Banff Classification Of renal

allograft pathology
Rida Malik
Resident Nephrology
Definition

 Rejection is a complex process in which “recepient immune

system recognize the graft as foreign and attacks it”.
 It involves
1. Cell mediated immunity
2. Circulating antibodies
 Rejection is defined by histological findings
 Adequate biopsy sample
 Atleast 10 glomeruli and 2 small arteries
 Stained with H&E, PAS or silver, and trichome stains.
 Two cores should be obtained.
 Slide 4
The
The Banff
Banff Schema
Schema was
was first
first developed
developed byby aa
group
group of
of pathologists,
pathologists, nephrologists,
nephrologists, andand
transplant
transplant surgeons at
at aafirst
surgeonswas meeting
meeting in
in Banff
Banff Canada
Canada
The
The Banff
Banff Schema
Schema was first developed
developed by
by aa
August
August 2-4,
2-4, 1991.
1991.
group
group of
of pathologists,
pathologists, nephrologists,
nephrologists, andand
transplant
transplant surgeons
surgeons at
at aa meeting
meeting inin Banff
Banff Canada
Canada
August
August 2-4,
2-4, 1991.
1991.

ItIt has
has continued
continued toto evolve
evolve through
through
meetings
meetings every
every two
two years
years and
and has
has
become
become thethe worldwide
worldwide standard
standard for
for
interpretation
interpretation of
of transplant
transplant biopsies.
biopsies.
Antibody Mediated Rejection

 It is called humoral rejections.

 Acute antibody mediated rejection occurs in 3 to 10 % of all transplants,

and 20 – 30 % of episodes of acute rejection.

 Typically within first few weeks

 Patients with pre existing donor specific HLA antibodies are at higher risk.
 Diagnosis of acute humoral rejection requires

1. Evidence of circulating donor specific antibodies

2. C4d deposition in peritubular capillaries
3. Evidence of tissue injury ( neutrophils and or macrophages in peritubular
capillaries )
C4d, basic marker of antibody mediated
rejection
 Based on the identification of antibody mediated injury indirectly through
evidence of complement deposition.

 C4d is a fragment of C4b that is generated on IgG and IgM deposition and
activation of the classical complement pathway.

 C4b/C4d binds with proteins on tissue such as capillary endothelial cells

and persists there after immunoglobulin and other complement products
have been released.

 Staining for C4d is currently the most sensitive marker for antibody-
mediated injury and should be routinely performed on renal transplant
biopsy specimens.
Acute antibodymediated
rejection. A, Peritubular and
glomerular capillaries contain
numerous
polymorphonuclear leukocytes
and
mononuclear cells. B,
Numerous polymorphonuclear
leukocytes are observed
in a peritubular capillary.
Interstitial
edema is noted. (Periodic acid–
Schiff) C,
Immunofluorescence
staining of peritubular
capillaries
with C4d. D,
Immunohistochemistry
demonstrating peritubular
capillary staining of C4d.
 Chronic active antibody-mediated rejection is likely due to
an indolent alloimmune response that results in transplant
glomerulopathy and arteriolopathy.

 Although transplant glomerulopathy is often associated with

circulating donor-specific antibodies and with C4d deposition,
30% to 50% of cases will be identified in the absence of these
diagnostic markers.
 The diagnosis of chronic humoral rejection requires

(1) evidence of donor-specific antibodies,

(2) C4d deposition in peritubular capillaries, and
(3) evidence of chronic tissue injury.

chronic tissue injury may include duplication of the glomerular

basement membrane (GBM), multilamination of the peritubular
capillary basement membrane, arterial intimal fibrosis without
elastosis, and interstitial fibrosis with tubular atrophy.
Chronic antibody-mediated
rejection. Glomerular

double contours (arrows) and

tubular atrophy (arrowhead).
(Periodic acid–

Schiff)

Inset: Diffuse C4d deposition in

peritubular

capillaries by
immunohistochemistry.
T Cell–Mediated Rejection

 The classification of acute T cell–mediated rejection (acute

cellular rejection) is based on the degree and location of
mononuclear cell inflammation.

