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American Journal of Transplantation 2007; 7: 2221–2226 Blackwell Munksgaard C 2007 The Authors Journal compilation C 2007 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/j.1600-6143.2007.01924.x Personal Viewpoint SWOT Analysis of Banff: Strengths, Weaknesses, Opportunities and Threats of the International Banff Consensus Process and Classification System for Renal Allograft Pathology M. Mengel a, , B. Sis a,b and P. F. Halloran a a Department of Medicine, Division of Nephrology & Immunology, Alberta Transplant Applied Genomics Centre and b Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada Corresponding author: Michael Mengel, [email protected] The Banff process defined the diagnostic histologic lesions for renal allograft rejection and created a standardized classification system where none had existed. By correcting this deficit the process had uni- versal impact on clinical practice and clinical and ba- sic research. All trials of new drugs since the early 1990s benefited, because the Banff classification of lesions permitted the end point of biopsy-proven re- jection. The Banff process has strengths, weaknesses, opportunities and threats (SWOT). The strength is its self-organizing group structure to create consensus. Consensus does not mean correctness: defining con- sensus is essential if a widely held view is to be proved wrong. The weaknesses of the Banff process are the absence of an independent external standard to test the classification; and its almost exclusive reliance on histopathology, which has inherent limitations in intra- and interobserver reproducibility, particularly at the in- terface between borderline and rejection, is exactly where clinicians demand precision. The opportunity lies in the new technology such as transcriptomics, which can form an external standard and can be in- corporated into a new classification combining the el- egance of histopathology and the objectivity of tran- scriptomics. The threat is the degree to which the renal transplant community will participate in and support this process. Received 27 April 2007, revised and accepted for publication 21 June 2007 Banff Process, Lesions and Classification The Banff consensus process is a moderated self- organizing group to define and standardize organ allograft biopsy interpretation. The goal of the process is to pro- mote international uniformity in the reporting of allograft pathology, which is needed for research, clinical trials and patient management. The consensus process engages in an ongoing dialectic among clinicians, pathologists and ba- sic scientists, highlighted by a meeting every 2 years in which the classification guidelines are reviewed and re- vised in the light of emerging information. The Banff sys- tem provides criteria for classifying various forms of re- jection as well as other pathologies such as drug toxicity (1–3). Starting with a historical overview, this paper presents an informal ‘SWOT’ analysis (Strengths, Weaknesses, Oppor- tunities, and Threats) of the current Banff process and clas- sification. The aim is to improve clinicians’ understanding of the Banff classification when using pathology reports to make treatment decisions, conduct clinical trials and per- form research. The paper focuses on the criteria for T-cell mediated rejection (TCMR), which remains a major thera- peutic challenge, a risk factor for outcomes, and a focus of drug development. The Beginning Inspired by efforts in heart and lung transplantation (4) and the need to standardize renal biopsy interpretation, a small group met in August 1991 in Banff, Alberta. Led by Kim Solez, Lorraine Racusen and Philip Halloran, this meeting established the spirit of the Banff process: it was interdis- ciplinary (pathologists, nephrologists, surgeons, tissue typ- ing physicians) and international (Canada, USA, Denmark, Finland, Australia). The task was to construct a classifi- cation system for allograft pathology (5). The initial work- ing title was ‘Workshop on International Standardization of the Nomenclature and Criteria for the Histologic Diagnosis of Kidney Transplant Rejection’, a title soon simply called ‘Banff’. Since 1991, a Banff meeting has occurred every 2 years, initially in Banff and later in other places, satisfying its international spirit. While the classification is in continuous evolution, the fun- damental criteria for rejection (now recognized as TCMR after antibody-mediated rejection (ABMR) was defined) developed at the first meeting remain valid. To diagnose TCMR, the Banff classification defines the key lesions 2221

SWOT Analysis of Banff: Strengths, Weaknesses, Opportunities and Threats of the International Banff Consensus Process and Classification System for Renal Allograft Pathology

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Page 1: SWOT Analysis of Banff: Strengths, Weaknesses, Opportunities and Threats of the International Banff Consensus Process and Classification System for Renal Allograft Pathology

