Landing on the Moon at Landing on the Moon at Last!Last!

New Pathologic New Pathologic Landscapes In Renal Landscapes In Renal Transplantation withTransplantation with

Lymphocyte-depleting Lymphocyte-depleting Anti-Rejection Protocols.Anti-Rejection Protocols.

Kim Solez, M.D.Kim Solez, M.D.

The Apollo The Apollo moon landing moon landing

of 1969 of 1969 became the became the model for model for adventure adventure

and and exploration exploration

for a for a generation.generation.

A quarter century A quarter century later in 1992 Cal later in 1992 Cal Stiller called me Stiller called me about the first about the first MMF biopsies:MMF biopsies:

“Kim, Kim, It’s like “Kim, Kim, It’s like landing on the landing on the

moon! Like moon! Like nothing you have nothing you have

ever seen before!”ever seen before!”

Calvin R. Stiller, M.D.ChairCanadian Medical Discoveries FundAwarded the Order of CanadaEstablished the Multi-Organ Transplant Service at UWO in London, Ontario

Calvin R. Stiller, M.D.ChairCanadian Medical Discoveries FundAwarded the Order of CanadaEstablished the Multi-Organ Transplant Service at UWO in London, Ontario

Cal Stiller Directed Cal Stiller Directed Canadian Canadian Multicenter Trials Multicenter Trials of Cyclosporine of Cyclosporine Therapy in Renal Therapy in Renal Allografts in 1980sAllografts in 1980s - A legendary figure in - A legendary figure in transplantationtransplantationIn 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.

Slide Slide 55

Virtual Pathology SlideVirtual Pathology Slide

http://www.telepathology.dcu.ie/vps02.http://www.telepathology.dcu.ie/vps02.php3php3 VPS Breast Needle Core Study (JMIR 2003)

http://http://www.medicine.uiowa.edu/pathology/www.medicine.uiowa.edu/pathology/uarep_histopathologyuarep_histopathology// Virtual slidebox of histopathology Virtual slidebox of histopathology

http://alf3.urz.unibas.ch/patho/pub/20http://alf3.urz.unibas.ch/patho/pub/2002-11.htm02-11.htm Human Pathology -- Volume 34, Human Pathology -- Volume 34, No. 10 (October 2003) -- pages No. 10 (October 2003) -- pages 968-974 968-974 Katharina Glatz-Krieger , Katharina Glatz-Krieger , Dieter Glatz , Michael J. Mihatsch Dieter Glatz , Michael J. Mihatsch Virtual Slide: high quality demand, Virtual Slide: high quality demand, physical limitations and physical limitations and affordability.affordability.

http://vmic.unibas.chhttp://vmic.unibas.ch

Slide Slide 66

The ScanScope SystemThe ScanScope SystemA Complete Virtual Microscopy SystemA Complete Virtual Microscopy System

The First MMF Biopsies The First MMF Biopsies from the University of from the University of

WisconsinWisconsin

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

Wrong at the time in 1992, Wrong at the time in 1992, but presaging events of the but presaging events of the present.present.However in a more general sense his However in a more general sense his words presaged an inevitable outcome of words presaged an inevitable outcome of the development of new anti-rejection the development of new anti-rejection agents: agents: 

Eventually there will be compounds or Eventually there will be compounds or strategies used which will profoundly strategies used which will profoundly alter the pathologic landscape and the alter the pathologic landscape and the rules for diagnosis of rejection, and such rules for diagnosis of rejection, and such a major morphologic development may a major morphologic development may usher in a new clinical era of anti-usher in a new clinical era of anti-rejection therapy.rejection therapy.

And the situation now?And the situation now?So are we there yet? Have we landed So are we there yet? Have we landed on the moon?on the moon?

Recently several biopsies from Recently several biopsies from lymphocyte depleting clinical trails lymphocyte depleting clinical trails have shown a picture of predominant have shown a picture of predominant infiltration by cells of macrophage infiltration by cells of macrophage monocyte lineage, behaving like monocyte lineage, behaving like rejection clinically but fulfilling none rejection clinically but fulfilling none of the usual criteria for rejection of the usual criteria for rejection which require lymphocytes in tubules which require lymphocytes in tubules and arteries. So perhaps indeed the and arteries. So perhaps indeed the rules are changing!rules are changing!

So are we there yet? Have we landed So are we there yet? Have we landed on the moon?on the moon?

Recently several biopsies from Recently several biopsies from lymphocyte depleting clinical trails lymphocyte depleting clinical trails have shown a picture of predominant have shown a picture of predominant infiltration by cells of macrophage infiltration by cells of macrophage monocyte lineage, behaving like monocyte lineage, behaving like rejection clinically but fulfilling none rejection clinically but fulfilling none of the usual criteria for rejection of the usual criteria for rejection which require lymphocytes in tubules which require lymphocytes in tubules and arteries. So perhaps indeed the and arteries. So perhaps indeed the rules are changing!rules are changing!

