Since its first consensus meeting in 1991,1 the Banff Classification of Allograft Pathology has provided a framework for the reporting of renal allograft biopsies. It was the first classification system of its kind and answered the need for an international consensus on renal transplant biopsy reporting, providing guidance for clinical diagnosis and enabling meaningful comparison between research studies and clinical trials investigating the diagnosis, treatment and outcome in kidney transplantation. The Banff Classification has since been further strengthened by evidence-informed biannual updates elaborated during open international expert meetings.2 As a result, the Banff Classification of Allograft Pathology has become the predominant classification system used worldwide.3
A total of 14 meetings reported in 10 articles reflect the developments of the Banff Classification from the first consensus meeting in 1991 to the recently published consensus after the 2017 meeting in Barcelona, Spain.1,4-12 Each of these iterations provides a short summary of the meeting and contributes to the classification in a cumulative fashion. The dispersal of both relevant and outdated content over 10 articles could make access to the Banff Classification difficult for beginners and experts and has created ambiguities in the past.3 Yet, accessibility and clarity are of utmost importance not only for clinical practice and research but also for the Banff Classification itself to evolve through accountability, critique, and change. To improve on these aspects, the Rules and Dissemination Banff Working Group was initiated at the last Banff meeting held in Barcelona, Spain in March 2017. With a scope beyond the helpful syllabus provided by the Banff group in the online supplement of the 2015 update11 and incorporating the latest changes introduced in the 2017 update,12 the aim of this Working Group is to collate all current content of the Banff Classification and improve its accessibility. A systematic inventory of the content is given in Figure 1. This practical guide is based on all content up to the 2017 update as the first output of our Working Group. It is divided in the following sections: a brief guide about the histopathological and serological work-up; a list of Banff Lesion Scores (previously known as components, eg, Banff t for tubulitis) with their current definitions, practical tips for their application and illustrative figures (see definitions below and thresholds in Table 2); and a list of Banff Diagnostic Categories in Table 1. Moreover, we provide a list of Additional Diagnostic Parameters, which need to be considered in addition to Banff Lesion Scores to reach a Banff Diagnostic Category (Table 3). Examples for these include “Severe Peritubular Capillary Basement Membrane Multilayering” which is among the criteria for antibody-mediated rejection (AMR) chronicity.12 A glossary of terms is provided as Supplemental Digital Content (see Glossary of Terms, SDC,http://links.lww.com/TP/B604), explaining important concepts and terminology underlying the Banff Classification. Lastly, we provide a critical appraisal of areas of the Banff Classification that require clarification and provide an outlook for future developments. All terms from the Banff Classification will be given in capitals for clarity, all abbreviations for Banff lesion scores will be given in italic typeface.
We hope this Banff 101 will serve as a handy reference for the clinicians and the pathologists, until the entire updated content appears online with the 2019 update of the Banff Classification of Renal Allograft Pathology, replacing this guide.
DIAGNOSTIC WORK-UP OF BIOPSIES
A kidney transplant biopsy should fulfill the criteria for specimen adequacy (see Glossary of Terms, SDC,http://links.lww.com/TP/B604) detailed in the Banff 1997 update.5 C4d staining is considered indispensable, either as immunofluorescence (IF) on fresh frozen or immunohistochemistry (IHC) on paraffin-embedded tissue. The paraffin block should be cut in several numbered level sections examined with hematoxylin-eosin, periodic acid-Schiff (PAS), trichrome-elastic and Jones or methenamine silver stains. Immunohistochemistry staining for simian virus-40, cross-reacting with BK virus is highly recommended when indicated. Where available, minute portions of cortex should be embedded for transmission electron microscopy (EM).
Depending on clinical and histopathological findings a complete nephropathological work-up including staining for immunoglobulin heavy and light chains and complement split products might be necessary to rule out or confirm a diagnosis of glomerulonephritis. Other ancillary staining might be necessary as for native kidney biopsies to establish specific recurrent or de novo kidney diseases (eg, Congo red stain).
Serological testing for donor-specific antibodies (DSAs) should be performed as described in respective consensus documents.13 Ancillary molecular tests, based on tissue and body fluids, are emerging.