American Journal of Transplantation 2007; 7: 2221–2226Blackwell Munksgaard

C© 2007 The AuthorsJournal compilation C© 2007 The American Society of

Transplantation and the American Society of Transplant Surgeons

doi: 10.1111/j.1600-6143.2007.01924.xPersonal Viewpoint

SWOT Analysis of Banff: Strengths, Weaknesses,Opportunities and Threats of the International BanffConsensus Process and Classification System forRenal Allograft Pathology

M. Mengela,∗, B. Sisa,b and P. F. Hallorana

aDepartment of Medicine, Division of Nephrology &Immunology, Alberta Transplant Applied Genomics Centreand bDepartment of Laboratory Medicine and Pathology,University of Alberta, Edmonton, Canada∗Corresponding author: Michael Mengel,[email protected]

The Banff process defined the diagnostic histologiclesions for renal allograft rejection and created astandardized classification system where none hadexisted. By correcting this deficit the process had uni-versal impact on clinical practice and clinical and ba-sic research. All trials of new drugs since the early1990s benefited, because the Banff classification oflesions permitted the end point of biopsy-proven re-jection. The Banff process has strengths, weaknesses,opportunities and threats (SWOT). The strength is itsself-organizing group structure to create consensus.Consensus does not mean correctness: defining con-sensus is essential if a widely held view is to be provedwrong. The weaknesses of the Banff process are theabsence of an independent external standard to testthe classification; and its almost exclusive reliance onhistopathology, which has inherent limitations in intra-and interobserver reproducibility, particularly at the in-terface between borderline and rejection, is exactlywhere clinicians demand precision. The opportunitylies in the new technology such as transcriptomics,which can form an external standard and can be in-corporated into a new classification combining the el-egance of histopathology and the objectivity of tran-scriptomics. The threat is the degree to which the renaltransplant community will participate in and supportthis process.

Received 27 April 2007, revised and accepted forpublication 21 June 2007

Banff Process, Lesions and Classification

The Banff consensus process is a moderated self-organizing group to define and standardize organ allograftbiopsy interpretation. The goal of the process is to pro-mote international uniformity in the reporting of allograft

pathology, which is needed for research, clinical trials andpatient management. The consensus process engages inan ongoing dialectic among clinicians, pathologists and ba-sic scientists, highlighted by a meeting every 2 years inwhich the classification guidelines are reviewed and re-vised in the light of emerging information. The Banff sys-tem provides criteria for classifying various forms of re-jection as well as other pathologies such as drug toxicity(1–3).

Starting with a historical overview, this paper presents aninformal ‘SWOT’ analysis (Strengths, Weaknesses, Oppor-tunities, and Threats) of the current Banff process and clas-sification. The aim is to improve clinicians’ understandingof the Banff classification when using pathology reports tomake treatment decisions, conduct clinical trials and per-form research. The paper focuses on the criteria for T-cellmediated rejection (TCMR), which remains a major thera-peutic challenge, a risk factor for outcomes, and a focus ofdrug development.

The Beginning

Inspired by efforts in heart and lung transplantation (4) andthe need to standardize renal biopsy interpretation, a smallgroup met in August 1991 in Banff, Alberta. Led by KimSolez, Lorraine Racusen and Philip Halloran, this meetingestablished the spirit of the Banff process: it was interdis-ciplinary (pathologists, nephrologists, surgeons, tissue typ-ing physicians) and international (Canada, USA, Denmark,Finland, Australia). The task was to construct a classifi-cation system for allograft pathology (5). The initial work-ing title was ‘Workshop on International Standardization ofthe Nomenclature and Criteria for the Histologic Diagnosisof Kidney Transplant Rejection’, a title soon simply called‘Banff’. Since 1991, a Banff meeting has occurred every 2years, initially in Banff and later in other places, satisfyingits international spirit.