 The predominant phenotype of these infiltrates is a mixture of

CD4+ and CD8+ T cells; however, B cells, eosinophils, and
macrophages may also be present.
 The finding of interstitial infiltrates and tubulitis in a kidney
transplant biopsy specimen is not specific to acute cellular
rejection, and other causes, such as
 viral nephropathy (BK virus, less commonly cytomegalovirus
[CMV]),
 pyelonephritis,
 post-transplantation lymphoproliferative disease, should be
considered on the basis of the clinical presentation.

 In contrast, the histologic finding of endothelialitis is

pathognomonic of acute cellular rejection.
Borderline Rejection
 The finding of inflammation in 10% to 25% of the interstitium with
tubulitis of fewer than four cells per tubular cross section is classified as
borderline rejection.

 This currently remains a pathologic definition without clear clinical

significance.

 When it is identified in the setting of graft dysfunction or with other

findings such as glomerulitis, the risk of progression to clinical rejection on
subsequent biopsies is increased, and thus treatment may be considered.
BANFF 97 diagnostic categories for renal
allograft biopsies

1. Normal
2. Antibody mediated rejection: rejection demonstrated to be due, at least in
part, to anti-donor antibodies
 a) Immediate (hyper-acute)
 b) Delayed (accelerated acute)
3. Borderline changes: suspicious for acute rejection.
4. Acute/active rejection
5. Chronic/sclerosing allograft nephropathy
BANFF CLASSIFICATION OF RENAL
ALLOGRAFT BIOPSY (2007 UPDATE)

 further updated recognizing separate pathology of antibody

mediated rejection (AMR) and T-cell mediated rejection and
incorporated key features of c4d staining, a marker of antibody
mediated rejection.
 antibody mediated rejection

 acute antibody mediated rejection 

 chronic antibody mediated rejection 
 T-cell mediated rejection

 Acute T-cell mediated (similar IA, IB, IIA, IIB and III

definitions)
 chronic T-cell mediated rejection (chronic allograft
arteriopathy) with arterial intimal fibrosis with mononuclear
cell infiltration in fibrosis and formation of neo-intima.

 Chronic/sclerosing allograft nephropathy was dropped from

new classification and interstitial fibrosis and tubular
atrophy was considered as a separate entity.
BANFF CLASSIFICATION OF RENAL
ALLOGRAFT BIOPSY (2017 UPDATE)
 In 2007 Banff classification of renal allograft; C4d deposition was as
essential feature of antibody mediated rejection (ABMR).

 But with the growing evidence of ABMR (with evidence of microvascular

injury and donor specific antibody [DSA]) in the absence of C4d
deposition, classification is revised in 2013 focusing mainly on redefining
ABMR.

 Additionally, electron microscopic (EM) findings are incorporated in to cg

(chronic glomerulopathy) scoring.

 suggestion is made for EM to be considered in all biopsies done ≥6

months post-transplant and ≥3 months in for-cause post-transplant
allografts to assess early changes of transplant glomerulopathy.
 There is also recognition of overlap between ABMR and
TCMR as mild to moderate arteritis (v1) and severe arteritis
(v2) which was solely part of TCMR in 2007 classification also
features in acute/active ABMR in the latest Banff
classification.

 In the revised classification, ABMR has been classified

as acute/active ABMR and chronic, active ABMR
 2017 REVISIONS TO THE BANFF
CLASSIFICATION
 T CELL–MEDIATED REJECTION

 The Banff 2015 meeting report noted for the first time that chronic active
TCMR may be manifest in the tubulointerstitial as well as in the vascular
compartment.

 However, the current Banff classification does not provide specific criteria
regarding how tubulointerstitial changes should be considered for
diagnosing chronic active TCMR, although semi quantitatively scoring
inflammation in areas of IFTA (i-IFTA) as a histologic lesion have been
established
 T cell–mediated rejection

 Paris group reported good agreement among 3 pathologists in grading i-

IFTA according to the Banff 2015 criteria

 It was independently demonstrated by 2 groups that i-IFTA is associated

with reduced graft survival

 Finding of Mengel et al showed that total cortical inflammation (Banff

tiscore) was more predictive of graft loss than inflammation in
nonsclerotic areas of cortex (Banff i score)

 The DeKAF study showed a strong association between the severity of i-

IFTA and graft loss, far stronger than that of IFTA alone
 T cell–mediated rejection
 The frequency of i-IFTA in protocol biopsy specimens has declined in
the era of tacrolimus-based immunosuppression compared with that of
cyclosporine-based immunosuppression