Preimplantation biopsies should be obtained, processed, and reported as described by the Banff Working Group on Preimplantation Biopsies.14
BANFF LESION SCORES
Banff Lesion Scores assess the presence and the degree of histopathological changes in the different compartments of renal transplant biopsies, focusing primarily but not exclusively on the diagnostic features seen in rejection. These Banff Lesion Scores are not by themselves sufficient to reach the various Banff Diagnostic Categories in Table 1; the Additional Diagnostic Parameters—histopathological, molecular, serological and/or clinical—may be required to determine the diagnosis. For each Banff Lesion Score we give the current consensus definitions below. As new knowledge emerges, these might be refined for the forthcoming Banff 2019 update. A synopsis of their semiquantitative thresholds is given in Table 2. However, use of this threshold table without knowledge of the precise definitions and regulatory statutes underlying each Banff Lesion Score is strongly discouraged.
Banff Lesion Score i (Interstitial Inflammation)
This score evaluates the degree of inflammation in nonscarred areas of cortex, which is often a marker of Acute T Cell–Mediated Rejection (TCMR). As per the Banff update from 1997, areas that must not be considered for Banff Lesion Score i are “fibrotic areas, the immediate subcapsular cortex, and the adventitia around large veins and lymphatics”.5 As can indirectly be derived from the definition of Banff Lesion Score ti in the 2007 update of the Banff classification, nodular infiltrates, if in unscarred cortex, are also considered for Banff Lesion Score i.8 An asterisk shall be added to Banff Lesion Score i (eg, i1*), “if there are more than 5% to 10% of eosinophils, neutrophils or plasma cells”.5 Exemplary lesions are shown in Figure 2.
i0—No inflammation or in less than 10% of unscarred cortical parenchyma.
i1—Inflammation in 10 to 25% of unscarred cortical parenchyma.
i2—Inflammation in 26 to 50% of unscarred cortical parenchyma.
i3—Inflammation in more than 50% of unscarred cortical parenchyma.11
Banff Lesion Score t (Tubulitis)
This Banff Lesion Score evaluates the degree of inflammation within the epithelium of the cortical tubules. As per the Banff 2003 update “Tubulitis—the presence of mononuclear cells in the basolateral aspect of the renal tubule epithelium” is one of the defining lesion of TCMR in kidney transplants.6 According to Banff 1997, in tubules cut longitudinally, the score shall be determined as the number of mononuclear cells per 10 tubular epithelial cells, which is the average number of epithelial cells per tubular cross-section (Figure 3). Tubulitis must be present in at least 2 foci. We have emphasized this by rephrasing the criteria for Banff Lesion Score t0 below; the most severely affected tubule determines the score.5,11 Please note also that we have returned from the altered definition with “leukocytes” in the Banff 2015 update11 to “mononuclear cells” as given in the 1997 update.5 According to the most recent Banff update from 2017, for Acute TCMR Grade IA, IB and Chronic Active TCMR Grade IA and IB but not Borderline (Banff Diagnostic Category 3), tubulitis is considered in all but severely atrophic cortical tubules. Tubulitis in severely atrophic tubules does not count toward a diagnosis of either Borderline, Acute or Chronic Active TCMR, and severely atrophic tubules are defined by a diameter of less than 25% of that of unaffected or minimally affected tubules on the biopsy, often with an undifferentiated appearing, cuboidal or flattened epithelium (or in some cases even loss of epithelium with denudation of the tubular basement membrane), and pronounced wrinkling and/or thickening of the tubular basement membrane. This definition of severely atrophic tubules also includes very small, endocrine-like tubules with very narrow lumens, although the basement membranes of the latter may not be thickened.12 An example of tubulitis in various stages of tubular atrophy is shown in Figure 4.
t0—No mononuclear cells in tubules or single focus of tubulitis only.
t1—Foci with 1 to 4 mononuclear cells/tubular cross section (or 10 tubular cells).
t2—Foci with 5 to 10 mononuclear cells/tubular cross section (or 10 tubular cells).
