B. Sis

Banff 07 Classification of Renal Allograft Pathology: Updates and Future Directions

The 9th Banff Conference on Allograft Pathology was held in La Coruna, Spain on June 23–29, 2007. A total of 235 pathologists, clinicians and scientists met to address unsolved issues in transplantation and adapt the Banff schema for renal allograft rejection in response to emerging data and technologies. The outcome of the consensus discussions on renal pathology is provided in this article. Major updates from the 2007 Banff Conference were: inclusion of peritubular capillaritis grading, C4d scoring, interpretation of C4d deposition without morphological evidence of active rejection, application of the Banff criteria to zero‐time and protocol biopsies and introduction of a new scoring for total interstitial inflammation (ti‐score). In addition, emerging research data led to the establishment of collaborative working groups addressing issues like isolated ‘v’ lesion and incorporation of omics‐technologies, paving the way for future combination of graft biopsy and molecular parameters within the Banff process.

Banff '05 Meeting Report: Differential Diagnosis of Chronic Allograft Injury and Elimination of Chronic Allograft Nephropathy (‘CAN’)

The 8th Banff Conference on Allograft Pathology was held in Edmonton, Canada, 15–21 July 2005. Major outcomes included the elimination of the non‐specific term ‘chronic allograft nephropathy’ (CAN) from the Banff classification for kidney allograft pathology, and the recognition of the entity of chronic antibody‐mediated rejection. Participation of B cells in allograft rejection and genomics markers of rejection were also major subjects addressed by the conference.

Banff 2013 Meeting Report: Inclusion of C4d‐Negative Antibody‐Mediated Rejection and Antibody‐Associated Arterial Lesions

The 12th Banff Conference on Allograft Pathology was held in Comandatuba, Brazil, from August 19–23, 2013, and was preceded by a 2‐day Latin American Symposium on Transplant Immunobiology and Immunopathology. The meeting was highlighted by the presentation of the findings of several working groups formed at the 2009 and 2011 Banff meetings to: (1) establish consensus criteria for diagnosing antibody‐mediated rejection (ABMR) in the presence and absence of detectable C4d deposition; (2) develop consensus definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score), associated with improved inter‐observer agreement and correlation with clinical, molecular and serological data; (3) determine whether isolated lesions of intimal arteritis (“isolated v”) represent acute rejection similar to intimal arteritis in the presence of tubulointerstitial inflammation; (4) compare different methodologies for evaluating interstitial fibrosis and for performing/evaluating implantation biopsies of renal allografts with regard to reproducibility and prediction of subsequent graft function; and (5) define clinically and prognostically significant morphologic criteria for subclassifying polyoma virus nephropathy. The key outcome of the 2013 conference is defining criteria for diagnosis of C4d‐negative ABMR and respective modification of the Banff classification. In addition, three new Banff Working Groups were initiated.

Banff 2013 meeting report

The 12th Banff Conference on Allograft Pathology was held in Comandatuba, Brazil, from August 19–23, 2013, and was preceded by a 2‐day Latin American Symposium on Transplant Immunobiology and Immunopathology. The meeting was highlighted by the presentation of the findings of several working groups formed at the 2009 and 2011 Banff meetings to: (1) establish consensus criteria for diagnosing antibody‐mediated rejection (ABMR) in the presence and absence of detectable C4d deposition; (2) develop consensus definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score), associated with improved inter‐observer agreement and correlation with clinical, molecular and serological data; (3) determine whether isolated lesions of intimal arteritis (“isolated v”) represent acute rejection similar to intimal arteritis in the presence of tubulointerstitial inflammation; (4) compare different methodologies for evaluating interstitial fibrosis and for performing/evaluating implantation biopsies of renal allografts with regard to reproducibility and prediction of subsequent graft function; and (5) define clinically and prognostically significant morphologic criteria for subclassifying polyoma virus nephropathy. The key outcome of the 2013 conference is defining criteria for diagnosis of C4d‐negative ABMR and respective modification of the Banff classification. In addition, three new Banff Working Groups were initiated.

Understanding the Causes of Kidney Transplant Failure: The Dominant Role of Antibody-Mediated Rejection and Nonadherence

We prospectively studied kidney transplants that progressed to failure after a biopsy for clinical indications, aiming to assign a cause to every failure. We followed 315 allograft recipients who underwent indication biopsies at 6 days to 32 years posttransplant. Sixty kidneys progressed to failure in the follow‐up period (median 31.4 months). Failure was rare after T‐cell–mediated rejection and acute kidney injury and common after antibody‐mediated rejection or glomerulonephritis. We developed rules for using biopsy diagnoses, HLA antibody and clinical data to explain each failure. Excluding four with missing information, 56 failures were attributed to four causes: rejection 36 (64%), glomerulonephritis 10 (18%), polyoma virus nephropathy 4 (7%) and intercurrent events 6 (11%). Every rejection loss had evidence of antibody‐mediated rejection by the time of failure. Among rejection losses, 17 of 36 (47%) had been independently identified as nonadherent by attending clinicians. Nonadherence was more frequent in patients who progressed to failure (32%) versus those who survived (3%). Pure T‐cell–mediated rejection, acute kidney injury, drug toxicity and unexplained progressive fibrosis were not causes of loss. This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody‐mediated or mixed rejection and also underscores the major role of nonadherence.

