Banff classification

The Banff classification was developed in 1991 in the Canadian city of Banff by the expert committee Solez, Axelsen et al. and represents an advance in the evaluation of rejection after kidney transplantation.

Over the years, the classification has been revised several times by new findings in order to continuously improve the diagnostic specificity (Klöppel 2016 / Rother 2018).

A fundamental extension of the Banff classification was the introduction of the AVA criteria (acute active antibody-mediated [humoral] transplant rejection) in 2001 (Klöppel 2016).

The Banff classification represents an international standard of histopathological changes of a transplant kidney, which allows the allocation of rejection reactions and other transplant pathologies (Rother 2018).

A diagnostically meaningful biopsy should contain at least 10 glomeruli and two small arteries (Mühlfeld 2015).

The Banff Working Classification of Renal Allograft Pathology (BANFF) reviews the classification every two years. The last update is from 2019 and divided into the following categories (Loupy 2020):

• Category 1: normal or non-specific changes
• Category 2: antibody-mediated rejection (type I-III)
• Category 3: Borderline rejection (cellular)
• Category 4: T-cell mediated rejection (type IA/B, IIA/B, III), cTCMR (grade IA, IB, II)
• Category 5: Polyomavirus nephropathy (PVN)
• Category 6: Non-rejection-related changes (Gäckler 2018)

Abbreviations:

• ABMR = antibody-mediated rejection
• TCMR = T Cell-Mediated Rejection
• HLA = Human leukocyte antigen
• DSA = donor specific antibodies
• IF = Immunofluorescence
• IHC = Immunohistochemistry

Category 2: Antibody-mediated rejection: Antibody-mediated rejection may occur within a few days after transplantation. Approximately 20 % occur within the first 3 months after transplantation (Kuhlmann 2015). The chronically active form of antibody-mediated rejection is the most important cause of later transplant failure.

In antibody-mediated rejection, donor-specific antibodies (DSA) directed against the donor's HLA antigen can be detected in the patient's serum. However, preformed antibodies are already present in about 30% of all transplant patients preoperatively and de novo between 20% - 30% of patients develop DSAs.

Histologically, DSAs are detectable in these patients:

• Disruption of the microcirculation
• Endothelial damage
• immunohistochemical detection: C4d- positive (marker for graft rejection [Frei 2001])(Herold 2020)

In category 2, a distinction is made between active, chronically active and chronically inactive ABMR.

Active ABMR: For active ABMR, all 3 of the following characteristics must be present for diagnosis:

1. Histological evidence of acute tissue lesions including at least one of the following criteria:
   1. microvascular inflammation (g > 0c and / or ptc > 0) without recurrent or de novo glomerulonephritis, although in acute TCMR, borderline infiltrate or infection ptc ≥ 1 alone is not sufficient, but g must also be 1 ≥
   2. Arteritis of the intima or transmural (v > 0)
   3. Acute thrombotic microangiopathy = TMA (in the absence of other causes)
   4. acute tubular lesion (in the absence of other obvious causes)
2. Evidence of recent antibody interaction with the vascular endothelium including at least one of the following criteria:
   1. linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 in the IF of frozen sections or C4d > 0 in the IHC of paraffin sections)
   2. at least moderate microvascular inflammation ([g + ptc] ≥ 2)
   3. increased expression of gene transcripts in biopsy tissue after thorough validation with evidence of endothelial lesions
3. Serological detection of donor-specific antibodies DSA (HLA or other antigens). A C4d staining according to criterion 2 may replace DSA (Loupy 2020).

Chronically active ABMR: For chronically active ABMR, all 3 of the following characteristics must also be present for diagnosis:

1. Morphological detection of chronic tissue lesions including one or more of the following criteria:
   1. Transplant glomerulopathy (TG; cg > 0) h, if there is no evidence of chronic thrombotic microangiopathy
   2. considerable peritubular multi-layering of the capillary basement membrane (an electron microscope is required for this)
   3. newly occurring arterial intimafibrosis, to the exclusion of other causes. If leukocytes are found within the sclerotic intima, this promotes chronic ABMR.
2. Evidence of recent antibody interaction with the vascular endothelium including at least one of the following criteria:
   1. linear C4d staining in the peritubular capillaries (C4d2 or C4d3 in the IF of frozen sections or C4d > 0 in the IHC of paraffin sections)
   2. at least moderate microvascular inflammation ([g + ptc] ≥ 2e
   3. increased expression of gene transcripts in biopsy tissue after thorough validation with evidence of endothelial lesions
3. Serological detection of donor-specific antibodies = DSA (HLA or other antigens). A C4d staining according to criterion 2 can replace DSA.