t3—Foci with >10 mononuclear cells/tubular cross section or the presence of ≥2 areas of tubular basement membrane destruction accompanied by i2/i3 inflammation and t2 elsewhere.12
Banff Lesion Score v (Intimal Arteritis)
This Banff Lesion Score evaluates the presence and the degree of inflammation within the arterial intima. Arteries are defined as having at least 2 layers of smooth muscle cells in the media (Glossary of Terms, SDC,http://links.lww.com/TP/B604). Note that intimal arteritis (also referred to as endothelialitis and endarteritis) is defined by the presence of inflammatory cells, mainly lymphocytes and monocytes, in the subendothelial space of 1 or more arteries.10 One such cell suffices. Examples of this lesion are shown in Figure 5. Intimal arteritis is a feature seen in both Acute TCMR and Active AMR. For Banff Lesion Score v, the most severely affected artery dictates the score.5 Similar lesions in arterioles are only coded as an asterisk behind the Banff Lesion Score ah and are disregarded for Banff Lesion Score v. Infiltrates buried deeper in the intima are not considered for the v Banff Lesion Score but have been recognized as Chronic Active TCMR since the 2005 update,7 and graded in the 2017 update as Grade II.12 In the presence of tubulointerstitial hemorrhage (see Glossary of Terms, SDC,http://links.lww.com/TP/B604) and/or and infarct (see Glossary of Terms, SDC,http://links.lww.com/TP/B604) an asterisk “*” is attached to the Banff Lesion Score v (eg, Banff v0*, v2*).5
v1—Mild to moderate intimal arteritis in at least 1 arterial cross section.
v2—Severe intimal arteritis with at least 25% luminal area lost in at least 1 arterial cross section.
v3—Transmural arteritis and/or arterial fibrinoid change and medial smooth muscle necrosis with lymphocytic infiltrate in vessel.11
Banff Lesion Score g (Glomerulitis)
This Banff Lesion Score evaluates the degree of inflammation within glomeruli (Figure 6). Glomerulitis is a form of microvascular inflammation (MVI) and is a feature of activity and antibody interaction with tissue in AMR. It can also be seen in recurrent or de novo glomerulonephritis which must be excluded by appropriate immunostains and EM.
Banff Lesion Score g is determined by the proportion of glomeruli showing glomerulitis defined as “complete or partial occlusion of 1 or more glomerular capillary by leukocyte infiltration and endothelial cell enlargement.”10 Leukocytes include polymorphonuclear cells and mononuclear cells. Both endothelial cell enlargement and leukocyte(s) must contribute to the complete or partial occlusion. The denominator in this proportion is the number of nonsclerosed glomeruli in the biopsy.
g1—Segmental or global glomerulitis in less than 25% of glomeruli.
g2—Segmental or global glomerulitis in 25 to 75% of glomeruli.
g3—Segmental or global glomerulitis in more than 75% of glomeruli.11
Banff Lesion Score ptc (Peritubular Capillaritis)
This Banff Lesion Score evaluates the degree of inflammation within peritubular capillaries (PTCs). Together with glomerulitis, peritubular capillaritis constitutes MVI as a feature of Active AMR or Chronic Active AMR. Peritubular capillaritis can be observed with pure Acute TCMR or Borderline as well.
According to the Banff 2005 update, the Banff Lesion Score ptc is determined by the most severely involved PTC (Figure 7). Peritubular capillaries are by definition found in the cortex, their medullary equivalent are medullary vasa recta. The number of luminal inflammatory cells includes polymorphonuclear and mononuclear leukocytes, with an asterisk “*” used to indicate only mononuclear cells and absence of neutrophils. The extent of the PTC inflammation in the biopsy should be documented, either as focal (10-50% of cortical area) or diffuse (>50% of cortical area), but this does not contribute to the score. The presence of associated PTC dilatation may also be noted. Areas affected by acute pyelonephritis or necrosis and subcapsular cortex with nonspecific inflammation should not be scored. Inflammatory cells within PTCs must be distinguished from interstitial inflammation by careful examination of basement membrane stains (PAS, silver). Inflammatory cells within veins and medullary capillaries (vasa recta) should not be scored.7 Consequently, peritubular capillaritis and Banff Lesion Score ptc can only be assessed in the cortex after exclusion of areas of pyelonephritis and infarcted areas and exclusion of areas close to lymphoid aggregates to avoid confusion with lymphatic vessels. Banff Lesion Score ptc should not be based on longitudinally cut PTCs.8 Peritubular capillaries in areas affected by tubular atrophy and interstitial fibrosis must explicitly be considered for this Banff Lesion Score. Note that we have simplified the definition of ptc0 from the original version in the Banff 2017 update.12
ptc0—Maximum number of leukocytes <3.
ptc1—At least 1 leukocyte cell in ≥10% of cortical PTCs with 3-4 leukocytes in most severely involved PTC.
ptc2—At least 1 leukocyte in ≥10% of cortical PTC with 5-10 leukocytes in most severely involved PTC.
