Dr. Kim Solez presents "Renal transplant pathology and future perspectives. Nephrology core lecture series Fall 2016, on October 5, 2016, at the University of Alberta, Edmonton, Alberta, Canada. Copyright (c) 2016, JustMachines Inc.

1. Kim Solez, MD

2. The Importance of Rooms and Places in the
Generation of Important Ideas and Actions.
Pathology Library, Johns Hopkins Hospital

3. Importance of Rooms and Places (Paris!) in
Generation of Important Ideas and Actions.

4. Objectives of this Presentation
 One hundred and thirty year history of transplant
pathology, 100 years back, 30 years forward.
 To present a general approach to transplant pathology,
special stains, and adjunctive procedures.
 To introduce you to the concept of tissue engineering
pathology and show its evolution from and relation to
transplant pathology.
 To present transplant pathology and tissue engineering
pathology in an accessible way so people who do not
regularly think about anatomical pathology like aviator
Charles Lindberg (1902-1974) could understand it.
 To introduce you to prototypical people from the future
your offspring may resemble someday (in 2045)!

5. Alexis Carrel/Charles Lindberg
 In February 2002, the
Medical University of South Carolina at Charleston in celebration
of Lindberg’s 100th birthday established the Lindberg-Carrel
Prize, given to major contributors to “development of perfusion
and bio reactor technologies for organ preservation and growth”.
M. E. DeBakey and nine other scientists received the prize, a
bronze statuette expressly created for the event by the Italian
artist C. Zoli and named “Elisabeth”, after Elisabeth Morrow, who
died as a result of heart disease. Lindberg was disappointed that
contemporary medical technology could not provide an artificial
heart pump that would allow for for heart surgery on Elisabeth
and that led to the first contact between Carrel and Lindberg.

6. Alexis Carrel
In 1902, Alexis Carrel started the modern field of transplantation
by describing surgical vascular anastomoses for transplantation,
work that eventually resulted in his receiving the Nobel Prize.
The first transplant pathology paper was published 13 years
later: Hesselberg C: A comparison of autoplastic and
homeoplastic transplantation of thyroid tissue in the guinea pig,
J. Exp. Med. 1915 Feb 1:21(2):164-178.
2015 was the centennial of this first publication in
transplantation pathology.

7. Robert Heptinstall/Ken Porter
My mentor was Robert Heptinstall. In the early editions of his
iconic textbook Kendrick Porter wrote the chapters on
transplantation pathology. Porter collaborated for more than
thirty years with transplant pioneer Thomas Starzl.

8. 25 years ago Kim Solez and Lorraine Racusen
Directed the First Banff Meeting Which Created
the Banff Classification of Transplant Pathology

9. BANFF CLASSIFICATION STANDARD
FOR TRANSPLANT BIOPSY
INTERPRETATION
Began in kidney (Solez et al. 1993), and was then
extended to liver, pancreas, composite tissue grafts
etc. Meetings also consider heart, lung, small
bowel.
Uses semiquantitative lesion scoring 0-3+ and
diagnostic categories. A pathologic classification of
all pathologic changes, not just rejection.

10. Polys in peritubular capillaries in antibody-mediated rejection.

13. The Banff Classification Deals with All Pathologic
Conditions, Not Just Rejection. For Genomic Approaches
to Take Off They Also Need to Deal with All Conditions,
Be Affordable, and Capable of Being Standardized.
At present the Banff Classification uses mainly
techniques from 30-60 years ago. More modern
approaches would be welcomed!
(Experts in pathology can skip next 12 slides, next 12
minutes.)
Affymetrix GeneChip® probe array.
Image courtesy of Affymetrix.

