Landing on the Moon at Last New Pathologic Landscapes In Renal Transplantation with Lymphocytedeplet

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Landing on the Moon at Last!New Pathologic
Landscapes In Renal Transplantation
withLymphocyte-depleting Anti-Rejection
Protocols.

• Kim Solez, M.D.

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The Apollo moon landing of 1969 became the model
for adventure and exploration for a generation.
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A quarter century later in 1992 Cal Stiller
called me about the first MMF biopsiesKim,
Kim, Its like landing on the moon! Like nothing
you have ever seen before!
Calvin R. Stiller, M.D. Chair Canadian Medical
Discoveries Fund Awarded the Order of
Canada Established the Multi-Organ Transplant
Service at UWO in London, Ontario
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Cal Stiller Directed Canadian Multicenter Trials
of Cyclosporine Therapy in Renal Allografts in
1980s - A legendary figure in transplantationIn
1978, Dr. Cal Stiller, who was attending a
transplant meeting in Rome, tried without success
to meet the scientist who had discovered a
promising new anti-rejection drug, to discuss
testing it in London.It was raining as Stiller
finally found a cab in St. Peter's Square.
Nearby, standing in the downpour, was a very wet
Swiss scientist, Jean F. Borel, discoverer of
cyclosporine.They shared the taxi and when the
trip was over, it was decided London would be the
site of clinical trials of the new agent that was
to save countless lives around the world.
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Virtual Pathology Slide

• http//www.telepathology.dcu.ie/vps02.php3 VPS
  Breast Needle Core Study (JMIR 2003)
• http//www.medicine.uiowa.edu/pathology/uarep_hist
  opathology/ Virtual slidebox of histopathology
• http//alf3.urz.unibas.ch/patho/pub/2002-11.htm
  Human Pathology -- Volume 34, No. 10 (October
  2003) -- pages 968-974 Katharina Glatz-Krieger ,
  Dieter Glatz , Michael J. Mihatsch Virtual
  Slide high quality demand, physical limitations
  and affordability.
• http//vmic.unibas.ch

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The ScanScope SystemA Complete Virtual
Microscopy System
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The First MMF Biopsies from the University of
Wisconsin

• Cal Stiller was wrong at that moment in 1992.
  There was nothing unique about the morphologic
  changes seen under the influence of MMF. His
  impression otherwise was due to his unfamiliarity
  with kidney sections embedded in plastic as
  opposed to the usual paraffin embedding.

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Wrong at the time in 1992, but presaging events
of the present.

• However in a more general sense his words
  presaged an inevitable outcome of the development
  of new anti-rejection agents 
• Eventually there will be compounds or strategies
  used which will profoundly alter the pathologic
  landscape and the rules for diagnosis of
  rejection, and such a major morphologic
  development may usher in a new clinical era of
  anti-rejection therapy.

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And the situation now?
So are we there yet? Have we landed on the
moon? Recently several biopsies from lymphocyte
depleting clinical trails have shown a picture of
predominant infiltration by cells of macrophage
monocyte lineage, behaving like rejection
clinically but fulfilling none of the usual
criteria for rejection which require lymphocytes
in tubules and arteries. So perhaps indeed the
rules are changing!
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For the details .
You must be patient!
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Assumptions
The fluidity of the pathological landscape in the
transplanted kidney seems to have been
consistently underestimated, the psychological
"some things never change" mindset of human
beings seems to promote the erroneous view that
some changes in the kidney are unidirectional and
permanent until the end of time. Much persuasive
evidence argues against this.
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Slides from Roz Mannon, Alan Kirk

• These pictures were taken by their pathologist,
  David Kleiner, on 15 Alemtuzumab patients. They
  received Alemtuzumab alone (n6), with rapa
  (n2), or Infliximab and rapa (n4) or with DSG
  and rapa (n3).

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Methods

• All patients enrolled on Alemtuzumab (CAMPATH 1H)
  treatment
• All biopsies taken through day 100
• BANFF 97 criteria used to grade rejections
• Infiltrates immuno-phenotyped using antibodies
  against CD3, CD4, CD8, CD20, CD45, CD45RO, CD68,
  HLA-DR, perforin, granzyme B

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Results - Biopsies

• 53 total biopsies (52 needle bx, 1 wedge)
• Adequacy 32 adequate, 13 subopt, 8 inadeq
• Glomeruli mean 15 (0-45)
• Arteries mean 2 (0-7)

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Clinical/Histological Rejection

• 12/15 patients had an episode of increased Cr to
  at least 1.5x baseline in the first 100 days
• Histologic correlation in 9 patients
• 3 Borderline
• 1 Grade IA
• 3 Grade IB
• 1 Grade IIA
• 1 Grade IIB

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HLA-DR Immunostaining Progression
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Progression of CD68 Infiltration in Alemtuzumab
Treated Recipients
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Focal Macrophage Infiltrate Corresponds to Focal
HLA-DR Expression
HLA-DR
CD68
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Composite of Campath Rejection vs.
Non-Depletional Rejection
CD3
CD68
HLADR
AR
Alem
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Practical Implications for Classification
? Routine staining for CD68 Probably no formal
change in classification until experience with
this new type of rejection grows. Sharing of
morphologic data as important as sharing of
genomics data.