ptc3—At least 1 leukocyte in ≥10% of cortical PTC with >10 leukocytes in most severely involved PTC.11
Banff Lesion Score C4d
This score evaluates the extent of staining for C4d on endothelial cells of PTCs and medullary vasa recta by IF on snap frozen sections of fresh tissue or IHC on formalin-fixated and paraffin-embedded tissue. Although Banff 2007 states that areas of tubular atrophy and interstitial fibrosis have reduced PTC density that could affect the extent of staining,15 scoring of C4d in such cortical areas is not excluded.8 Scoring of C4d staining is based on the percentage of peritubular capillaries and vasa recta that has a linear, circumferential staining pattern (Figure 8). The minimal sample for evaluation is 5 high-power fields of cortex and/or medulla without scarring or infarction. C4d must not be scored in areas of infarction. On IF, staining should be at least 1+ in intensity.8 Strong staining is not required for a positive reading for IHC.11 In terms of extent of staining, with IF, Banff Lesion Score C4d ≥ 2 is considered positive and a criterion for antibody interaction with tissue and as equivalent to DSA (see Table 1 and SDC, Glossary of Terms,http://links.lww.com/TP/B604), whereas with IHC, Banff Lesion Score C4d ≥ 1 is counted as positive already.11 Note that the definition below deviates from the one provided in the Banff 2015 update,11 in that it explicitly allows scoring in medullary vasa recta as originally intended, not only PTCs. The thresholds remain unchanged.
C4d0—No staining of PTC and medullary vasa recta (0%).
C4d1—Minimal C4d staining (>0 but <10% of PTC and medullary vasa recta).
C4d2—Focal C4d staining (10-50% of PTC and medullary vasa recta).
C4d3—Diffuse C4d staining (>50% of PTC and medullary vasa recta).
Banff Lesion Score ci (Interstitial Fibrosis)
This lesion score evaluates the extent of cortical fibrosis. The Banff Classification has never given a precise definition for individual areas of interstitial fibrosis (Figure 9). The reason for this is that Banff Lesion Score ci was meant to purely reflect the cortex composed of fibrous tissue, which does not necessarily correspond to areas that a pathologist would pick up as a patch of pathological tubulointerstitial fibrosis. The fraction of fibrous tissue in the cortex was considered as up to 5% for normal kidneys, hence the difference in cut-offs between ci1 and ct1. A Working Group on this topic has produced useful reference guides (Figures 10 and 11).17
ci0—Interstitial fibrosis in up to 5% of cortical area.
ci1—Interstitial fibrosis in 6 to 25% of cortical area (mild interstitial fibrosis).
ci2—Interstitial fibrosis in 26 to 50% of cortical area (moderate interstitial fibrosis).
ci3—Interstitial fibrosis in >50% of cortical area (severe interstitial fibrosis).11
Banff Lesion Score ct (Tubular Atrophy)
This Banff Lesion Score evaluates the extent of cortical tubular atrophy which is usually tightly associated with the areas affected with interstitial fibrosis (Figure 9). Both correlate with time posttransplantation in the setting of progressive disease of any cause. Accordingly, neither Banff Lesion Scores ct nor ci have diagnostic specificity, but both have significant correlation with allograft function and prognosis.
Historically, the Banff classification has defined tubular atrophy as reflected in the Banff Lesion Score ct in the 1995 update4 as tubules with a thickened basement membrane or a reduction of greater than 50% in tubular diameter. Banff Lesion Score ct is still based on this definition of tubular atrophy. The definitions of moderate and severe atrophy from the Banff 2017 update are irrelevant for Banff Lesion Score ct. In the following definition, we have omitted the designation as “mild” for ct1, “moderate” for ct2 and “severe” for ct3 which was still included in the Banff 2015 update to avoid confusion between the definition of atrophy for an individual tubule as described above and the extent of tubular atrophy reflected in the Banff Lesion Score ct.
ct0—No tubular atrophy.
ct1—Tubular atrophy involving up to 25% of the area of cortical tubules.
ct2—Tubular atrophy involving 26 to 50% of the area of cortical tubules.
ct3—Tubular atrophy involving in >50% of the area of cortical tubules.11
Banff Lesion Score cv (Vascular Fibrous Intimal Thickening)
This Banff Lesion Score reflects the extent of arterial intimal thickening in the most severely affected artery (see Definition of Terms, SDC,http://links.lww.com/TP/B604), not the average of all arteries.5 It does not discriminate between bland arterial intimal fibrosis and fibrosis containing leukocytes (Figure 12), although the latter is more likely to reflect chronic rejection (AMR and/or Chronic Active TCMR Grade II).12 A visual analog scale for application in daily practice is provided in Figure 13.
