rejection and 7 from patients with clinical signs of dysfunction but an absence of histological findings of rejection. Plasma cells, B and T lymphocytes, natural killer cells, and macrophages, with a special focus on the M1 and M2 subsets, were studied. A major difference among the Banff rejection groups was in the total amount of cells/mm2 tissue. Principal component analysis identified some distinctive associations. The borderline category grouped with CD4+ lymphocytes and M1 macrophages, and active antibody-mediated rejection (aAMR) clustered with natural killer cells. Despite these findings, the search for characteristic profiles linked to the rejection types proved to be a very difficult task since the cellular composition varied significantly among individuals within the same diagnostic category. The results of this study will be analyzed from the perspective of reconciling the classic way of diagnosing rejection and the immune situation “in situ” at the time of diagnosis., This study was supported by the Spanish Ministry of Economy, Instituto de Salud Carlos III, Grants 17/1403 and the Andalusian government, Consejería de Economía, Innovación, Ciencia y Empleo, Proyecto de Excelencia CTS-7846, and was co-funded by FEDER from the Regional Development European Funds (European Union).

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

The aim of this study was to determine how the Banff antibody-mediated rejection (ABMR) classification for kidney transplantation is interpreted in practice and impacts therapy. The Banff Antibody-Mediated Injury Workgroup electronically surveyed clinicians and pathologists worldwide regarding diagnosis and treatment for six case-based scenarios. The participants’ (95 clinicians and 72 renal pathologists) assigned diagnoses were compared to the Banff intended diagnoses (reference standard). The assigned diagnoses and reference standard differed by 26.1% (SD 28.1%) for pathologists and 34.5%(SD 23.3%) for clinicians. The greatest discordance between the reference standard and clinicians’ diagnosis was when histologic features of ABMR were present but donor-specific antibody was undetected [49.4%(43/87)]. For pathologists, the greatest discordance was in the case of acute/active ABMR C4d staining negative in a positive crossmatch transplant recipient[33.8%(23/68)]. Treatment approaches were heterogeneous, but linked to the assigned diagnosis. When acute/active ABMR was diagnosed by the clinician, treatment was recommended 95.3%(SD 18.4%) of the time versus only 77.7%(SD 39.2%) of the time when chronic active ABMR was diagnosed (P

To review changes in the Banff schema for antibody-mediated renal allograft rejection over the past decade, including key revisions agreed upon during and immediately subsequent to the 2017 Banff Conference on Allograft Pathology.The original Banff schema for diagnosis of acute and chronic active antibody-mediated rejection (ABMR) in renal allografts was formulated at the 2001 and 2007 Banff Conferences, and required histologic (primarily microvascular inflammation and transplant glomerulopathy), immunohistologic (C4d in peritubular capillaries), and serologic [circulating donor-specific antibodies (DSA)] evidence for a definitive diagnosis of ABMR. This schema was updated at the 2013 Banff Conference, recognizing C4d-negative ABMR, intimal arteritis as a potential manifestation of ABMR, and revising definitions and thresholds for glomerulitis and transplant glomerulopathy to improve interobserver agreement and correlation with clinical, molecular, and serologic data. Compared with the 2007 criteria, Banff 2013 improved the sensitivity of the classification for diagnosing ABMR and the correlation of ABMR diagnosis with graft outcomes. At the 2017 Banff Conference, new modifications to the classification were discussed and have subsequently been agreed upon, accepting C4d and thoroughly validated molecular classifiers as surrogate markers for DSA.From a consensus reached at the 2017 Banff Conference, updated criteria for diagnosis of active and chronic active ABMR have been developed that recognize C4d and molecular classifiers as surrogate markers for DSA. In addition, specific recommendations for the use of molecular diagnostics in the diagnosis of ABMR were developed.

The Banff schema is the most widely used standard grading system for liver allograft rejection. To investigate the relationship between the Banff rejection activity index (RAI) and the presence of lymphocyte subpopulations in allograft liver tissue, assuming these cells to probably play an important role in the mechanism of acute cellular rejection (ACR), we performed immunohistological examinations using liver tissues with various ACR severities after living related liver transplantation (LRLT). In total, 37 needle liver biopsy specimens with ACR in LRLT were examined using antibodies to CD4, CD8, and CD20. Formalin-fixed and paraffin-embedded liver tissues were used to maintain morphology. Immunohistological findings and RAI score according to the Banff schema were compared. In the results, mainly CD8-positive (CD8+), rather than CD4-positive (CD4+), cells were detected in the portal tract and were also found in bile duct epithelium and subendothelial areas of portal veins. The number of CD8+ cells increased according to ACR grade, whereas CD4+ cells tended to decrease. There were significant correlations between the presence of CD8+ cells (p = 0.0006) and CD4+ cells (p = 0.0003) and ACR severity. On the other hand, CD20-positive cells did not correlate with ACR severity (p = 0.472). The results indicate that CD8+ cells play important roles in ACR severity of LRLT, suggesting the number of CD8+ cells in liver tissue to be useful as a supplementary tool, in addition to RAI of the Banff schema, for objective evaluation of ACR severity.

