Kidney allografts with biopsy features
of chronic mixed rejection reflect
poorer survival than those with pure
chronic antibody-mediated rejection
D. Dobi, Zs. Bodó, É. Kemény, K. Bodaa, P. Szenohradszkyb, E.
Szederkényib, B. Iványi
Departments of Pathology, Medical Physics and Informaticsa and Surgeryb
University of Szeged, Szeged, Hungary
Introduction
In late dysfunctional kidney allograft biopsies
three rejection phenotypes can be observed:
• chronic antibody-mediated rejection (AMR)
• acute T-cell-mediated rejection (TMR)
• chronic active TMR
Chronic AMR: transplant glomerulopathy and/or transplant capillaropathy
cg
ptcml
Acute TMR: interstitial infiltrates and tubulitis (interstitial rejection,
ISR) with or without intimal arteritis
Chronic active TMR: mononuclears in intimal fibrosis (cvmo)
• Frequency: chronic AMR > acute TMR;
chronic active TMR is exceptional
• Chronic AMR and TMR may concur, termed
chronic mixed rejection (CMR)
Objectives
To analyze
• the histological patterns of chronic mixed
rejection (CMR)
• the clinicopathological relevance of the
different patterns of CMR
Material and methods
• From 2001 to 2011, 61 biopsies displayed the
histological features of chronic AMR (cg and/or ptcml ±
C4d-positivity)
• Luminex data were not avaible
• Re-evaluation according to the Banff scheme (v, g, i, t,
ptc, cg, ci,ct, ah) plus
• Scoring of chronic arterial changes: mononuclears in
intimal fibrosis (cvmo), intimal fibrosis (cvIF), intimal
fibroelastosis (cvIFE); and tubular HLA-DR and ptcml
• Staining of chronic active arteritis (cvmo) cases
with CD3 and CD68 in adjacent sections
• Two groups for clinicopathological analysis:
purely CAMR vs CMR
• Statistics: Spearman’s correlation, hierarchical
cluster analysis, Kaplan-Meier estimator, Cox
regression
Results: main clinical data
All
patients
(n=61)
Purely
CAMR
(n=35)
CMR
(n=26)
p
Posttransplant time
(months)
66±49
70±49
60±49
ns
eGFR (ml/min/1.73 m2)
26±12
28±12
23±13
ns
Postbiopsy follow-up
(months)
23±22
26±22
19±20
ns
Histological patterns
35
12
10
4
Chronic active TMR
Purely CAMR
Chronic active TMR
and acute ISR
CMR
Acute ISR
Features of chronic active
arteritis
CD3
Severe luminal narrowing
(median score 3),
mononuclears scattered
throughout the fibrotic intima,
T-cell predominance
PAS
CD68
Significant (p<0.05) and positive Spearman correlation
coefficients between Banff scores and chronic arterial changes
t HLA-DR cvmo ptc C4d g
cg ptcml cvIF
ci
ct
ah cvIFE
i 0.769 0.606
0.347
0.301 0.264
t
0.654
0.2750.354
HLA-DR
0.363
cvmo
ptc 0.3280.331
C4d 0.303
g
0.338
cg 0.258
ptcml 0.414 0.269 0.263
cvIF
ci 0.806 0.299
ct
ah
cvIFE
Hierarchical cluster analysis
cvIF
cvmo
cvIFE
50
45
40
35
30
purely
CAMR
25
20
CMR
15
-36
-33
-30
-27
-24
-21
-18
-15
-12
-9
-6
-3
-1
Bx
+1
+3
+6
+9
+12
Mean eGFR value (ml/min/1.73 m2)
Mean eGFR values in purely CAMR and CMR
Time before (-) and after (+) biopsy (Bx) (months)
Postbiopsy therapy
Purely
CAMR
Therapy
Steroid pulse
CMR
Chronic active
CAMR Chronic active TMR and
(n=35) TMR (n=12)
acute ISR
(n=4)
5
5
4
Acute ISR
(n=10)
10
Intensification of
maintenance
immunosuppression
8
6
1
0
Anti-thymocyte
globulin
0
0
2
0
Plasmapheresis
0
0
2
0
Left untreated
22
2
0
0
Mean graft survival in purely CAMR and CMR groups
50 vs 22 months
Purely CAMR
CMR
p=0.011
Multivariable Cox regression of
morphological variables
HLA-DR
cvmo
ptc
g
cvIF
cg
ptcml
ct
ci
cvIFE ah
C4d
CNI-tox.
t
i
Discussion
I. CMR was frequent in our series (43%)
II. Chronic active arteritis appeared to be Tcell-related
a. T-cell predominance in 14/16 cases
b. Clustered with TMR lesions
C. Lefaucheur et al. Antibody-mediated vascular rejection of kidney allografts: a
population-based study. Lancet 2013; 381: 313-319.
III. CMR was characterized by poorer
allograft survival and more reduced
allograft function than purely chronic
AMR if chronic active arteritis was part of
the TMR component
IV. The immunohistochemical profiling of
chronic active arteritis is recommended