cv0—No chronic vascular changes.
cv1—Vascular narrowing of up to 25% luminal area by fibrointimal thickening.
cv2—Vascular narrowing of 26 to 50% luminal area by fibrointimal thickening.
cv3—Vascular narrowing of more than 50% luminal area by fibrointimal thickening.11
Banff cg Score (Glomerular Basement Membrane Double Contours)
Banff Lesion Score cg is based on the presence and extent of glomerular basement membrane (GBM) double contours or multilamination in the most severely affected glomerulus (Figure 14). Scoring should be carried out on PAS or silver stains; a designation as cg1a requires transmission EM to exclude cg0. With Banff Lesion Score cg > 0 (including both cg1a and cg1b), a diagnosis of transplant glomerulopathy (TG) (see Glossary of Terms, SDC,http://links.lww.com/TP/B604) can be made, if other causes can be excluded. Banff Lesion Score cg > 0 can be a feature of Chronic AMR or Chronic Active AMR, but can also be seen in association with thrombotic microangiopathy of other causes than AMR, e.g., hepatitis C virus infection,18 hypertensive glomerulopathy,19 and glomerulonephritis. In analogy to Banff Lesion Score g, even in the presence of an explanation other than rejection for GBM double contours, Banff Lesion Score cg shall still be applied. Banff Lesion Score cg is not scored in ischemic or segmentally sclerosed glomeruli.1,11 Late ischemic glomerulopathy is defined as “thickening, wrinkling and collapse of glomerular capillary walls associated with extracapillary fibrotic material”.1 As stated above, the earliest lesion of TG (cg1a) requires transmission EM for diagnosis. To detect such lesions, it is recommended that at centers with EM capability, “ultrastructural studies should be performed in all biopsies from patients who are sensitized, have documented DSA at any time posttransplantation and/or who have had a prior biopsy showing C4d staining, glomerulitis and/or peritubular capillaritis”. It is also advised that EM be considered in all biopsies performed from 6 months posttransplantation onward and in for-cause biopsies done from 3 months posttransplantation onward to determine if early changes of TG are present, prompting testing for DSA.10 Electron microscopy is also recommended for any biopsy done for the indication of increasing or new onset proteinuria.
cg0—No GBM double contours by light microscopy (LM) or EM.
cg1a—No GBM double contours by LM but GBM double contours (incomplete or circumferential) in at least 3 glomerular capillaries by EM, with associated endothelial swelling and/or subendothelial electron-lucent widening.
cg1b—Double contours of the GBM in 1-25% of capillary loops in the most affected nonsclerotic glomerulus by LM; EM confirmation is recommended if EM is available.
cg2—Double contours affecting 26 to 50% of peripheral capillary loops in the most affected—glomerulus.
cg3—Double contours affecting more than 50% of peripheral capillary loops in the most affected-glomerulus.11
Banff Lesion Score mm (Mesangial Matrix Expansion)
This score evaluates the percentage of glomeruli with “moderate mesangial matrix expansion” in relation to all nonsclerosed glomeruli. Banff 1997 defines moderate mesangial matrix increase as “expansion of the matrix in the mesangial interspace to exceed the width of 2 mesangial cells in the average in at least 2 glomerular lobules”.5 An example is shown in Figure 15. Banff Lesion Score mm is currently not used to reach a Diagnostic Category and is purely descriptive.
mm0—No more than mild mesangial matrix increase in any glomerulus.
mm1—At least moderate mesangial matrix increase in up to 25% of nonsclerotic glomeruli.
mm2—At least moderate mesangial matrix increase in 26% to 50% of nonsclerotic glomeruli.
mm3—At least moderate mesangial matrix increase in >50% of nonsclerotic glomeruli.11
Banff Lesion Score ah (Arteriolar Hyalinosis)
This score evaluates the extent of arteriolar hyalinosis (Figure 16). The first edition of the Banff Classification defined ah as “nodular hyaline afferent arteriolar thickening suggestive of cyclosporine toxicity”; however, in Banff 1997 and later updates, Banff Lesion Score ah is defined simply as PAS-positive arteriolar hyaline thickening, as a finding of “uncertain significance”. An asterisk “*” is added to the ah score when arteriolitis is present (eg, ah0*, ah2*).5 Banff Lesion Score ah is currently not used to reach a diagnostic category and is purely descriptive.
ah0—No PAS (PAS)-positive hyaline arteriolar thickening.