Acute transplant glomerulitis, characterized by accumula-tionofinflammatorycellsinglomerularcapillaries,haslongbeen associated with graft rejection. Glomerulitis can bea feature of T cell-mediated acute rejection, but it is thetubulointerstital and vascular inflammation that makes thatdiagnosis and determines the Banff grade. An isolatedglomerulitis lesion with no associated interstitial inflam-mation, tubulitis or intimal arteritis has not previously beenrecognized as a feature of T cell-mediated rejection, andthus glomerulitis has never been integrated into the Banffcriteria for that diagnosis. In humoral rejection, neutrophilpolymorphs may accumulate in the glomerular capillariesin addition to mononuclear cells, and in 2003 glomerulitiswas included as a morphological component of the tis-sue injury in acute antibody-mediated rejection (1). Sincethen, glomerulitis along with peritubular capillaritis havebeen increasingly recognized components of the micro-circulatory injury associated with chronic active antibody-mediatedinjury(2),andinsomecasesofhumoralrejectionthese lesions are the only morphological evidence of graftinflammation.The grading of peritubular capillaritis (ptc score) hasrecently been incorporated into the Banff schema, fol-lowing appropriate reproducibility studies (3). Grading ofglomerulitis (g score) has been a component of Banfflesion scoring since the first version of the Banff classi-fication for renal allograft pathology in 1993 (4), and thecriteriaforscoringhavenotsignificantlyalteredsincethen.The score is determined from the percentage of glomeruliaffected by glomerulitis and whether the process issegmental or global. At the last Banff conference in 2009,glomerulitis scoring was identified as an area warrantingup-to-date studies, particularly to increase reproducibilityof the diagnosis.In this issue (5), Batal and colleagues from University ofPittsburgh Medical Center report one of the largest clini-copathological studies on glomerulitis (111 index biopsiesevaluated), including correlations with peritubular capillary(PTC) C4d deposition and donor-specific antibody (DSA)status. They assessed three separate histological grad-ing systems for glomerulitis, including percentage of af-fected glomeruli, most severely inflamed glomerulus andpresence of endocapillary occlusion by inflammatory cells.All three methods correlated with each other and showedclinicopathological correlations, but percentage of involvedglomeruli showed the most, including correlations withsubsequent graft failure, proteinuria, peritubular capillari-tis, PTC C4d+ and development of DSA.Thiscomprehensivestudyconfirmstheutilityofglomeruli-tis scoring, and the validity of the existing Banff approachto this lesion. The scoring method requires that everyglomerulus in a biopsy be evaluated; for reproducibilitythere needs to be clear guidelines for the cut-off betweenwhatiswithinnormallimitsandamilddegreeofglomeruli-tis. Batal et al. applied a longstanding WHO definitionfrom native kidney glomerular disease of ≥5 leukocytesper glomerulus in standard PAS-stained sections. Whilesevere cases of glomerulitis do often show unequivocalglomerularendothelialswelling,thisfeatureislikelytohavepoor inter-observer reproducibility, and is often not presentwithmilderglomerularinflammation.Theauthorsprovideastrong argument for not requiring endothelial enlargementto diagnose glomerulitis. The percentage cut-offs for Banffgrade of glomerulitis have not been critically assessedin this study, and a more uniform spread of glomerulitisscores would be desirable. Also, reproducibility of scoringhasnotbeenaddressed,butconsiderationshouldcertainlybe given to incorporating these refined definitions into fu-ture Banff criteria for glomerulitis.Some of the most clinically relevant findings of this studywere the association of glomerulitis with other markers ofhumoralrejection,thepersistenceofsevereglomerulitisinfollow-up biopsies following antirejection therapy and fur-ther confirmation of previous studies showing progressionfrom acute endocapillary glomerulitis to chronic transplantglomerulopathy.Thisstudydidnotfindanyassociationwithgrade of T cell-mediated rejection, and the significanceof glomerulitis in the absence of detectable DSA remains

