Transcript INSUFFISANCE RENALE AIGUE IRREVERSIBLE AU COURS DE …

Predictors of outcome in
Acute Antibody-Mediated
Rejections
Experience of the Broussais /
H.E.G.P. / Saint-Louis hospitals
1992-2009
Possible predictors
Histologic type of rejection
Renal function at diagnosis
Antibody specificity
Treatment
Histologic lesions
Kinetics of DSAs
Types of AHR
Mauiyyedi, JASN 2002
Renal function at diagnosis
Good Outcome
(N=17)
Bad Outcome
(N=7)
242.6 ± 104.4
420 ± 96
15
15
p
At time of AMR
Scr (µmol/L) ± SD
Time Tx-AMR (days)
<.01
Lefaucheur AJT 2007
Antibody specificity
Anti-HLA
Lefaucheur AJT 2008
Antibody specificity
Anti-Angiotensin II receptors
Dragun, NEJM 2005
Antibody specificity
Anti-MICA
Zou, NEJM 2007
Antibody specificity
Different modes of action
Reliable detection assays
Allowing diagnosis of AMR
Allowing adapted Treatment
Reducing delay AMR-TT
Adapted Treatment is essential
OKT3 IVIg
Pts
43
Pt Surv
G Surv
Author
57%
Feucht
Kidney I
1993
PP/IVI
PP/IVI Ritux/
g/Ritu Bort.
(Velcade)
g
PP
x
21
16
100%
84%
100% 100% 100%
70%
81%
75%
Lefaucheur
AJT
2007
Rocha
Transpl
2003
8
Faguer
Transpl
2007
12
94%
Lefaucheur
AJT
2009
6
100%
Everly
Transpl
2008
Impact of a single agent
difficult to juge..
Kapotzas, Clin Tx 2008
Impact of a single agent
difficult to judge..
N=13
P=0,044
N=11
Slatinska, Ther Aph Dial 2009
Comparison of Combination Plasmapheresis/IVIg/anti-CD20
versus High-Dose IVIg in the Treatment of AMR
• Group A: High-dose intravenous immunoglobulin
(IVIg) regimen
01/2000-12/2003
N=12 pts
• Group B: Plasmapheresis (PP) / IVIg / anti-CD20
(PP/IVIg/anti-CD20) regimen
01/2004-12/2005
N=12 pts
Lefaucheur AJT 2009
Kaplan Meier plot of graft survival in patients with AMR
according to treatment type
Lefaucheur AJT 2009
Adapted treatment may vary
according to the Ab
specificity….
ARBs
Dragun, NEJM 2005
Adapted treatment may vary
according to the Ab
specificity….
Anti-thrombotic
Sumitran-Holgersson, Transpl. 2002
Anti-endothelial cells Abs
160
140
120
100
VCAM
80
ICAM
60
40
20
0
S1
S2
N.H.S.
TNF
Anti-adhesion
Lucciari Hum Immunol 2000
Anti HLA class I antibodies
The Good, the Bad and the Ugly…
mTor
mTor
raptor
rictor
GbL
Cell survival
GbL
Proliferation
Anti-prolif
Proliferation
E.F. Reed, JI 2008
Determinants of poor graft outcome
in patients with AMR
Study design
Renal transplants
1998 – 2004
N=237
Desensitization (IVIg)
N=18
Renal transplants without
pretransplant desensitization
N=219
Pretransplant Class I or Class II
anti-HLA Ab (ELISA)
N=60
No
Pretransplant DSA
AMR +
N=6
AMR +
N=5
AMR N=13
Pretransplant DSA
Class I or Class II
N=31
AMR +
N=10
AMR N=21
Lefaucheur AJT 2007
21 pts (8.9%) with AMR
AMR treatment:
• For all patients  boluses of steroids + IVIg (2 g/kg
monthly X 4 doses)
• For certain patients
 plasma exchange (28.6%)
 OKT3 (14.3%)
 Rituximab (4.8%)
Follow-up: 30 ± 20 mo (8-78 mo)
Lefaucheur AJT 2007
Prognostic factors of poor
outcome in patients with AMR
Bad outcome : GFR < 15 ml/min/1.73m2
N=8 pts
Good outcome : GFR > 15 ml/min/1.73m2
N=13 pts
SCr : 160 µmol/l ± 44 ≈ ACR
Lefaucheur AJT 2007
Histologic factors associated with bad outcome in AMR pts
Good Outcome
Bad Outcome
p
13 pts
8 pts
Glomerular PMNs
3.2  2.5
6.8  4.1
0.02
Peritubular Capillary PMNs
1.0  0.7
3.4  2.5
0.004
Peritubular Capillary Dilatation
1.1  0.9
2.1  0.9
0.03
Interstitial Edema
0.7  0.8
1.7  0.8
0.02
9 pts
5 pts