ah1—Mild to moderate PAS-positive hyaline thickening in at least 1 arteriole.
ah2—Moderate to severe PAS-positive hyaline thickening in more than 1 arteriole.
ah3—Severe PAS-positive hyaline thickening in many arterioles.11
Banff Lesion Score aah (Hyaline Arteriolar Thickening)
This Banff Lesion Score provides an alternative way of quantifying arteriolar hyalinosis. It was proposed in the 2007 update, because of the insufficient reproducibility of the Banff Lesion Score ah.8 This alternative tries to reach better reproducibility by focusing on circumferential or noncircumferential hyalinosis and the number of involved arterioles. Still, this lesion cannot be considered specific, that is, diagnostic for calcineurin inhibitor-related arteriolopathy. The use of this Banff Lesion Score aah has been left as optional since its introduction in 2007, no final decision has been reached whether it shall replace Banff Lesion Score ah. Banff Lesion Score aah is currently not used to reach a diagnostic category and is purely descriptive.
aah0—No typical lesions of calcineurin inhibitor-related arteriolopathy.
aah1—Replacement of degenerated smooth muscle cells by hyaline deposits in only 1 arteriole, without circumferential involvement.
aah2—Replacement of degenerated smooth muscle cells by hyaline deposits in more than 1 arteriole, without circumferential involvement.
aah3—Replacement of degenerated smooth muscle cells by hyaline deposits with circumferential involvement, independent of the number of arterioles involved.11
Banff Lesion Score ti (Total Inflammation)
This lesion score evaluates the extent of total cortical inflammation. According to the Banff 2007 update and in contrast to the Banff Lesion Score i, all of the cortical parenchyma, including areas of interstitial fibrosis and tubular atrophy (IFTA), subcapsular cortex and perivascular cortex including nodular infiltrates are considered for ti scoring.8 Mengel et al found Banff Lesion Score ti to be better predictive of poor graft outcomes than the Banff Lesion Score i in cases where at least mild IFTA was present.20 The association between interstitial inflammation in areas of IFTA as reflected in Banff Lesion Score i-IFTA and decreased graft survival was noted by Mannon et al21 and subsequently confirmed by others.22,23 As a consequence, Banff Lesion Score ti became part of the criteria for a diagnosis of Chronic Active TCMR Grade IA and IB;12 both Banff Lesion Scores ti and i-IFTA must be at least 2 to consider a diagnosis of Chronic Active TCMR Grade IA or IB.12
ti0— No or trivial interstitial inflammation (<10% of total cortical parenchyma).
ti1— 10-25% of total cortical parenchyma inflamed.
ti2— 26-50% of total cortical parenchyma inflamed.
ti3— >50% of total cortical parenchyma inflamed.11
Banff Lesion Score i-IFTA (Inflammation in Area of IFTA)
This score evaluates the extent of inflammation in scarred cortex, ie, areas that qualify for Banff Lesion Scores ci and ct (Figure 17). The Banff Lesion Score i-IFTA was first introduced to the Banff Classification in 2015.11 Both Banff Lesion Scores ti and i-IFTA must be at least 2 to consider a diagnosis of Chronic Active TCMR Grade IA or IB.12
i-IFTA0—No inflammation or less than 10% of scarred cortical parenchyma.
i-IFTA1—Inflammation in 10% to 25% of scarred cortical parenchyma.
i-IFTA2—Inflammation in 26% to 50% of scarred cortical parenchyma.
i-IFTA3—Inflammation in >50% of scarred cortical parenchyma.11
BANFF DIAGNOSTIC CATEGORIES
Table 1 presents the Banff Diagnostic Categories and is based on the original table of the most recent Banff update from 2017.12 Readers should stay alert to future updates on the Banff Foundation website (www.banfffoundation.org) informed by updates to the Banff Classification from 2019 onward.
Since 1991, the Banff classification has undergone several amendments, reflecting the growing body of knowledge in transplant pathology. These amendments have been based on a consensus reached at the biannual Banff meetings. This constant refinement based on emerging data is a strength of the Banff process and has led to the worldwide dominance of the Banff Classification for diagnostic practice, research and clinical trials. However, the iterative fashion in which the definitions and rules were published has dispersed the relevant content and created ambiguities. This has led to the creation of the Banff Rules and Dissemination Working Group in the aftermath of the Banff Meeting in Barcelona in March 2017. The aim of the Working group is not to alter the content of the Banff Classification. Rather, it shall collate all relevant Banff content in a central repository under the auspices of the Banff Foundation for Allograft Pathology, with a single updatable content, similar to the Union for International Cancer Control's TNM Classification. Changes in the content of the Banff Classification must only be made through review of evidence and expert consensus at the Banff meetings or within the relevant other Working Groups. Like the collation of content above, the following critical appraisal is based on this mission and does not touch on the content of the Banff Classification itself.