While the classification is in continuous evolution, the fun-damental criteria for rejection (now recognized as TCMRafter antibody-mediated rejection (ABMR) was defined)developed at the first meeting remain valid. To diagnoseTCMR, the Banff classification defines the key lesions

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in different compartments of kidney and outlines how tosemi-quantitatively record these lesions. The lesion scores(g-, i-, t-, v-score) are summarized into a final Banff TCMRgrade (1,5) and empirically defined thresholds of scores andgrades decide whether a case is designated TCMR. Thehistologic lesions of TCMR are (5): interstitial inflammation(i-score); tubulitis (t-score = invasion of tubular epitheliumby lymphocytes) and intimal arteritis (v-score = invasionof inflammatory cells beneath the endothelium), whereasincreasing quantities of each lesion reflects more severerejection.

However, as early as the late 1970s, it was known thatthe tubulitis and interstitial inflammation are not specificfor TCMR and can be observed in acute tubular necrosis(6), posttransplant lymphoproliferative disorder, in biopsiesfrom stably functioning allografts, and in infectious or drug-induced interstitial nephritis (5). Because of concerns withover-diagnosing and over-treating TCMR, the founders in-troduced minimum thresholds for the i- and t-score to di-agnose TCMR (1,5). In the absence of intimal arteritis, atleast 25% of the cortex with interstitial infiltrate and simul-taneously at least moderate tubulitis (t2 = 5–10 mononu-clear cells/tubular cross section) must be found to diagnoseTCMR. Lesser degrees of interstitial infiltrates plus tubulitisqualifies for the so-called borderline category (suspiciousfor rejection).

In contrast, intimal arteritis has long been regarded aspathogonomic for rejection (1,7), almost as a dogma. In-terestingly, a single lymphocyte under the endothelium ofan artery is enough to make the diagnosis of rejection in-dependent of interstitial inflammation, but severe tubulitiswithout significant interstitial infiltrates does not qualify asrejection. This seems biologically implausible and needsreassessment.

In 1991 when Banff criteria for TCMR were first described,immunosuppression was less advanced, and renal biop-sies displayed more frequent and severe TCMR than to-day. Hence, the Banff thresholds were more sensitive forTCMR because the frequency and severity of the diseasewas higher. With the advent of improved immunosuppres-sive agents, however, the frequency and severity of TCMRlessened, reducing the sensitivity and probably also thespecificity of the criteria, and increasing the frequency ofborderline changes, which are still of uncertain clinical rel-evance. Moreover, data at that time were mostly based onfindings in biopsies for cause and not protocol biopsies.Even today, functional deterioration of a graft is a crucialelement of the diagnosis of TCMR: in most centers diag-nosis of TCMR is based on evaluating the extent of lesionsin the clinical context (8). Notably, even the first Banff pa-per posed the question of whether ‘subclinical’ lesions orborderline changes in biopsies without dysfunction shouldbe regarded as rejection (5), a question that remains open(9).

Evolution

During the 1993 and 1995 meetings, the first studies ap-plying the new criteria validated the 1991 decisions. It wasagreed that no changes should be made to the criteria un-less supported by acceptable studies from two indepen-dent groups. Meanwhile, an independent, NIH-sponsoredgroup—the Cooperative Clinical Trials in Renal Transplan-tation (CCTT)—was working under the guidance of RobertColvin on diagnostic criteria (10). Hence, at the 1997 Banffmeeting, a consensus between both groups was workedout and jointly published in 1999 as the revised Banff’97classification (1). Since the same lesions (i, t, v) were usedto diagnose rejection in both Banff and CCTT (7), they wereretained and all centers use these same lesions for clas-sification. However, major differences between the twoclassifications are as follows: the CCTT differentiates threetypes of rejection (tubulo-interstitial, vascular and humoral)and does not grade rejection. In addition, with CCTT mostcases of the Banff borderline category would be classifiedas CCTT type I rejection, and thus CCTT has a lower thresh-old for rejection than the Banff classification.

