Kim Solez Chronic rejection - current concepts and newer perspectives, presentation for Tx Update meeting in Ahmedabad, India, September 28th, 2012.

1. Chronic rejection- current
concepts and newer perspectives
Kim Solez, M.D.

2. Mentor influences: Smelling the Flowers
Meetings – Not A Waste of Time!
 “You should take time to smell the flowers.” (1972)
 “Medical meetings are just social events. Nothing important happens at
them. They are a waste of time. You should avoid organizing medical
meetings.” - Robert H. Heptinstall, M.D.
 I did not follow the latter advice. Physicians need to be socialized,
humanized. Organized my first Acute Renal Failure Symposium in 1982,
published as a book in 1984 Acute Renal Failure: Correlations Between
Morphology and Function. Many other meetings since then. Banff
meetings began 1991, continued every two years since then.
 Technology and Future of Medicine course began 2011, mixes science
and humanities, technological Singularity, futurism, exponential change.
 High impact education changes human behavior, like advertising does. In
the area of late biopsies and the scarred allograft in Banff consensus
process we have been working to change behavior for some time.
 Evolution of thinking from chronic rejection, to chronic allograft
nephropathy, to interstitial fibrosis and tubular atrophy.

3. An Evolution in Which We Find Evidence of the
Human Tendency to Try to Believe in Specific Entities
There Is No Evidence For!
 Originally all late scarring processes in the transplanted kidney were
called “chronic rejection”.
 In order to stop perpetuating the idea that everything was chronic rejection
we coined the term “chronic allograft pathology” – “CAN” for these
nonspecific chronic changes.
 People seized on CAN as a new entity, devised strategies to prevent it,
animal models for it etc. Soon there were hundreds of articles about CAN.
 To stop this artificial glorification of nonspecific changes as a new entity
we eliminated the phrase CAN and used the descriptive terms interstitial
fibrosis and tubular atrophy instead - IFTA.

4. Number of CAN Articles Per Year

5. Elaborate Schemes Explaining CAN At The
Height of Its Popularity

6. Elaborate Schemes Explaining CAN At The
Height of Its Popularity

7. In the early post-transplant biopsy, many specific
lesions which provide evidence of clinically
significant processes. Biopsy is helpful.
 Tubulitis – Rejection
 Intimal arteritis – Rejection
 Transmural arteritis – Rejection
 Hyaline arteriolar change – Calcineurin inhibitor toxicity
 Glomerulitis, peritubular capillary cell accumulation, C4d
positivity – Antibody-mediated rejection

8. Slide 8

9. Slide
9

10. Slide
10

11. Slide
11

12. Slide 12

13. Slide 13

14. Slide
14

15. Slide 15

16. In the late post-transplant biopsy, many non-
specific lesions. Often biopsy is not helpful.
 Interstitial fibrosis, tubular atrophy – Non-specific.
 Fibrous intimal thickening – Non-specific
 Chronic transplant glomerulopathy – Antibody-mediated
rejection, or thrombotic microangiopathy or MPGN
(hepatitis related)
 True chronic rejection vascular changes, with intimal
arteritis, elastica breaks etc. – rare.
 Peritubular capillary multilayering on electron
microscopy – usually chronic antibody mediated
rejection.

17. Slide
17

18. Slide
18

20. Sclerosing Rejection:
“neo-media” formation supe
imposed on donor disease
(0.9 years post grafting)
PAS stain
Elastic stain

22. Transplant Glomerulitis and Glomerulopathy
4.5 years post transplantation

23. Slide
23

24. INTERSTITIAL FIBROSIS AND TUBULAR ATROPHY (IFTA)
IN RENAL ALLOGRAFTS

25. IFTA WITH INFLAMMATION – MENGEL ET AL.

26. INFILTRATES IN AREAS OF FIBROSIS AND TUBULAR ATROPHY

27. perivascular
SUBCAPSULAR

28. NODULAR INFILTRATES

29. BANFF I- AND TOTAL I-SCORE AND DIAGNOSIS: INTERSTITIAL INFILTRATES ARE
NOT DISEASE SPECIFIC
* i-score total i-score
*p<0.05
*
*
% cortex with infiltrate
*
*
*

30. INFILTRATES IN BIOPSIES FOR CAUSE ARE TIME
DEPENDENT
100
fibrosis/atrophy
90 i-Banff
i-IFTA
80
70
% cortex involved
60
50
40
30
20
10
0
1 6 11 16 21 26 31 36 41 46 51 56 61 66 71 76 81 86 91 96 101 106 111 116 121 126
3 8 27 79 246
months months months months months
129 biopsies ordered by time post TX
Mengel et al. Am J Transplant. 2009 Jan;9(1):169-78.