Glomerular Macrophages
4.7 ± 3.5
9.3 ± 3.7
0.04
g1 – g3†
1.8 ± 0.8
2.8 ± 0.4
0.03
Peritubular capillary macrophages
5.8 ± 2.7
17.8 ± 16.5
0.04
Interstitial inflammation
0.5 ± 0.4
2.0 ± 1.8
0.03
v1 – v3†
0.2 ± 0.7
1.7 ± 0.9
0.01
First Biopsy
Last Biopsy
Lefaucheur AJT 2007
Histologic factors associated with bad outcome in AMR pts
•
Glomerular and capillary PMNs (first bx)
Lefaucheur AJT 2007
Histologic factors associated with bad outcome in AMR pts
•
Glomerular and capillary MNCs (bx > 3 mo)
CD68
CD68
Lefaucheur AJT 2007
Histologic factors associated with bad outcome in AMR pts
•
Vascular lesions (v1-v3) (p=0.01)
CD68
C4d staining: no correlation
Lefaucheur AJT 2007
Serologic factors associated with bad outcome in AMR pts
Relationship of anti-HLA DSA status to outcome in the 21 pts with AMR
DSA
p*
PreTransplant
Class I and/or Class II
NS
Class I (+/- Class II)
NS
Class II (+/- Class I)
NS
Post-transplant
Class I (+/- Class II)
0.006
Class II (+/- Class I)
0.10**
Persistence of Class I or Class II
0.035
Persistence of Class I
0.020
Persistence of Class II
0.10**
Lefaucheur AJT 2007
Comparison of Combination Plasmapheresis/IVIg/anti-CD20
versus High-Dose IVIg in the Treatment of AMR
• Group A: High-dose intravenous immunoglobulin
(IVIg) regimen
01/2000-12/2003
N=12 pts
• Group B: Plasmapheresis (PP) / IVIg / anti-CD20
(PP/IVIg/anti-CD20) regimen
01/2004-12/2005
N=12 pts
Lefaucheur AJT 2009
Comparison of clinical, histologic and serologic data of patients
with Good Outcome (GFR > 15 mL/min/1.73m2)
and patients with Bad Outcome (GFR ≤ 15 mL/min/1.73m2)
Good Outcome
(N=17)
Bad Outcome
(N=7)
p
242.6 ± 104.4
420 ± 96
<.01
Glomerular PMNs
1.5 ± 1.4
6.5 ± 5.2
.008
C4d+ (N, %)
17 (100%)
7 (100%)
NS
DSA ELISA (N, %)
13 (76.5%)
6 (85.7%)
NS
DSA ELISA score 6-8 (N, %)
11 (64.7%)
6 (85.7%)
NS
DSA MFImax ± SD
8360 ± 5869
13638 ± 2121
.045
DSA mean MFI ± SD
3804  2682
6758  2188
.018
Total MFI ± SD
17742  12204
26650  8306
NS
At time of AMR
Scr (µmol/L) ± SD
Histological characteristics *
Serological characteristics
Diminution of DSAs levels is significantly greater in patients treated
by PP/IVIg/anti-CD20 as compared to those treated by IVIg
IVIg
PP/IVIg/anti-CD20
Variations in DSA MFImax between
day 0 and 3 months post-AMR
Variations in DSA MFImax
between day 0 and 3 mo
post-AMR
expressed as % Δ MFI
Lefaucheur AJT 2009
DSA Monitoring is key
The absence of decrease of DSA post-treatment is associated with poor prognosis
24 patients, DSA at rejection and 3 months post TT
8000
7000
6000
% Δ: -21%
5000
Good evol. (n=18)
Bad evol. (n=6)
4000
3000
% Δ: -52%
2000
1000
0
P: 0,02
Rejection
P< 0,001
M3
Lefaucheur, A.J.T. 2009
DSA Monitoring is key
The absence of decrease of DSA post-treatment is associated with poor prognosis
Everly, A.J.T. 2009
High levels of DSA post-treatment are associated
with a higher risk of graft loss
MFI max > 5000
Se 100%
Sp 77.8%
Receiver operating characteristic (ROC) curve
for the MFImax of DSAs detected 3 mo
post-AMR associated with
GFR ≤ 15 mL/min/1.73m2 at 36 months post-AMR.
Conclusion
•We need more studies…
•We need more markers….
• Omics?
• High levels of DSA post-treatment  higher risk of graft loss
Monitoring of DSAs post-AMR
to optimize the treatment
Many Thanks to:
-C. Lefaucheur, C. Antoine
Nephrology and Transplantation
-C. Superbielle, J. Andrade
Histocompatibility
-D. Nochy, G. Hill
Pathology