 Taken together, these findings suggest that i-IFTA, is related to chronic

under immunosuppression and thus can represent Chronic active TCMR
 2015 BANFF

 2017 BANFF
 SCORING AND CLASSIFICATION OF HISTOLOGIC
FINDINGS ON ALLOGRAFT BIOPSY
Prevention of Acute T Cell–Mediated Rejection:
Induction Therapy

 The use of a brief course of potent immunosuppression at the time of

transplantation, referred to as induction therapy

 higher risk patients, such as those with prior sensitization ( high percent
panel reactive antibodies), prior transplantation, or African American
ethnicity, induction therapy is usually combined with standard doses of
immunosuppression to prevent rejection.

 For those with lower risk (living donor kidney recipients, primary kidney
transplants), induction therapy is often employed in an effort to minimize
exposure to maintenance immunosuppression.
 Induction agents

 T cell depleting
1. antithymocyte globulin
2. OKT3 ( anti CD3 ,mouse monoclonal antibody )
3. anti-CD52 ( alemtuzumab ) humanized antibody, suppress both B
cells and T cells.

 T cell non depleting

 Monoclonal humanized interleukin 2 receptor antibody
1. Daclizumab ( no longer available )
2. Basiliximab
Prevention of Acute Antibody-Mediated
Rejection: Desensitization

 The patient who has donor-specific antibodies or is blood type incompatible

to the donor before transplantation has a nearly universal risk for
development of acute antibody-mediated rejection after transplantation.

 Desensitization protocols typically involve removal of preformed antibody

with plasma exchange and suppression of antibody with intravenous
immune globulin (IVIG).

 Or B cell inhibition by rituximab, a humanized anti-CD20 monoclonal

antibody that depletes B cells.
Maintenance Therapy for the Prevention
of Acute Rejection

 Current maintenance immunosuppression most commonly

includes a CNI, an antiproliferative agent, and corticosteroids.

 Cyclosporine has been replaced by tacrolimus as the preferred

CNI in the United States and together with the antiproliferative
agent MMF forms the most common immunosuppressive
regimen in current practice in the United States and most
Western countries.
TREATMENT
Acute T Cell–Mediated Rejection
 directed by the findings on biopsy and the clinical response to pulse
corticosteroids.

 Banff class IA or IB  i/v methylprednisolone, 3 to 5 mg/kg (250 to 500

mg/day), for 3 to5 days

 Banff class IIA, IIB or If inadequate response after corticosteroid pulse

therapy then corticosteroids often must be supplemented with 7- to 14-day
treatment courses of T cell–depleting antibody therapies.

 For patients who are on a maintenance regimen that is not tacrolimus based,
tacrolimus conversion may also be considered in the setting of rejection
Acute Antibody-Mediated Rejection
 Treatment entails removal of the pathogenic immunoglobulins with plasma
exchange and inhibition/suppression of antibody production with IVIG.

 In general, at least five plasma exchange treatments should be administered

with 1 to 2 g/kg total dose of IVIG.

 As IVIG is removed by plasma exchange, a common strategy employed is

to administer IVIG 100 to 200 mg/kg after each exchange.
 For refractory cases

1. Rituximab ( targets B cells at an earlier phase )

2. Bortezomib ( directly inhibits antibody producing plasma

cells )

3. Eculizumab ( humanized monoclonal antibody that blocks

terminal complement activation )
Chronic Rejection (T Cell or Antibody
Mediated)

 No specific intervention has been proven

 consideration should be given to optimizing or enhancing the

maintenance immunosuppression by transitioning to
tacrolimus/MMF therapy or increasing the dose of these agents
if CNI nephrotoxicity is not identified.
The bridge between transplantation & regenerative medicine:

 In the next decades, the field of transplantation will enlarge at least

tenfold, through a hybrid of tissue engineering combined with existing
approaches to lessening the organ shortage

 Gradually, transplantation pathologists will become tissue-( re-)

engineering pathologists with enhanced skill sets to address concerns
involving the use of bioengineered organs

 A new Banff classification was proposed of tissue engineering pathology

to standardize and assess de novo bioengineered solid organs
transplantable success in vivo
Thank You