31. Coming Full Circle – In the Original Banff Paper
.
The Editor Insisted We Put Everything About the
Non-Specificity of Interstitial Infiltrates at the
Beginning “So The Message Will Reach Even
Those Who Only Read The First Page!”
 Solez, K., Axelsen, R.A., Benediktsson, H., Burdick, J.F.,
Cohen, A.H., Colvin, R.B.,Croker, B.P., Droz, D., Dunnill,
M.S., Halloran, P.F., Hayry, P., Jennette, J.C., Keown, P.A.,
Marcussen, N., Mihatsch, M.J., Morozumi, K., Myers, B.D.,
Nast, C., Olsen, S., Racusen, L.C., Ramos, E.L., Rosen,
S., Sachs, D.H., Salomon, D.R., Sanfilippo, F., Verani, R.,
von Willebrand, E., and Yamaguchi, Y.: International
standardization of nomenclature and criteria for the
histologic diagnosis of renal allograft rejection : the Banff
working classification of kidney transplant pathology.
Kidney Int. 44:411-422, 1993.

32. CURRENT RESEARCH
 Microarray analysis of both human & mouse
kidney transplants with rejection and other
complications
 Correlate with Clinical data & Banff lesions.
Common entities like glomerulonephritis,
bacterial infection, and calcineurin inhibitor
toxicity have no genomics signature at present.

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

34. TABLE 1: CORRELATIONS BETWEEN INFILTRATE TYPES
AND PATHOGENESIS BASED TRANSCRIPT SETS (PBTS)
Gene sets*# i-Banff t-score i-IFTA IFTA nodular perivascular
T-cell associated (CATs) 0.534 0.484 0.284 0.246 0.298 ns
γ-Interferon dependent (GRITs) 0.532 0.441 0.258 0.211 0.241 ns
Kidney parenchyma associated (KTs) -0.296 -0.303 -0.199 -0.156 ns ns
Injury and repair associated (IRITs) 0.379 0.355 0.246 0.206 ns ns
Immunoglobulin associated (IGTs) 0.174 ns 0.434 0.398 0.336 ns
B-cell associated (BATs) 0.281 0.279 0.423 0.387 0.355 ns
# given is the highest r-value revealed for one PBT of
each particular biological process
*Spearman correlation, p<0.001

35. Paula Blanco – Superiority of Virtual Microscopy
A B
C D

36. Figure 2.
Average intra-observer reproducibility of 3 observers
0.90
all comparisons p>0.05
0.80
0.70
(overall kappa values)
0.60
0.50 Virtual Slide
0.40 Glass Slide
0.30
0.20
0.10
0.00
g i t v ptc cg ci ct cv ah mm Diagnosis
v
ah
cv
t
cg
c
ct
m
i
sis
g
ci
pt
m
no
g
ia
D

37. Figure 3.
Inter-observer reproducibility among 3 observers
0.90 p=0.04
0.80
0.70 p=0.03
(overall kappa values)
p=0.08
0.60
p=0.03
0.50 p=0.08 Virtual Slide
p=0.08 p=0.05
NS p=0.08 Glass Slide
0.40 p=0.03 NS
0.30 NS
0.20
0.10
0.00
g i t v ptc cg ci ct cv ah mm Diagnosis
t
ci
v
cg
ah
i
ct
m
g
c
cv
is
pt
s
m
g no
ia
D

38. Figure 4.
p = 0.29
p = 0.11
A. B.
100% 100%
Virtual vs. Virtual slides
Agreement rate in diagnosis
90% 90%
Glass vs. Glass slides
80% 80%
Virtual vs. Glass slides
70% 70%
60% 60% Virtual vs. Virtual slides
50% 50% Glass vs. Glass slides
40% 40% Virtual vs. Glass slides
30% 30%
20% 20%
10% 10%
0% 0%
Observer 1 Observer 2 Observer 3

39. CHANGES NOT CONSIDERED TO BE DUE TO REJECTION:
 Post-transplant lymphoproliferative disorder
Slide 39
 Non-specific changes
a) Focal interstitial inflammation without tubulitis: Nodular infiltrates, parivasular
infiltrates.
b) Vascular changes: endothelial reactive changes, vacuolization, venulitis.
 Acute tubular injury
 Acute Interstitial nephritis
 Cyclosporine-associated changes, acute or chronic
 Subcapsular injury
 Pre-transplant acute endothelial injury
 Papillary necrosis
 De novo glomerulonephritis
 Recurrent disease
 Pre-existing disease
 Other-viral infection (CMV), obstruction and reflux

40. Slide 40

41. POST-TRANSPLANT LYMPHOPROLIFERATIVE
DISEASE (PTLD): WHO 2008
Early lesions
a. plasmacytic hyperplasia,
b. infectious mononucleosis type
Polymorphic PTLD
Monomorphic PTLD
a. B-cell neoplasms
b. T-cell neoplasms
Classic Hodgkin lymphoma-type PTLD

42. DIFFERENTIAL DIAGNOSIS OF PTLD
 T-cell rich PTLDs occur in 10-30% of cases
 EBV negative PTLDs occur in 10-30% of cases
 Endarteritis may be PTLD associated.
 PTLD is not associated with edema.

43. MY PRESENTATION TOMORROW “BANFF AND BEYOND”
CONTINUES THIS DISCUSSION, SO STAY TUNED!
 The pathologic spectrum of chronic allograft injury
is very broad, and we should keep all entities in
mind, even the rare ones. Technology is advancing
in some areas much more quickly than you think,
and in other areas not at all.
 Further conclusions (big and small!) tomorrow.