Accurate diagnosis and grading of rejection and other pathological processes are of paramount importance to guide therapeutic interventions in patients with pancreas allograft dysfunction. A multi-disciplinary panel of pathologists, surgeons and nephrologists was convened for the purpose of developing a consensus document delineating the histopathological features for diagnosis and grading of rejection in pancreas transplant biopsies. Based on the available published data and the collective experience, criteria for the diagnosis of acute cell-mediated allograft rejection (ACMR) were established. Three severity grades (I/mild, II/moderate and III/severe) were defined based on lesions known to be more or less responsive to treatment and associated with better- or worse-graft outcomes, respectively. The features of chronic rejection/graft sclerosis were reassessed, and three histological stages were established. Tentative criteria for the diagnosis of antibody-mediated rejection were also characterized, in anticipation of future studies that ought to provide more information on this process. Criteria for needle core biopsy adequacy and guidelines for pathology reporting were also defined. The availability of a simple, reproducible, clinically relevant and internationally accepted schema for grading rejection should improve the level of diagnostic accuracy and facilitate communication between all parties involved in the care of pancreas transplant recipients.

The relationship between acute renal allograft rejection and histopathologic biopsy alterations recognized by the Banff Schema as “borderline changes” is not clear. Some evidence supports the contention that about one third of patients with borderline infiltrates and clinical evidence of graft dysfunction do indeed have acute rejection, which, if left untreated, progresses to a histologically more advanced stage of rejection. Several investigators recognize that not all patients with mild tubulitis respond clinically to antirejection therapy; a significant number of these biopsy specimens display additional histological alterations. The most common concurrent lesions are chronic allograft nephropathy, arteriolar lesions consistent with calcineurin inhibitor toxicity, acute tubular necrosis, and obstructive nephropathy. Management of patients with borderline changes must tightly correlate the pathologic features and the clinical information.

The pathological findings on renal allograft biopsy specimens are often complex. By carefully defining the morphological features of acute allograft rejection, the Banff schema provides an important tool for the differential diagnosis of acute allograft dysfunction. This article reviews the criteria for diagnosis of rejection, and its differentiation from other inflammatory infiltrates in renal allograft biopsy specimens.

Chronic allograft nephropathy (CAN) is the major cause of graft loss, and early detection is desirable to avoid irreversible graft damage. We have evaluated a new technique of color Doppler quantification using Cineloop (Philips Medical Systems, Bothell, WA) imaging for noninvasive diagnosis of CAN.Provisional normal ranges were defined by pilot study (n=13) and prospectively tested in stable recipients in whom CAN was independently quantified by contemporaneous histology (n=67), using the Banff schema.The maximal fractional area (MFA, systolic color pixels/total area) was 28.7+/-9.7% in normal subjects and reduced to 18.8+/-8.0% in grade 1 and 12.5+/-6.4% in grade 2 CAN (both P0.001). The minimum color fractional area was reduced from 10.3+/-5.3% in normal subjects to 3.1+/-2.6% in grade 2 CAN (P0.001), but was less useful. Distance from peripheral color pixels to capsule increased in CAN grade 2 versus 0 (6.0+/-1.6 vs. 3.9+/-1.0 mm, respectively; P0.001). Calcineurin inhibitor nephrotoxicity reduced MFA (18.0+/-9.3 vs. 26.9+/-10.7%; P0.001) and other dynamic measurements. Parenchymal damage exerted minimal effect on resistance index, mean variance, and peak Doppler velocity. MFA (cutoff17.3%) can diagnose CAN (sensitivity 69%, specificity 88%, positive predictive value 86%) and severe CAN (sensitivity 87%, specificity 71%, negative predictive value 95%). Distance to capsule5 mm was less sensitive (49%) but more specific (91% alone, and 97% combined with MFA).In conclusion, quantitative Doppler ultrasound can reliably detect CAN and, although imperfect at correctly grading, allows recognition of significant tubulointerstitial damage for initiation of a confirmatory needle core biopsy.

A panel of recognized experts in liver transplantation pathology, hepatology, and surgery was convened for the purpose of developing a consensus document for the grading of acute liver allograft rejection that is scientifically correct, simple, and reproducible and clinically useful. Over a period of 6 months pertinent issues were discussed via electronic communication media and a consensus conference was held in Banff, Canada in the summer of 1995. Based on previously published data and the combined experience of the group, the panel agreed on a common nomenclature and a set of histopathological criteria for the grading of acute liver allograft rejection, and a preferred method of reporting. Adoption of this internationally accepted, common grading system by scientific journals will minimize the problems associated with the use of multiple different local systems. Modifications of this working document to incorporate chronic rejection are expected in the future.