14. Diseases Which Commonly Recur Following
Transplantation
FSGS
Membranous Glomerulopathy
IgA Nephropathy
MPGN I
MPGN II (Dense Deposit Disease,
C3 Glomerulopathy)
SLE

15. Diseases Which Commonly Appear De Novo
Following Transplantation
Diabetic Nephropathy
Anti-GBM Nephritis in Alport Syndrome
IgA Nephropathy
Membranous Nephropathy
FSGS
Post-Infectious GN

16. Transplanted Kidney is Still A Kidney, Can
Be Affected By Any of the Diseases that
Affect Native Kidneys Such As Post-
Infectious Glomerulonephritis

17. Transplanted Kidney is Still A Kidney, All
Four Compartments Should Be Described,
With Number of Glomeruli and Vessels.
Tubules
Interstitium
Glomeruli
Vessels
Light microscopy, electron microscopy,
and immunofluorescence are standard.

19. Transplanted Kidney is Still A Kidney,
Standard Special Stains Should Be
Employed.
H&E, PAS,
Silver Stain,
Trichrome.
Martius Scarlet
for Fibrin.
Membranous GN
This case shows “spikes” on silver stain.

26. BV Virus Nephropathy, Nuclear Inclusions,
SV40 stain.
http://ndt.oxfordjournals.org/content/15/3/32
4/F1.expansion

28. The Influences Shaping This Presentation
 Kim Solez, Korey C. Fung, Khouloud Saliba, Victoria
Sheldon, James F. Burdick, William H. Fissell, Anthony J.
Demetris, and Lynn D. Cornell - Authors of the tissue
engineering pathology manuscript in preparation.
 Jason Wertheim, Harald Ott, and Shuvo Roy, regenerative
medicine experts who teach in my Technology and Future
of Medicine course LABMP 590
http://www.singularitycourse.com

29. Stem Cell Technologies on Google
Trends – News Headlines and Forecast

30. Current transplant protocols reach
fewer than 10% of those in need.

31. Worldwide 1.2 million people are in
need of transplantation for end
stage organ failure. Current
transplant protocols reach fewer
than 10% of this number.
Regenerative medicine can save the
remaining 90%, over one million
people annuallly!

32.  ViaCyte Announces Highly
Anticipated Encapsulation Clinical
Trial Site Expansion into Canada
 JDRF-funded researcher, Dr. James Shapiro
will be the lead investigator at the Canadian
site. TORONTO, July 29, 2015 -- ViaCyte, Inc.
announced the opening of a second site in its
Phase 1/2 trial for Type I Diabetes which utilizes
PEC-01™ pancreatic progenitor cells and the
proprietary Encaptra® drug delivery system which
is designed to protect the transplanted cells from a
patient’s immune system.
Regenerative Medicine Already Here!
Viacyte Trial for Diabetes Therapy.

33. Double Think: Stem Cells are Greatest Hope
and Greatest Hype, Stem Cell Tourism
Estimated to be $3 Billion a Year Industry and
Growing, with More than 700 Clinics Worldwide
 Mason C et al. Regen Med. 2011 May;6(3):265-72. doi:
10.2217/rme.11.28. Cell therapy industry: billion dollar
global business with unlimited potential.
 Timothy Caulfield - Stem Cell Tourism June 2015
https://www.youtube.com/watch?v=B0r89nMtg10

34. Channel the Energy of the Regret Felt About
Stem Cell Hype, Stem Cell Tourism, and Stem
Cell Fraud into Support for the Enormous
Benefit for Humanity that Can Come from Well-
Conducted Stem Cell Research.
 My Avoca Central School high school graduation speech
“Youth Rebellion” many years ago talked about
sublimation, rechanneling the raw energy of primitive
instincts into productive pursuits. The same concept
applies here. Channel the emotional energy we feel about
stem cells into support of high quality stem cell research.

