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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