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Schemas for
Histopathological Diagnosis
of Rejection: Kidney
Kim Solez, M.D.
Having fun creating order out of chaos.
Bird formations at edge of Iguassu Falls!
Slide 2
The Banff consensus
process is like that!
Consensus Generation Online, Not Just
Face to Face, Role of Protest.
Slide 3
A good example of successful use
is the World Wide Web
Consortium. “We reject kings,
presidents, and voting. We
believe in rough consensus and
running code.” David Clark (MIT)
“Consensus stops the majority
ruling the minority and is more
consistent with anarchist
principles.” Anarchist FAQ.
ConsensUs: Computer-moderated
Structured Discourse.
http://faculty.washington.edu/gm
obus/consensus.html
FacilitatePro – Online collab. tool.
Consensus Generation Online, Not Just Face
to Face, Role of Protest, Alternate Views.
Slide 4
(Possible if Banff participants knew
I researched this stuff as a
science, my facilitator role would
be less effective. So shhh!
Mum’s the word!)
History of the Banff Classification,
Antecedents before 1991!
Slide 5
 Hard to know where to begin! Always building unusual things,
assisted, inspired by female friends - muses. Three-story shack in
back yard, age 9.
 Lorraine Racusen and I have worked together since she joined me as
a fellow in 1979.
 I left for Chairmanship in Pathology at University of Alberta in
Edmonton in 1987.
 Consensus generation experience: Future of Pathology/Laboratory
Medicine in Canada Consortium, gave Canadian laboratory physicians
political clout.
 ISHLT Heart Classification published in 1990. Lorraine and I
started working on Banff classification in early 1991.
Slide 6
Lorraine Racusen in 1998 and today.
Slide 7
Banff Classification: Milestones
 1991 First Conference
 1993 First Kidney International publication
 1995 Integration with CADI
 1997 Integration with CCTT classification
 1999 Second KI paper. Clinical practice guidelines. Implantation
biopsies, microwave.
 2001 Classification of antibody-mediated rejection
 Regulatory agencies participating
 2003 Genomics focus, ptc cell accumulation scoring
 2005 Gene chip analysis. Elimination of CAN, identification of chronic
antibody-mediated rejection.
 2007 First meeting far from a town called “Banff” – La Coruna, Spain.
Slide 8
BBC Creativity
artist
citizen
“connecting with
audiences”
entrepreneur
We need to connect with
audiences too! If we do it
right we will be changing the
face of medicine!
Someday the percutaneous
biopsy will be replaced by
some superior noninvasive
approach lacking the sampling
error, invasiveness, relative
non-specificity of current
diagnostic assessment.
“Wow, then we will be out of
a job!”
vs.
“Hey that will be really
exciting to practice pathology
like that!”
The replacement of the
invasive percutaneous biopsy
approach by a noninvasive
molecular biology/genomics
approach has analogy in major
political change.
In the 80s one knew that
sometime apartheid in South
Africa would end and the
Berlin Wall would come down
but would that happen in a
day, a year, a decade, a
century?
Also have to be prepared for
changes that could not be
predicted, like the fall of the
Soviet Union. The unexpected
change that alters everything!
We now await similar positive
tumultuous changes in the
field of transplantation.
And life will be better after
than before.
We need the right approach.
"Possess the right thinking, in
this you must never lapse."
Splinter - the ninja master/talking
rat - Teenage Mutant Ninja Turtle
movie (1990)
Banff Conferences on
Allograft Pathology 1991-?
Slide 18
Global consensus generation
while maintaining intellectual
freedom.
Like the mosh pit at a great
rock concert. No partner,
the ultimate in individuality,
dangerous, but
when the music is
good everyone
dances in sync
and life is good.
Slide 21
Two future phases in the relationship between
renal biopsies and management of the renal
allograft recipient
 In the short term, the rigorous quantitation and
internationally-agreed-upon evaluation of renal
biopsies via the Banff Classification, which has proven
itself quite useful in the early post-transplant period,
will be extended to apply fully to late graft biopsies
 In the long term,perhaps years or decades away, the
processes of acute and chronic rejection will be so
well understood mechanistically that a test for specific
markers in blood or urine will completely replace the
percutaneous biopsy as a means of diagnosing these
conditions
Slide 22
Other Causes of Kidney Scarring –
Why “CAN” does us a disservice!
 Hypertensive vascular disease.
 Chronic calcineurin inhibitor toxocity.
 Obstruction.
 Chronic polyoma virus infection.
 Donor origin vascular disease.
 Chronic bacterial infection.
 Recurrent or de novo glomerular disease
 Recurrent or de novo vascular disease.
Slide 23
Chronic scarring in Banff
Classification – CAN gone.

5. Interstitial fibrosis and tubular atrophy (nephron loss),
cause unknown. (Every attempt should be made to assign
cases to known etiologies from other categories 2, 4, and
6.".... With interstitial fibrosis and tubular atrophy"
Assignment to this cause-unknown category is a last resort.)