A consensus between Banff and CCTT was elaboratedwith aspects of the CCTT system being incorporated (1).The Banff borderline category survived the merger. Therevised Banff’97 classification also includes detailed tech-nical guidelines and minimal adequacy of a specimen to besufficient for reliable review to minimize the influence ofsampling errors. Because tubulitis in atrophic tubules is afrequent finding, and regarded as nonspecific, the Banff’97paper introduced the rule that tubulitis can only be scoredin nonatrophic or mildly atrophic tubules (1). Also, inflam-mation in the immediate subcapsular cortex, fibrotic areasand the adventitia of large vessels was considered to benonspecific and was therefore excluded from the i-score(1).

Features of ABMR were added to the schema in 2001and 2005, introducing immunohistochemistry (i.e. C4d) tothe previous light microscopic classification (3,11). Thus,what had previously been called ‘rejection’ was now des-ignated TCMR. More recently, the concept of ‘intersti-tial fibrosis and tubular atrophy not otherwise specified’(IFTANOS) was introduced to permit discrimination of non-specific scarring and atrophy from specific entities of allo-graft damage (3), like transplant glomerulopathy (TG) andother consequences of slow ABMR. This eliminated theimprecise term chronic allograft nephropathy (CAN), whichhad unfortunately lumped IFTANOS and all other specificentities of chronic allograft damage (e.g. TG) together.

Application of the classification to protocol biopsies of‘stable’ kidneys is an ongoing and controversial process(12,13). The main finding in protocol biopsies is that thelesions of TCMR can be observed in allografts with no sig-nificant change in function, and thus do not necessarily

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SWOT Analysis of Banff

have a fixed relationship to the immunologic mechanismsof TCMR. How the criteria designed for grafts with dys-function should be applied to protocol biopsies remains tobe clarified, and is a topic at the 2007 Banff meeting. Thisillustrates the Banff process, addressing unsolved issuesto create new consensus in a classical dialectic of thesis,antithesis and synthesis (Figure 1).

Strengths

The Banff process is one of the key engines of progress inrenal transplantation, applied to basic and clinical research,virtually all drug trials, and in routine clinical care. The clin-ical relevance of the Banff classification has been shownby independent groups (14–16). Banff lesions respond totreatment, and pure tubulointerstitial TCMR responds bet-ter to treatment than cases with intimal arteritis, whichhas a worse prognosis and often requires more aggres-sive treatment. Severe tubulitis (t3) has a worse prognosisthan mild tubulitis (t1) (14). In addition, the internationallystandardized grading of the lesions has provided objectiv-ity for publication, data sharing and statistical analysis—all of which are essential prerequisites for clinical trials.Most Banff meeting participants report that they alter clin-ical practice as a direct consequence of the meeting (2).

The Banff lesions have been confirmed in animal mod-els of rejection, allowing analysis of basic mechanismsof TCMR (17). Thus, in a mouse kidney transplant model,the lesions of TCMR have been shown to be T-cell de-pendent but independent of granzymes and perforin, aswell as being independent of B cells and antibody (17,18).It seems that the tubulitis reflects epithelial deterioration

Figure 1: The Banff process. A self-organizing consensus communication in renal transplantation.

secondary to a delayed-type hypersensitivity reaction in theinterstitium. Changes in the epithelium such as loss of cad-herins develop before apparent direct contact with effec-tor T cells (19). The changes in the epithelium are part of amassive alteration in gene expression, including reexpres-sion of embryonic genes and loss of many solute carriersand metabolism genes (20), that is a stereotyped injuryresponse evoked by the interstitial inflammation.

An essential strength of the Banff process is its consen-sus approach (Figure 1). The willingness and capacity of theprocess to continuously adapt in response to new researchensures that it will remain relevant, incorporating new sci-ences as they emerge. Nobody owns Banff: it has been amoderated self-organizing system from the beginning. It isnot the classification of ‘Dr. Banff’, nor of one center, but ofthe community. The moderator, Kim Solez, supervises theprocess but does not direct or drive the outcome. Refine-ment of the classification has always been an open source,like today’s ‘Linux’ or ‘Wikipedia’. Banff reflects the state ofthe art, which should be in motion forever, and no method(e.g. histology) is more important than other emerging ap-proaches (e.g. transcriptomics) if they are superior. If well-conducted studies indicate that the current criteria shouldbe changed, or that the new technology can add to es-tablished procedures, a process follows (Figure 1) (21): (1)the respective groups are invited to the next Banff meet-ing to present their results (only the speakers are invited,everybody else can present his data as poster presenta-tions and participate at the meeting and discussion), (2)the results are discussed by all participants moderated bya session chair, and (3) outcome of this consensus discus-sion might be acceptance of changes by the group, requestfor further data and adjourn until the next meeting, or a