For the details ….For the details ….

You must be patient!You must be patient!You must be patient!You must be patient!

AssumptionsAssumptionsThe fluidity of the pathological The fluidity of the pathological landscape in the transplanted landscape in the transplanted kidney seems to have been kidney seems to have been consistently underestimated, the consistently underestimated, the psychological "some things never psychological "some things never change" mindset of human beings change" mindset of human beings seems to promote the erroneous seems to promote the erroneous view that some changes in the view that some changes in the kidney are unidirectional and kidney are unidirectional and permanent until the end of time. permanent until the end of time. Much persuasive evidence argues Much persuasive evidence argues against this.against this.

The fluidity of the pathological The fluidity of the pathological landscape in the transplanted landscape in the transplanted kidney seems to have been kidney seems to have been consistently underestimated, the consistently underestimated, the psychological "some things never psychological "some things never change" mindset of human beings change" mindset of human beings seems to promote the erroneous seems to promote the erroneous view that some changes in the view that some changes in the kidney are unidirectional and kidney are unidirectional and permanent until the end of time. permanent until the end of time. Much persuasive evidence argues Much persuasive evidence argues against this.against this.

Slides from Roz Mannon, Slides from Roz Mannon, Alan KirkAlan Kirk

These pictures were taken by their pathologist, These pictures were taken by their pathologist, David Kleiner, on 15 Alemtuzumab patients. They David Kleiner, on 15 Alemtuzumab patients. They received Alemtuzumab alone (n=6), with rapa (n=2), received Alemtuzumab alone (n=6), with rapa (n=2), or Infliximab and rapa (n=4) or with DSG and rapa or Infliximab and rapa (n=4) or with DSG and rapa (n=3).(n=3).

Slide Slide 1313

MethodsMethods

All patients enrolled on Alemtuzumab (CAMPATH All patients enrolled on Alemtuzumab (CAMPATH 1H) treatment1H) treatment

All biopsies taken through day 100All biopsies taken through day 100

BANFF 97 criteria used to grade rejectionsBANFF 97 criteria used to grade rejections

Infiltrates immuno-phenotyped using antibodies Infiltrates immuno-phenotyped using antibodies against CD3, CD4, CD8, CD20, CD45, CD45RO, against CD3, CD4, CD8, CD20, CD45, CD45RO, CD68, HLA-DR, perforin, granzyme BCD68, HLA-DR, perforin, granzyme B

Slide Slide 1414

Results - BiopsiesResults - Biopsies

53 total biopsies (52 needle bx, 1 wedge)53 total biopsies (52 needle bx, 1 wedge)

Adequacy: 32 adequate, 13 subopt, 8 inadeqAdequacy: 32 adequate, 13 subopt, 8 inadeq

Glomeruli: mean 15 (0-45)Glomeruli: mean 15 (0-45)

Arteries: mean 2 (0-7)Arteries: mean 2 (0-7)

Slide Slide 1515

Clinical/Histological RejectionClinical/Histological Rejection

12/15 patients had an episode of increased Cr to 12/15 patients had an episode of increased Cr to at least 1.5x baseline in the first 100 daysat least 1.5x baseline in the first 100 days

Histologic correlation in 9 patients:Histologic correlation in 9 patients:

3 Borderline3 Borderline

1 Grade IA1 Grade IA

3 Grade IB3 Grade IB

1 Grade IIA1 Grade IIA

1 Grade IIB1 Grade IIB

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Day 0Day 0

Day 14Day 14

Day 21Day 21

HLA-DR Immunostaining ProgressionHLA-DR Immunostaining Progression

Slide Slide 1717

Day 0 Day 14

Day 22Day 21

Progression of CD68 Infiltration in Alemtuzumab Treated Progression of CD68 Infiltration in Alemtuzumab Treated RecipientsRecipients

Slide Slide 1818

Focal Macrophage Infiltrate Corresponds to Focal HLA-DR Focal Macrophage Infiltrate Corresponds to Focal HLA-DR ExpressionExpression

CD68 HLA-DR

Slide Slide 1919

AR

Alem

CD3 CD68 HLADR

Composite of Campath Rejection vs. Composite of Campath Rejection vs. Non-Depletional RejectionNon-Depletional Rejection

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Practical Implications for ClassificationPractical Implications for Classification

? Routine staining for CD68? Routine staining for CD68

Probably no formal change in classification Probably no formal change in classification until experience with this new type of until experience with this new type of rejection rejection grows.grows.

Sharing of morphologic data as important as Sharing of morphologic data as important as sharing of genomics data.sharing of genomics data.

? Routine staining for CD68? Routine staining for CD68

Probably no formal change in classification Probably no formal change in classification until experience with this new type of until experience with this new type of rejection rejection grows.grows.

Sharing of morphologic data as important as Sharing of morphologic data as important as sharing of genomics data.sharing of genomics data.