35. The Positive Aspects of Stem Cell Therapies,
The True Hope, Has Potential to Reverse Three
Looming Problems in Medicine:
1. The loss of “luster” in transplantation.
2. Workforce problems in nephrology due to lack of appeal
to young people/potential trainees worldwide.
3. Technological unemployment in medicine due to

36. Nephrologists & Renal Pathologists May
Be Only People Still Employed in 2045!

37. Sina Marzoughi Found An Image
Showing What 2045 Will Look Like

38. What Human Beings Will Look Like in
2045!

39. Banff Classification of Kidney Transplant Pathology
Histologic criteria for the diagnosis of rejection and
other conditions in the transplanted kidney, began
1991, updated and expanded every two years in
consensus meeting.

40. Banff Lesion Scoring: Sign of Educated Tx Pathologist
imprimatur 1. The formula (=‘let it be printed’), signed by an official
authorizing printing of a book;hence as sb. an official license to print.
The Oxford English Dictionary (2nd. ed.)
Banff lesion scoring: g cg i ci t ct v cv ah mm ptc C4d

41. Significance of ‘Banff papers’
• More than 5,000 citations of the 14 Banff meeting reports
• 977 Banff / Transplantation papers in PubMed
• Banff 2003 meeting report (ABMR criteria) = most cited AJT
paper
• 3 Banff meeting reports are among the top 4 cited AJT articles

42. Tissue Engineering Pathology Added Soon!
•

43. The Banff Process
Consensus communication in renal transplantation
a
The Banff
lesions
g, i, t, v - score
The Banff
community
Pathologists
Nephrologists
Tx-Surgeons
Lab-Medicine
established by
consensus in 1991
The Banff
classification
Current consensus for
diagnostics
moderated
Banff meetings
thesis-antithesis-synthesis
tentative
thresholds
participate
refinementBanff Working
Groups
Feedback concerning weaknesses and strengths by results
from independent research
New members
Biostaticians
Molecular Biologists
“Omics”-specialists
Off-springs
Liver
Pancreas
Lung, Heart
CTA

44. Organizational structure of the Banff Foundation For Allograft Pathology
Board of Trustees:
K. Solez (Chair), L. Racusen, D. Glotz, J. Demetris, M. Mengel, M. Mihatsch, D. Seron
2015 Local Conference
chair: Michael Mengel
Organ Steering committee
Chairs:
Composite tissues: Linda Cendales
Heart : Patrick Bruneval
Kidney: Mark Haas
Liver: Jake Demetris
Lung: William Wallace and Carol
Farver
Pancreas: Cinthia Drachenberg
Banff Working Group (BWG) Leads:
Molecular transplantation pathology: Michael Mengel, Banu Sis
Isolated v-lesions: Banu Sis, Ed Kraus
Quality assurance in transplantation diagnostics: Michael Mengel and
Parmjeet Randhawa
C4d-negative ABMR: Mark Haas, Banu Sis, Alexandre Loupy
Fibrosis scoring: Robert Colvin, Brad Farris, Michael Mengel
Digital Pathology in Transplantation: Jake Demetris
2015 Scientific program committee:
Alex Loupy (Chair)
Mark Haas, Banu Sis, Kathryn Tinkham, Candice
Rofousse, Chris Bellamy, Lynn Cornell, Carmen
LeFaucheur
Composite tissues: Linda Cendales
Heart : Patrick Bruneval
Liver: Jake Demetris
Lung: William Wallace and Carol Farver
Pancreas/Islets: Cinthia Drachenberg and John
Papadimitriou
Secretary/Treasurer:
Michael Mengel
funding
collaboration
reports to
reports to
collaboration
collaboration
reports to
collaboration
progress
reports to Budged
proposal and
accountability
for meeting
costs
support

47. The World is Changing Rapidly!

48. The World is Changing Rapidly!

49. The World is Changing Rapidly!

50. The World is Changing Rapidly!

51. Canadian Data on Public Interest in
Regenerative Medicine

52. The Technological
Singularity

53. Podocytes go wandering into the
interstitium! Song et al.

54. Many problems with stem cell generate
organs not being discussed. Do not exclude
yourself from the conversation in this area!