Although the Banff Lesion Scores required for a diagnosis of AMR have recently undergone a partial overhaul10 and although a dedicated Working Group is reexamining the Banff Lesion Scores for TCMR, no or little effort has been devoted to the Additional Diagnostic Parameters in Table 3. For example, “Acute Tubular Injury In The Absence Of Any Other Cause” as a criterion for active AMR is as important as Banff Lesion Scores v, g or ptc,12 yet this feature is still imperfectly defined, the last definition dating back to the 1995 update.4 Another example is “infection,” which precludes the use of Banff Lesion Score ptc alone as a criterion for AMR.11 Use of the isolated term “infection” is ambiguous in the context of whether inflammation in the transplant should be considered as evidence for rejection or not. We would recommend treating these Additional Diagnostic Parameters like the Banff Lesion Scores, presenting them in clear and consistent wording, and, whenever necessary, by providing guidance through meaningful definitions elaborated over time through Working Groups and in alignment with the respective diagnostic criteria applied.
Among the Banff Lesion Scores, the Banff Lesion Score cv has a confusing array of terminologies, appearances and diagnostic implications. “Arterial fibrointimal thickening” or “vascular fibrous intimal thickening” imply a chronic fibrous change, whereas arterial intimal thickening can be cellular and nonfibrous in “transplant vasculopathy” or “chronic allograft arteriopathy”. As a manifestation of chronic TCMR, it is defined as “arterial intimal fibrosis with mononuclear cell infiltration in fibrosis, formation of neointima12 whereas, as a criterion for AMR chronicity, it is defined as “arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic AMR if there is no prior history of biopsy-proven TCMR with arterial involvement but are not required”.12 In clinical practice, it might not always be possible to exclude prior TCMR or to precisely diagnose “Arterial intimal fibrosis of new onset” as a criterion for AMR chronicity.12 A related problem is attached to Banff Lesion Score cg: “evidence of chronic thrombotic microangiopathy (TMA)” excludes the use of Banff Lesion Score cg > 0 as a criterion for AMR chronicity, whereas Active AMR can be diagnosed with TMA, as long as it is “in the absence of any other cause [than AMR]”. Because Active AMR causing TMA can lead to glomerular lesion qualifying as TG, it would make sense to change the cg criterion to only exclude chronic TMA of any other cause than AMR.
The use of asterisks (“*”) attached to Banff Lesion Scores v, i, ah and ptc5,7 is problematic and widely neglected. Their reproducibility and diagnostic value are unknown, and they are ambiguous: an asterisk behind the Banff Lesion Score ptc signifies only mononuclear cells and absence of neutrophils, whereas the asterisk behind Banff Lesion Score i denotes a significant neutrophilic, eosinophilic or plasmacellular component in the infiltrate, and these different cell types can have widely differing implications. We suggest the Banff community should reassess these modifiers, either by improving their definitions and assigning them a significance or by abandoning them.
Inevitably, the Banff Classification has focused mainly on features of rejection, but with Banff Lesion Scores developed for other features with little or no guidance on their contribution to diagnosis. An example for this is Banff Lesion Score aah, originally intended to replace the poorly reproducible Banff lesion score ah.7 However, its use is still optional, and it has neither been widely adopted nor used in any of the Banff Diagnostic Categories. The Banff community should reassess arteriolar hyalinosis lesion scores, and clarify grading and diagnostic implications.
Regarding the Banff Diagnostic Categories, a clear diagnostic pathway should be recommended when dealing with Borderline or Acute TCMR (Banff Diagnostic Categories 3 and 4) in the presence of BK Virus Nephropathy, Pyelonephritis or other infectious diseases of the transplant, as well as AMR with glomerulitis in the presence of recurrent or de novo glomerulonephritis. These issues could be referred to the Banff TCMR and Glomerulonephritis Working Group respectively. The definition of Banff Borderline with regards to the Banff Lesion Score i threshold (i0 or i1) is still ambiguous11 but should be resolved by the TCMR Working Group.