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Table 1: Banff process and classification of rejection issues inprogress, still warranting further discussion

1. Reproducibility2. Independent validation of thresholds and diagnostic features

of rejection3. Robust quantification and measurement of rejection/

inflammation4. Borderline category5. Subclinical rejection/application to protocol biopsies6. Integration of features with sole prognostic impact

decision not to change(usually revealed by voting). Follow-ing every meeting, a report describing its outcome shouldbe published (2,3,21). This time-consuming procedure isnot only needed to describe the rationale underlying the re-cent changes on the schema but also useful as being a con-tinued platform to discuss controversial issues.

Weaknesses of Banff Classification

The Banff classification of rejection possesses two mainweaknesses (Table 1): poor reproducibility, and lack of in-dependent validation (discussed in the next section). Thecontinuing problem of borderline changes and the lack ofmechanistic understanding are also noteworthy.

Reproducibility is a major issue, as it is for all histopatho-logical classification systems (22). Two types of repro-ducibility have to be considered: intra- and interobserver re-producibility. Both are assessed mathematically by Kappastatistics, which measure the percent agreement be-tween two votes (15). Studies on Banff scoring (15,22–25)(Table 2) showed reproducibility as ‘moderate’ (Kappa:0.41–0.60) and more often ‘fair’ (Kappa: 0.21–0.40). Dis-criminating between rejection/no rejection without scor-ing was better. Furness meticulously analyzed numer-ous parameters potentially influencing reproducibility ofBanff classification (15,23). He circulated slides betweenEuropean transplant pathologists and found alarmingly lowKappa values. Grading tubulitis was essentially not repro-ducible (Kappa value 0.17) (15). Earlier studies based onthe 1991 Banff classification reporting better Kappa val-ues were done by pathologists who were trained together

Table 2: Reproducibility of Banff process and classification scores measured by Kappa values

Solez Marcussen Furness Gough Furness VeroneseReference 1995 (24) 1995 (22) 2001 (15) 2002 (25) 2003 (23) 2005 (26)

Kappa value fori-score 0.33 0.33 0.34 0.42 0.35 NAt-score 0.35 0.35 0.17 0.48 0.21 NAv-score 0.47 0.47 0.35 0.50 0.38 NARejection (yes/no) 0.62 0.56 NA 0.77 NA 0.46–0.72∗

Kappa values: <0.20 = poor, 0.21–0.40 = fair, 0.41–0.60 = moderate, 0.61–0.80 = good, >0.80 = excellent.NA = not available.∗Three observers were compared to one another.

and were involved in developing the classification (22,24).Pathologists participating in the Furness trial were nevertrained together and were truly testing the operation of theclassification in practice. Lesions where the definition wasbased on ‘percent area involved’ (i-score) had worse re-producibility. When different pathologists review the sameslide, much variation resulted from examining different ar-eas of the slide and different interpretation of the rules.

However, in the Furness trials, the pathologists showedconsistency in individual scores and diagnosis (excellent in-traobserver reproducibility) (15). If all participants are awareof the Banff ‘wobble’, harm to patients should be minimal.In contrast, in the setting of multicentric trials, the Banffvariability is a problem, and may account for different cen-ters reporting different rejection rates despite compara-ble immunosuppression (15). Central pathological reevalu-ation of biopsies should be obligatory in multicenter drugtrials, but this does not solve the problem: it is still just oneopinion.

