Revised Banff 2017 classification of antibody-mediated rejection in renal allografts

Active ABMR; all 3 criteria must be met for diagnosis*^¶

1. Histologic evidence of acute tissue injury, including one or more of the following:

Microvascular inflammation (g >0^Δ and/or ptc >0), in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥1 alone is not sufficient and g must ≥1

Intimal or transmural arteritis (v >0)^◊

Acute TMA, in the absence of any other cause

Acute tubular injury, in the absence of any other apparent cause

2. Evidence of current/recent antibody interaction with vascular endothelium, including at least one of the following:

Linear C4d staining in ptc (C4d2 or C4d3 by IF on frozen sections, or C4d >0 by IHC on paraffin sections)

At least moderate microvascular inflammation ([g + ptc] ≥2)^§

Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated^¥

3. Serologic evidence of DSAs (HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met.

Chronic, active ABMR; all 3 criteria must be met for diagnosis*^‡

1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:

TG (cg >0)^†, if no evidence of chronic TMA or chronic/de novo glomerulonephritis

Severe ptc basement membrane multilayering (requires EM)**

Arterial intimal fibrosis of new onset, excluding other causes^¶¶

2. Evidence of current/recent antibody interaction with vascular endothelium, including at least one of the following:

Linear C4d staining in ptc (C4d2 or C4d3 by IF on frozen sections, or C4d >0 by IHC on paraffin sections)

At least moderate microvascular inflammation ([g + ptc] ≥2)^§

Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated^¥

C4d staining without evidence of rejection; all 4 features must be present for diagnosis^ΔΔ

1. Linear C4d staining in ptc (C4d2 or C4d3 by IF on frozen sections, or C4d >0 by IHC on paraffin sections)

2. Criterion 1 for active or chronic, active ABMR not met

3. No molecular evidence for ABMR as in criterion 2 for active and chronic, active ABMR

4. No acute or chronic, active TCMR or borderline changes

ABMR: antibody-mediated rejection; g: Banff glomerulitis score; ptc: peritubular capillary; TCMR: T cell-mediated rejection; v: Banff arteritis score; TMA: thrombotic microangiopathy; IF: immunofluorescence; IHC: immunohistochemistry; DSA: donor-specific antibody; HLA: human leukocyte antigen; TG: transplant glomerulopathy; cg: Banff chronic glomerulopathy score; EM: electron microscopy; ENDAT: endothelial activation and injury transcript; GBM: glomerular basement membrane.
* For all ABMR diagnoses, it should be specified in the report whether the lesion is C4d positive (C4d2 or C4d3 by IF on frozen sections; C4d >0 by IHC on paraffin sections) or without evident C4d deposition (C4d0 or C4d1 by IF on frozen sections; C4d0 by IHC on paraffin sections).
¶ These lesions may be clinically acute, smoldering, or subclinical. Biopsies showing two of the three features, except those with DSA and C4d without histologic abnormalities potentially related to ABMR or TCMR (C4d staining without evidence of rejection^ΔΔ), may be designated as "suspicious" for acute/active ABMR.
Δ Recurrent/de novo glomerulonephritis should be excluded.
◊ It should be noted that these arterial lesions may be indicative of ABMR, TCMR, or mixed ABMR/TCMR. "v" lesions are only scored in arteries having a continuous media with two or more smooth muscle layers.
§ In the presence of acute TCMR, borderline infiltrates or evidence of infection, ptc ≥2 alone is not sufficient to define moderate microvascular inflammation, and g must be ≥1.
¥ The only validated molecular marker meeting this criterion is ENDAT expression^[1], and this has only been validated in a single center (University of Alberta). The use of ENDAT expression at other centers or other test(s) of gene expression within the biopsy as evidence of ABMR must first undergo independent validation as was done for ENDAT expression^[1].
‡ Lesions of chronic, active ABMR can range from primarily active lesions with early TG evident only by EM (cg1a) to those with advanced TG and other chronic changes in addition to active microvascular inflammation. In the absence of evidence of current/recent antibody interaction with the endothelium (those features in the Second Section), the term active should be omitted; in such cases, DSA may be present at the time of biopsy or at any previous time posttransplantation.
† Includes GBM duplication by EM only (cg1a) or GBM double contours by light microscopy.
** Seven or more layers in one cortical ptc and ≥5 in two additional capillaries^[2], avoiding portions cut tangentially.
¶¶ While leukocytes within the fibrotic intima favor chronic rejection, these are seen with chronic TCMR as well as chronic ABMR and are therefore helpful only if there is no history of TCMR. An elastic stain may be helpful as absence of elastic lamellae is more typical of chronic rejection, and multiple elastic lamellae are most typical of arteriosclerosis, although these findings are not definitive.
ΔΔ The clinical significance of these findings may be quite different in grafts exposed to anti-blood-group antibodies (ABO-incompatible allografts), where they do not appear to be injurious to the graft^[3,4] and may represent accommodation. However, with anti-HLA antibodies, such lesions may progress to chronic ABMR^[5], and more outcome data are needed.

References:

Sis B, Jhangri G, Bunnag S, et al. Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining. Am J Transplant 2009; 9:2312.
Liapis G, Singh HK, Derebail VK, et al. Diagnostic significance of peritubular capillary basement membrane multilaminations in kidney allografts: Old concepts revisited. Transplantation 2012; 94:620.
Haas M, Rahman MH, Racusen LC, et al. C4d and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts: Correlation with histologic findings. Am J Transplant 2006; 6:1829.
Setoguchi K, Ishida H, Shimmura H, et al. Analysis of renal transplant protocol biopsies in ABO-incompatible kidney transplantation. Am J Transplant 2008; 8:86.
Bravou V, Galliford J, McLean A, et al. A case of chronic antibody-mediated rejection in the making. Clin Nephrol 2013; 80:306.

From: Haas M. An updated Banff schema for diagnosis of antibody-mediated rejection in renal allografts. Am J Transplant 2014; 14:272. http://onlinelibrary.wiley.com/doi/10.1111/ajt.12590/abstract. Copyright © The American Society of Transplantation and the American Society of Transplant Surgeons. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: [email protected] or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com).

Updated with information from:

Haas M, Loupy A, Lefaucheur C, et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant 2018; 18:293.

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Revised Banff 2017 classification of antibody-mediated rejection in renal allografts