Schemas for Histopathological Diagnosis of Rejection: Kidney Kim Solez, M.D.

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Schemas for Histopathological Diagnosis of
Rejection Kidney Kim Solez, M.D.
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Having fun creating order out of chaos. Bird
formations at edge of Iguassu Falls!

• The Banff consensus process is like that!

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Consensus Generation Online, Not Just Face to
Face, Role of Protest.

• 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/gmobus/co
  nsensus.html
• FacilitatePro Online collab. tool.

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Consensus Generation Online, Not Just Face to
Face, Role of Protest, Alternate Views.

• (Possible if Banff participants knew I researched
  this stuff as a science, my facilitator role
  would be less effective. So shhh! Mums the
  word!)

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History of the Banff Classification, Antecedents
before 1991!

• 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.

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Lorraine Racusen in 1998 and today.
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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.

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BBC Creativity
artist
citizen

• connecting with
• audiences

entrepreneur
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We need to connect with audiences too! If we do
it right we will be changing the face of
medicine!
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Someday the percutaneous biopsy will be replaced
by some superior noninvasive approach lacking the
sampling error, invasiveness, relative
non-specificity of current diagnostic
assessment.
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Wow, then we will be out of a job!vs.Hey
that will be really exciting to practice
pathology like that!
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The replacement of the invasive
percutaneous biopsy approach by a noninvasive
molecular biology/genomics approach has analogy
in major political change.
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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?
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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!
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We now await similar positive tumultuous changes
in the field of transplantation.And life will
be better after than before.
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We need the right approach.
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"Possess the right thinking, in this you must
never lapse."Splinter - the ninja
master/talking rat - Teenage Mutant Ninja Turtle
movie (1990)
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Banff Conferences on Allograft Pathology 1991-?
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Global consensus generation while maintaining
intellectual freedom.
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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.

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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

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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.

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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)

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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

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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 (gt25 of
  parenchyma affected) and foci of moderate
  tubulitis (gt4 mononuclear cells/tubular cross
  section or group of 10 tubular cells) IB Cases
  with significant interstitial infiltration (gt25
  of parenchyma affected) and foci of severe
  tubulitis (gt10 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 gt25 of the luminal area (v2) III
  Cases with transmural arteritis and/or arterial
  fibrinoid change and necrosis of medial smooth
  muscle cells (v3)

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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.

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Non- Circumferential vs. Circumferential
hyalinosis
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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

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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 (plt0.05). 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.

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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 HE, 3 PAS or
  silver stains, and 1 trichrome
• Must do C4d!

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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

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Affymetrix GeneChip probe array. Image courtesy
of Affymetrix.
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From DNA to Protein
DNA synthesis (replication)
DNA
RNA synthesis (transcription)
microarrays
RNA
protein synthesis (translation)
real-time RT-PCR
Protein
amino acids
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CTL genes in human kidney biopsies normalized vs
well functioning transplants
Tx1 Tx8 Tx4 Tx5 NR1 NR2 NR3 Tx7 AR2 AR3 AR4 AR6 AR
1 AR7 NR5 AR5 Tx2 Tx6 Tx10 Tx9 Tx3
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Current Research

• Microarray analysis of both human mouse kidney
  transplants with rejection and other
  complications
• Correlate with Clinical data Banff lesions

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Human and Mouse similar genes and similar
development
The Cell 2002.
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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

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Become part of the ongoing discussions

• Contact Kim.Solez_at_UAlberta.ca or
  Michele.Hales_at_UAlberta.ca

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Future Banff Meetings

• 2007 - La Coruna, Spain
• 2009 - Whistler, British Columbia, Canada
• 2011 - Paris, France
• 2013 - Banff, Alberta, Canada
• 2015 - Stockholm, Sweden