Borderline lesions remain an unsolved problem. Somestudies conclude that the most borderline cases are in-deed TCMR (27), but discrepant percentages (30–80%) ofborderline cases have been reported to progress to TCMRwithout treatment (28,29). Such discrepancy may be ex-plained by the ‘single cell cut off concept’ of a histologicclassification: having sufficient interstitial inflammation de-tecting four or five lymphocytes in a tubule, discriminatesbetween borderline and TCMR. Acknowledging such con-cerns, the classification insists that the therapeutic deci-sions in borderline cases must be made in the clinical con-text (1,5).

Opportunities: The ‘Omics’ Approaches

The emerging ‘omic’ sciences—transcriptomics andlater metabolomics and ultimately proteomics—offeropportunities for objective, quantitative, biology-basedmeasurements that will improve on histopathology-baseddiagnoses. After new diagnostic criteria are accepted inprinciple, the choice of the platform will follow, and thetechnology must be validated in independent laboratories.Incorporation of omics technologies into diagnostics will

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SWOT Analysis of Banff

require standardization of many issues, that is sample stor-age, RNA purification, RNA quality, normalization methods,etc.

Transcriptome measurements can be highly reproducible,because the assays can be internally controlled and normal-ized. We have data in our own laboratory showing high in-tralaboratory reproducibility (correlation coefficient of 0.98)of microarrays run on different days. Some variation be-tween multiple cores is inevitable, but our experience todate is that this is much less than morphology variations.Such efforts will benefit from progress in the use of tran-scriptomics and microarray technology for other diagnosticapplications such as cancer.

At that point, the results of the new technology as an exter-nal validation of the existing criteria, especially in problemareas, will be exciting and transforming, infusing new dy-namism into clinical research and inviting basic researchersto examine mechanisms. The long process of understand-ing and interpreting these new insights will then follow,integrating the new methods into the existing histopathol-ogy criteria to create a true gold standard that is robustlymeasured and biologically rational.

Ultimately transcript measurements will be incorporatedinto the existing histology-based Banff classification. Thus,TCMR would be classified by a combination of morphol-ogy and objective measurement by transcripts represent-ing infiltrating cells and parenchymal changes (30,31). Suchnumbers should be standardized so that they mean thesame to clinicians in Prague or Pittsburg.

At the 2005 Banff meeting, the development of a ‘ge-nomics’ supported Banff classification was already an im-portant objective (3), and the participants concluded thatgene expression analysis would be complementary ratherthan being competitive with conventional histopathology.This suggests greater interdisciplinary participation: clini-cians, pathologists, ‘omics-specialists,’ bioinformaticians,with the development of mathematically based algorithmsintegrating clinical, histological and molecular features.However, a principle of the Banff process is that the classi-fication should be applicable worldwide, including devel-oping countries. Therefore, optimization of conventionalhistology will continue, guided by insights arising frommolecular studies.

Threats: Avoid Splitting and Stay Relevant

The Banff process can adapt indefinitely to evolving chal-lenges and technologies, incorporating new findings withthe best of the old, but only if the participants support theprinciple of bringing all opinions together in one process.By dialogue, merger and consensus, the Banff process haslargely avoided emergence of competitive and contradic-

tory systems, as it occurred with the European and North-American lymphoma classifications (32).

Priorities change, and the process must address thesechanges. The incidence and severity of TCMR has de-creased with the advances in immunosuppression (mostachieved by trials using the Banff classification). But long-term prognosis has improved less, underscoring the needto define mechanisms and pathogenesis of late graft de-terioration and develop criteria that can guide clinical tri-als. For example, new therapeutic strategies for patientswith mild or ‘nonspecific’ inflammation below the currentBanff thresholds might be developed (33). The continu-ing definition of ABMR phenotypes also opens prospectsfor intervention studies. The basis for any new therapeuticstrategies has to be reliably refined classification criteria.

As in the past, future refinement will be driven by the dy-namic, self-organized Banff process (Figure 1). This mayrequire that more biologists and bioinformaticians and‘omics’ specialists join the Banff process alongside clini-cians and pathologists. In 1991, the ultimate hope of theinitiators of the Banff process was that this classificationwould lead to major improvements in patient care and man-agement (5)—it has achieved this goal and continues to doso!

Acknowledgment

We are indebted to Kim Solez for critical reading and comments.

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