Banff ’09 Meeting Report: Antibody Mediated Graft Deterioration and Implementation of Banff Working Groups

The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v‐lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics‐technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future.

Antibody‐Mediated Microcirculation Injury Is the Major Cause of Late Kidney Transplant Failure

We studied the phenotype of late kidney graft failure in a prospective study of unselected kidney transplant biopsies taken for clinical indications. We analyzed histopathology, HLA antibodies and death‐censored graft survival in 234 consecutive biopsies from 173 patients, taken 6 days to 31 years posttransplant. Patients with late biopsies (>1 year) frequently displayed donor‐specific HLA antibody (particularly class II) and microcirculation changes, including glomerulitis, glomerulopathy, capillaritis, capillary multilayering and C4d staining. Grafts biopsied early rarely failed (1/68), whereas grafts biopsied late often progressed to failure (27/105) within 3 years. T‐cell‐mediated rejection and its lesions were not associated with an increased risk of failure after biopsy. In multivariable analysis, graft failure correlated with microcirculation inflammation and scarring, but C4d staining was not significant. When microcirculation changes and HLA antibody were used to define antibody‐mediated rejection, 17/27 (63%) of late kidney failures after biopsy were attributable to antibody‐mediated rejection, but many were C4d negative and missed by current diagnostic criteria. Glomerulonephritis accounted for 6/27 late losses, whereas T‐cell‐mediated rejection, drug toxicity and unexplained scarring were uncommon. The major cause of late kidney transplant failure is antibody‐mediated microcirculation injury, but detection of this phenotype requires new diagnostic criteria.

Endothelial Gene Expression in Kidney Transplants with Alloantibody Indicates Antibody‐Mediated Damage Despite Lack of C4d Staining

Anti‐HLA alloantibody is a risk factor for graft loss, but does not indicate which kidneys are experiencing antibody‐mediated rejection (ABMR). C4d staining in biopsies is specific for ABMR but insensitive. We hypothesized that altered expression of endothelial genes due to alloantibody acting on the microcirculation would be sensitive indicator of ABMR. We identified 119 endothelial‐associated transcripts (ENDATs) from literature, and studied their expression by microarrays in 173 renal allograft biopsies for cause. Mean ENDAT expression was increased in all rejection but was higher in ABMR than in T‐cell‐mediated rejection and correlated with histopathologic lesions of ABMR, and alloantibody. Many individual ENDATs were increased in ABMR and predicted graft loss. Kidneys with high ENDATs and antibody showed increased lesions of ABMR and worse prognosis in comparison to controls. Only 40% of kidneys with high ENDAT expression and chronic ABMR or graft loss were diagnosed by C4d positivity. High ENDAT expression with antibody predicts graft loss with higher sensitivity (77% vs. 31%) and slightly lower specificity (71% vs. 94%) than C4d. The results were validated in independent set of 82 kidneys. High renal endothelial transcript expression in patients with alloantibody is indicator of active antibody‐mediated allograft damage and poor graft outcome.

Banff 2011 Meeting Report: New Concepts in Antibody‐Mediated Rejection

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

De Novo Donor‐Specific Antibody at the Time of Kidney Transplant Biopsy Associates with Microvascular Pathology and Late Graft Failure

We studied whether de novo donor‐specific antibodies (DSA) in sera from patients undergoing kidney transplant biopsies associate with specific histologic lesions in the biopsy and prognosis. DSA were assessed in 145 patients at the time of biopsy between 7 days to 31 years posttransplant. DSA was detected in 54 patients (37%), of which 32 represented de novo DSA. De novo DSA was more frequent in patients having late biopsies (34%) versus early biopsies (4%), and was usually either against class II alone or class I and II but rarely against class I alone. Microcirculation inflammation (glomerulitis, capillaritis) and damage (glomuerulopathy, capillary basement membrane multilayering), and C4d staining were associated with de novo DSA. However, the degree of scarring, arterial fibrosis and tubulo‐interstitial inflammation did not correlate with the presence of de novo DSA. De novo DSA correlated with reduced graft survival after the biopsy. Thus, de novo DSA at the time of a late biopsy for clinical indication is primarily against class II, and associates with microcirculation changes in the biopsy and subsequent graft failure. We propose careful assessment of de novo DSA, particularly against class II, be performed in all late kidney transplant biopsies.