Grade I Mild interstitial fibrosis and tubular atrophy ( 25% of
cortical area

Grade II Moderate interstitial fibrosis and tubular atrophy
(26-50% of cortical area)

Grade III Severe interstitial fibrosis and tubular atrophy/ loss
( 50% of cortical area)
Slide 24
Antibody Mediated Rejection in
Banff Classification

2. Antibody-mediated rejection Rejection due, at least in
part, to documented anti-donor antibody (‘suspicious for’ if
antibody not demonstrated)

Acute

ATN-like – C4d +, minimal inflammation

Capillary- margination and/or thromboses, C4d +

Arterial – v3, C4d +

Chronic active

PTC basement membrane multilayering. chronic transplant
glomerulopathy (cg 1-3, mm 1-3), C4d +
Slide 25
T Cell Mediated Rejection

4. Acute/active cellular rejection may coincide with
categories 2 and 5 Type (Grade) Histopathological
findings IA Cases with significant interstitial infiltration
(>25% of parenchyma affected) and foci of moderate
tubulitis (>4 mononuclear cells/tubular cross section or
group of 10 tubular cells) IB Cases with significant
interstitial infiltration (>25% of parenchyma affected) and
foci of severe tubulitis (>10 mononuclear cells/tubular
cross-section or group of 10 tubular cells) IIA Cases with
mild to moderate intimal arteritis (v1) IIB Cases with
severe intimal arteritis comprising >25% of the luminal
area (v2) III Cases with ‘transmural’ arteritis and/or
arterial fibrinoid change and necrosis of medial smooth
muscle cells (v3)
Slide 26
Slide 27
Slide 28
Slide 29
More than half of transplant biopsies
in 2005 do not show rejection!
Calcineurin inhibitor toxicity most common
entity.
Scoring/classification system must deal with
all entities, not just rejection!
New onset hyaline arteriolar thickening (ah) a
sign of calcineurin inhibitor toxicity.
Slide 30
Slide 31
Non- Circumferential vs. Circumferential hyalinosis
Slide 32
Quantitative Criteria for Arteriolar Hyaline
Thickening – Proposed new scoring - Mihatsch
0 = No PAS-positive hyaline thickening
1 = PAS-positive hyaline thickening present in only one
arteriole, no circular involvement
2 = PAS-positive hyaline thickening present in more
than one arteriole, but no circular involvement
3 = PAS-positive hyaline thickening with circular
involvement, independent of the number of arterioles
involved
Slide 33
Quantitative Criteria for Arteriolar Hyaline
Thickening – Study of Sis et al. (Banff ’05)
 The severity of ah scored by both criteria, was significantly correlated
with serum creatinine at biopsy (p<0.05). Using Banff criteria, the
mean rate of pairwise agreement was 57.8% with an overall kappa
value of 0.39. With the newly proposed criteria, the mean rate of
pairwise agreement was 70% and the overall kappa value was 0.51.
The mean interslide variation rates using Banff criteria and the new
criterion were 30.7% and 36.7%, respectively.
 Conclusion: While Banff and the recently proposed criteria for ah
scoring resulted in fair to moderate interobserver agreement, the new
criterion seems to be more objective and results in better
interobserver reproducibility. There is a substantial variation in the
distribution and severity of arteriolar lesions in an individual biopsy,
therefore, evaluation of more than one section is crucial to determine
the severity of arteriolar damage more accurately.
Slide 34
Specimen Adequacy – (Banff ’97,
‘05) Minimum Sampling,procedures
 Unsatisfactory – No glomeruli or arteries
 Marginal – 7 glomeruli with an artery
 Adequate – 10 or more glomeruli with at least two
arteries
 Minimum Sampling: 7 slides – 3 H&E, 3 PAS or
silver stains, and 1 trichrome
 Must do C4d!
Slide 35
Slide 36
DNA Microarrays
 Transcription of many thousands of genes can be
measured on one tiny chip
 Define mechanisms of rejection and other
complications that arise in transplant kidneys
Slide 37
Affymetrix
GeneChip®
probe array. Image
courtesy of Affymetrix.
Slide 38
From DNA to Protein
DNA synthesis
(replication)
DNA
RNA synthesis
(transcription)
microarrays
RNA
protein synthesis
(translation)
real-time RT-PCR
Protein
amino acids
Slide 39
Tx3
Tx9
Tx10
Tx6
Tx2
AR5
NR5
AR7
AR1
AR6
AR4
AR3
AR2
Tx7
NR3
NR2
NR1
Tx5
Tx4
Tx8
Tx1
CTL genes in human kidney biopsies
normalized vs well functioning transplants
Slide 40
Current Research
 Microarray analysis of both human & mouse
kidney transplants with rejection and other
complications
 Correlate with Clinical data & Banff lesions
Slide 41
Human and Mouse
similar genes and similar development
The Cell 2002.
Slide 42
Outlook
 Discover patterns in mouse and human kidney tx

define molecular basis of Banff lesions

develop an array-based Banff classification

identify blood patterns correlating with biopsy patterns
 Validate patterns in large scale study

USA, Canada centers c.f. Matas-Halloran consortium
 Develop new gold standard

consensus in Banff process

recognition by FDA: endpoints
 Develop commercial opportunities: IP, products, services
 Extend
 Other organ and tissue transplants
 Autoimmune and infectious diseases e.g. hepatitis c
Slide 43
Become part of the ongoing discussions
Contact: [email protected] or
[email protected]
Slide 44
Future Banff Meetings:
 2007 - La Coruna, Spain
 2009 - Whistler, British Columbia, Canada
 2011 - Paris, France
 2013 - Banff, Alberta, Canada
 2015 - Stockholm, Sweden