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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 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

This article will concentrate on two main areas of liver allograft pathology where there have been significant advances during the past few years. The first is rejection, which continues to be a common cause of graft dysfunction in the early postoperative period and a rare cause of graft failure. Histological assessment remains essential to confirm the diagnosis of rejection. A recently developed, internationally accepted schema (the Banff schema) for grading acute rejection and staging chronic rejection will be described. With increasing numbers of people surviving long-term following transplantation, the issue of disease recurrence is becoming increasingly important. The second part of the paper deals with the histological diagnosis of disease recurrence and the assessment of other changes seen in biopsies obtained more than 12 months following liver transplantation.

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.

This Practice Point commentary discusses Solez et al.'s most recent update to the Banff criteria for the classification of renal transplant pathology. The update focused on various aspects of antibody-mediated rejection, in particular the incorporation of a validated scoring system for peritubular capillary complement 4d staining and inflammation. A new scoring system for interstitial inflammation was also introduced, to be tested over the next 2 years. The report advocates the application of the Banff schema to zero-time and protocol biopsies, and several working groups have been set up to investigate the importance of new research data (including genomics and proteomics) for practical use. This commentary describes the new additions and proposals and places them in perspective.