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Kim Solez Chronic rejection - current concepts and newer perspectives, presentation for Tx Update meeting in Ahmedabad, India, September 28th, 2012.
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Chronic rejection- current concepts and newer perspectives
Kim Solez, M.D.
Mentor influences: Smelling the FlowersMeetings – 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.
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.
Number of CAN Articles Per Year
Elaborate Schemes Explaining CAN At The Height of Its Popularity
Elaborate Schemes Explaining CAN At The Height of Its Popularity
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
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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.
Slide 17
Slide 18
Sclerosing Rejection: “neo-media” formation super-
imposed on donor disease (0.9 years post grafting)
PAS stain
Elastic stain
Transplant Glomerulitis and Glomerulopathy 4.5 years post transplantation
Slide 23
INTERSTITIAL FIBROSIS AND TUBULAR ATROPHY (IFTA) IN RENAL ALLOGRAFTS
IFTA WITH INFLAMMATION – MENGEL ET AL.
INFILTRATES IN AREAS OF FIBROSIS AND TUBULAR ATROPHY
SUBCAPSULARperivascular
NODULAR INFILTRATES
i-score total i-score
% c
ort
ex
wit
h i
nfi
ltra
te
*p<0.05
*
*
*
*
*
*
BANFF I- AND TOTAL I-SCORE AND DIAGNOSIS: INTERSTITIAL INFILTRATES ARE NOT DISEASE SPECIFIC
0
10
20
30
40
50
60
70
80
90
100
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
% c
ort
ex in
volv
ed
fibrosis/atrophy
i-Banff
i-IFTA
INFILTRATES IN BIOPSIES FOR CAUSE ARE TIME DEPENDENT
3 months
8 months
27 months
79 months
246 months
129 biopsies ordered by time post TX
Mengel et al. Am J Transplant. 2009 Jan;9(1):169-78.
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.
.
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.
Human and Mouse similar genes and similar development
The Cell 2002.
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
TABLE 1: CORRELATIONS BETWEEN INFILTRATE TYPES AND PATHOGENESIS BASED TRANSCRIPT SETS (PBTS)
Paula Blanco – Superiority of Virtual Microscopy
A B
C D
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0.60
0.70
0.80
0.90
g i t vpt
c cg ci ct cv ah mm
Diagno
sis
Virtual Slide
Glass Slide
g i t v ptc cg ci ct cv ah mm Diagnosis
all comparisons p>0.05
Ave
rag
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epro
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of
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Figure 2.
0.00
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0.90
g i t vptc cg ci ct cv ah m
m
Diagno
sis
Virtual Slide
Glass Slide
g i t v ptc cg ci ct cv ah mm Diagnosis
p=0.03
p=0.08 NS
p=0.08
p=0.03
p=0.04
p=0.03p=0.05
NS
p=0.08
NS p=0.08
Figure 3.
Inte
r-o
bse
rver
rep
rod
uci
bili
ty a
mo
ng
3 o
bse
rver
s (
ove
rall
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0%
10%
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30%
40%
50%
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70%
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90%
100%
Virtual vs. Virtual slides
Glass vs. Glass slides
Virtual vs. Glass slides
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Glass vs. Glass slides
Virtual vs. Glass slides
p = 0.11
Virtual vs. Virtual slides
Observer 1 Observer 2 Observer 3
p = 0.29
Figure 4.
A. B.
Ag
ree
me
nt
rate
in
dia
gn
os
is
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9CHANGES NOT CONSIDERED TO BE DUE TO REJECTION:
Post-transplant lymphoproliferative disorder 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
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POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE (PTLD): WHO 2008
Early lesions
a. plasmacytic hyperplasia,
b. infectious mononucleosis type
Polymorphic PTLD
Monomorphic PTLD
c. B-cell neoplasms
d. T-cell neoplasms
Classic Hodgkin lymphoma-type PTLD
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.
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.