55. Many problems with stem cell generate
organs not being discussed. Need to get
those conversations to happen.
 The recellularized organ clots like crazy, impossible to
regenerate more than 80% of endothelial surface. Artificial
heparinized surface not fenestrated. Cell traffic abnormal.
 Hard to get right types of cells to right places.
 Podocytes seems to be terminally differentiated cells,
when attempt to culture them they turn into different type of
cell.
 Kidney progenitor stem cell difficult to identify, kidney work
has lagged behind.
 Easy to make stem cell generated kidneys that lack loop of
Henle. Could produce lethal polyuria. What is “function”?
 Many old fashioned questions of physiology about how the
stem cell generated organ works, not just true for kidney,
true for every organ. Logo still works for future!

56.  Transplant
pathologists will also
become tissue
engineering
pathologists,
pathologists who
analyze organs grown
from stem cells. This is
not something beyond
us, we can adapt to a
work life that includes
stem cells. Someone
needs to cross the
disciplines.

57.  Many of the questions
that need to be posed
about stem cell
generated organs are old
fashioned questions,
intact nephron
hypothesis, cell
regeneration, stunned
myocardium, contraction
band necrosis etc. Use
your nostalgia! Stimulate
conversations between
stem cell researchers and
transplant physicians.

58. Beginning at the Very Beginning!
 “We are at the very beginning of time for the human race. It
is not unreasonable that we grapple with problems. But
there are tens of thousands of years in the future. Our
responsibility is to do what we can, learn what we can,
improve the solutions, and pass them on.” - Richard P.
Feynman, (1918-1988) Physicist, Nobel Prize Winner
 "The sense of the future is behind all good policies. Unless
we have it, we can give nothing either wise or decent to
the world." - Snow CP, (1905-1980) Novelist and
Philosopher.
 "To a large extent, the future lies before us like a vast
wilderness of unexplored reality. The God who created and
sustained the evolving universe through eons of progress
and development has not placed our generation at the tag
end of the creative process. God has placed us at a new
beginning. We are here for the future." - Sir John
Templeton (1912-2008 ), Financial Analyst

59. Beginning at the Very Beginning!
 Like 1851 when the first International Classification of
Diseases was presented in the Grand Exhibition of
Technology at London’s Crystal Palace
 Emphasis was on cause of death

60. Classification focus is on sustaining life.
 Native and transplanted organ diseases can also occur in
tissue engineered organs. Includes ex vivo repair.
 The classification focus of the new pathology discipline of
Regenerative Medicine/Tissue Engineering Pathology is
exactly the opposite of traditional classification of disease
which starts with causes of death. In Regenerative
Medicine/Tissue Engineering Pathology the emphasis is on
the degree of normality necessary to sustain life:
 Normal,
 Abnormalities of unknown functional significance,
 Abnormalities which will impair the main functions of the
organ,
 Abnormalities leading to severe organ dysfunction where
function may not be great enough to sustain life.

61. Song et al. Interstitium, vessels, and glomeruli with missing cells.
Disordered tubule formation with multiple interconnecting
lumina of differing sizes. “Can you really call this a kidney?” (Yes!)

62. Song et al. In addition to missing cells and disordered structures,
you have cells in the wrong places. Podocytes in the interstitium.

63. Focus of Tissue Engineering Pathology
 The specific questions become: 1. Are too many cells
missing, 2. Are too many cells in in the wrong places? 3.
Are too many structures missing (long loops of Henle)?
4. Is there too much endothelial disruption for the organ
to be properly perfused? 5. What are the risks of
neoplastic transformation?
 Classification categories should be not one-off, but
reproducible, generalizable.
 Tissue engineering pathology has been up to now really
dull (articles since 1967), since most reports were of
scaffolds with no inflammatory reaction "Move along,
nothing to see here" pathology, but from today becomes
really exciting with novel morphological changes and
lives hanging in the balance, clinical trials starting!
 Banff Classification of Tissue Engineering Pathology
major focus of 2019 Banff meeting in Pittsburgh..