Biopsies that meet criterion 1 but not criterion 2 and where DSA has been detected currently or previously after transplantation can also be classified as chronic ABMR (Loupy 2020).

Chronic (inactive) ABMR: Here too, a distinction is made between 3 criteria:

1. cg > 0 and/or an elevated value for multilayer peritubular basement membrane ptcml (ptcml 1)
2. Absence of criterion 2 in acute or chronically active ABMR
3. Acute or chronically active ABMR or previous evidence of DSA (Loupy 2020)

• C4d- staining without evidence of rejection: all 4 characteristics must be present for diagnosis

1. Linear C4d staining in the peritubular capillaries (C4d2 or C4d3 in the IF of frozen sections or C4d > 0 in the IHC of paraffin sections)
2. Criterion 1 for active or chronically active ABMR is not met
3. No molecular evidence of ABMR as described for active or chronically active ABMR under criterion 2
4. No evidence of acute or chronically active TCMR or borderline changes (Loupy 2020)

to category 3: Borderline alterations: The borderline alteration is a cellular rejection reaction in which the following alterations are found:

1. Tubulitis plaque (t1, t2 or t3),
   1. a slight interstitial inflammation (il)
   2. or have a mild tubulitis (tl)
   3. and a moderately severe interstitial inflammation (i2 or i3)
2. Intimate or transmural arteritis is not present (v = 0) (Loupy 2020)

to category 4: T-cell-mediated rejection:

• Active TCMR (three degrees of severity are distinguished):
• Grade IA:
  • interstitial inflammation (i2 or i3) is found in > 25 % of the non-sclerotic cortical parenchyma
  • with moderate tubulitis (t2)
  • with 1 or more tubules without strong atrophy of the tubules
• Grade IB:
  • in > 25 % of the non-sclerotic cortical parenchyma there is interstitial inflammation (i2 or i3)
  • severe tubulitis (t3) with 1 or more tubules without severe atrophy of the tubules
• Grade IIA:
  • There is a mild to moderate intima arteritis (v1)
  • with or without interstitial inflammation
  • and / or tubulitis
• Grade IIB:
  • Here a severe intima arteritis (v2) is found
  • with or without interstitial inflammation
  • and / or tubulitis
• Grade III:
  • transmural arteritis
  • and / or arterial fibrinoid necrosis with involvement of the medial smooth muscle
  • concomitant intima arteritis of the mononuclear cells
  • with or without interstitial inflammation
  • and / or tubulitis (Loupy 2020)

Chronically active TCMRe (there are 2 different degrees of severity):

• Grade IA
  • in > 25 % of the sclerotic cortical parenchyma there is an interstitial inflammation (i- IFTA2 or i- IFTA3)
  • plus interstitial inflammation in 25% of the total cortical parenchyma (ti2 or ti3)
  • a moderate tubulitis (t2 or - t- IFTA2)
  • with 1 or more tubules without strong atrophy of the tubules
  • other known causes of i- IFTA should be excluded
• Degree IB
  • in > 25 % of the sclerotic cortical parenchyma there is interstitial inflammation (i- IFTA2 or i- IFTA3)
  • plus interstitial inflammation of more than 25 % of the total cortical parenchyma (ti2 or ti3)
  • a severe tubulitis (t3 or - t- IFTA3)
  • with 1 or more tubules without strong atrophy of the tubules
  • other known causes of i- IFTA should be excluded
• Grade II
  • chronic allograft arteriopathy with
    • arterial intimafibrosis and
    • mononuclear cell inflammation in fibrosis and
    • Formation of neointima

These changes may also be the manifestation of a:

• chronically active ABMR
• chronic ABMR
• mixed ABMR / TCMR (Loupy 2020)

concerning category 5: Polyomavirus nephropathy (PVN)

At the last Banff Conference of the Banff Working Groups (BWG) in 2019, data on the classification of the PVN were added to the classification.

One differentiates between two different histological markers:

• interstitial fibrosis (ci)
• intrarenal polyomavirus exposure level (pvl)

These two markers allow conclusions to be drawn about graft function and graft survival.

The ci and pvl scores can be assigned to 3 PVN classes:

• PVN Class I:
  • pvl 1 and ci 0 - 1
• PVN Class II:
  • pvl 1 and ci 2 - 3
  • pvl 2 and ci 0 - 3
  • pvl 3 and ci 0 - 1
• PVN Class III:
  • pvl 3 and ci 2 - 3 (Loupy 2020)

Note: Previously category 5 was called "chronic allograft nephropathy (CAN)" (Herold 2020).

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