There are uncertainties around the application of transmission EM in the diagnosis of AMR which are currently being addressed by the Electron Microscopy Working Group. These issues include precise guidelines for indications and methods for application of EM in transplant biopsies; perhaps also the introduction of a new Banff Lesion Score for multilamination of the basement membranes of peritubular capillaries which we have covered as an Additional Diagnostic Parameter for now.
Another critical issue is related to the molecular diagnostics of AMR and TCMR. Although the current Banff classification endorses the use of molecular diagnostics in the definition of AMR, there is limited guidance regarding methods and diagnostic cut-offs, which could be elaborated by the Molecular Working Group.
Lastly, the introduction of the new diagnostic categories of Chronic Active TCMR is likely to undergo changes informed by the TCMR Working Group. Before Banff 2017, there were no specific criteria for Chronic Active TCMR outside of arteries, and tubulitis was only scored in nonatrophic and mildly atrophic tubules, effectively excluding moderately and severely atrophic tubules. To avoid having 2 separate criteria for Banff Lesion Score t in Acute versus Chronic Active TCMR, it was decided that for both diagnoses tubulitis would be scored in all tubules except severely atrophic tubules. The difference between Banff 2017 and previous versions of the classification with respect to Acute TCMR is that tubulitis in moderately atrophic tubules is now counted toward Banff Lesion Score t. Because the latter was done for clarity and to avoid confusion rather than on the basis of specific evidence, it would be beneficial that future studies be done to address the most clinically relevant threshold for the level of atrophy permitted in scoreable tubules, especially for diagnosis of Acute TCMR. In addition, the 2017 changes to the TCMR criteria also suggest future work be aimed at examining the response of Chronic Active TCMR to steroids and other anti–T cell therapies (eg, thymoglobulin), determining if there are differences in this response between: (1) Grade IA versus Grade IB Chronic Active TCMR and (2) biopsies with Chronic Active TCMR that would otherwise meet criteria for acute TCMR (ie, with Banff Lesion Score i ≥ 2) and those that would not (with Banff Lesion Score i ≤ 1). The alignment of diagnoses from the spectrum of Acute TCMR with those from the spectrum of Chronic Active TCMR of different compartments could be problematic. For example, a biopsy with Banff Lesion Score v1 fulfilling also the criteria for chronic active TCMR grade IB would be diagnosed as the latter only,12 as according to Banff 2017, a diagnosis of Chronic Active TCMR precludes the diagnosis even of higher grade Acute TCMR. In such cases, however, the use of modifying text independent from Banff diagnostic categories should be considered (eg, Acute TCMR Grade II with a chronic active tubulointerstitial component; Acute TCMR Grade II with isolated intimal arteritis [isolated v]).
Although this article is intended to provide a comprehensive and convenient desk-top reference, it is destined to expire with the publication of the 2019 Banff update. After this update, a Web resource will serve as the continuously updated go-to resource for the relevant Banff content. Depending on the progress in the definitions and diagnostic rule sets we are aiming to develop web-based resources such as diagnostic algorithms to further strengthen standardization and reproducibility of the Banff Classification for clinical practice and research. It should be emphasized that the Banff Classification of Kidney Allograft Pathology does not cover all relevant aspects of transplantation medicine. Allograft transplantation only reaches 10% of patients needing new organs. Through regenerative medicine and tissue engineering and other optimizing initiatives we will eventually be able to provide organs to everyone in need. For this, we will need a new Banff Classification of Tissue Engineering Pathology24,25 reflecting the new challenges of delivering the right cells to the right places in a bioengineered organ and having them function normally. Rejection will no longer be the primary threat in bioengineered organs. For a decade or more the new Banff Classification of Tissue Engineering Pathology will be used concurrently with the existing Banff Classification of Allograft Pathology.
Getting the right cells in the right places sounds simple, but in fact, we have poor knowledge of what all the normal cell types in transplanted organs are. For instance, in the kidney, we have traditionally taught that there are 26 cell types,26 but in fact, high throughput single cell analysis in the Human Cell Atlas Project27-29 shows many more than that and can determine not only cell identity but also lineage and activation state. The transplantation and transplantation pathology community need to embrace Human Cell Atlas technology, so we are not blindsided by this new technology. The scale of the likely impact of the Human Cell Atlas Project on nephrology and transplantation is currently being analyzed (Moghe I, Magor B, and Solez K, article in preparation, 2018).
The authors would like to acknowledge the help in the preparation of the visual analog scales from Christopher Bellamy, Alton “Brad” Farris and Daniel Serón.
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