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Predictors of outcome in Acute Antibody-Mediated
Rejections
Experience of the Broussais / H.E.G.P. / Saint-Louis hospitals
1992-2009
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Possible predictors
Histologic type of rejection
Renal function at diagnosis
Antibody specificity
Treatment
Histologic lesions
Kinetics of DSAs
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Types of AHR
Mauiyyedi, JASN 2002
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Renal function at diagnosis
Good Outcome(N=17)
Bad Outcome(N=7)
p
At time of AMR
Scr (µmol/L) ± SD 242.6 ± 104.4 420 ± 96 <.01
Time Tx-AMR (days) 15 15
Lefaucheur AJT 2007
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Antibody specificityAnti-HLA
Lefaucheur AJT 2008
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Antibody specificityAnti-Angiotensin II receptors
Dragun, NEJM 2005
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Antibody specificityAnti-MICA
Zou, NEJM 2007
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Antibody specificity
Different modes of action
Reliable detection assays
Allowing diagnosis of AMR
Allowing adapted Treatment
Reducing delay AMR-TT
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Adapted Treatment is essential
OKT3 IVIg PP/IVIg
Ritux/PP
PP/IVIg/Ritux
Bort. (Velcade)
Pts 43 21 16 8 12 6
Pt Surv 100% 84% 100% 100% 100%
G Surv 57% 70% 81% 75% 94% 100%
AuthorFeucht Kidney I 1993
Lefaucheur AJT 2007
Rocha Transpl 2003
Faguer Transpl 2007
Lefaucheur AJT 2009
EverlyTranspl2008
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Impact of a single agent difficult to juge..
Kapotzas, Clin Tx 2008
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Impact of a single agent difficult to judge..
Slatinska, Ther Aph Dial 2009
N=13
N=11
P=0,044
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Comparison of Combination Plasmapheresis/IVIg/anti-CD20 versus High-Dose IVIg in the Treatment of AMR
• Group A: High-dose intravenous immunoglobulin (IVIg) regimen01/2000-12/2003
N=12 pts
• Group B: Plasmapheresis (PP) / IVIg / anti-CD20 (PP/IVIg/anti-CD20) regimen01/2004-12/2005
N=12 pts
Lefaucheur AJT 2009
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Kaplan Meier plot of graft survival in patients with AMR according to treatment type
Lefaucheur AJT 2009
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Adapted treatment may vary according to the Ab
specificity….
Dragun, NEJM 2005
ARBs
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Adapted treatment may vary according to the Ab
specificity….
Sumitran-Holgersson, Transpl. 2002
Anti-thrombotic
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Anti-endothelial cells Abs
S1 S2 N.H.S. TNF
0
20
40
60
80
100
120
140
160
VCAM
ICAM
Lucciari Hum Immunol 2000
Anti-adhesion
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Anti HLA class I antibodies The Good, the Bad and the Ugly…
E.F. Reed, JI 2008
ProliferationProliferationCell survival
mTor
GbL
rictor raptor mTor
GbL Anti-prolif
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Renal transplants1998 – 2004
N=237
AMR +N=10
AMR -N=21
Renal transplants withoutpretransplant desensitization
N=219
Pretransplant Class I or Class IIanti-HLA Ab (ELISA)
N=60
Pretransplant DSAClass I or Class II
N=31
Desensitization (IVIg)N=18
AMR +N=5
AMR -N=13
NoPretransplant DSA
AMR +N=6
Study design
Determinants of poor graft outcome in patients with AMR
Lefaucheur AJT 2007
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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
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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
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Histologic factors associated with bad outcome in AMR pts
Good Outcome Bad Outcome p
First Biopsy
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
Last Biopsy
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
Lefaucheur AJT 2007
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• Glomerular and capillary PMNs (first bx)
Histologic factors associated with bad outcome in AMR pts
Lefaucheur AJT 2007
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Histologic factors associated with bad outcome in AMR pts
• Glomerular and capillary MNCs (bx > 3 mo)
CD68
CD68Lefaucheur AJT 2007
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• Vascular lesions (v1-v3) (p=0.01)
Histologic factors associated with bad outcome in AMR pts
C4d staining: no correlation
CD68
Lefaucheur AJT 2007
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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**
Relationship of anti-HLA DSA status to outcome in the 21 pts with AMR
Serologic factors associated with bad outcome in AMR pts
Lefaucheur AJT 2007
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Comparison of Combination Plasmapheresis/IVIg/anti-CD20 versus High-Dose IVIg in the Treatment of AMR
• Group A: High-dose intravenous immunoglobulin (IVIg) regimen01/2000-12/2003
N=12 pts
• Group B: Plasmapheresis (PP) / IVIg / anti-CD20 (PP/IVIg/anti-CD20) regimen01/2004-12/2005
N=12 pts
Lefaucheur AJT 2009
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Good Outcome(N=17)
Bad Outcome(N=7) p
At time of AMR
Scr (µmol/L) ± SD 242.6 ± 104.4 420 ± 96 <.01
Histological characteristics *
Glomerular PMNs 1.5 ± 1.4 6.5 ± 5.2 .008
C4d+ (N, %) 17 (100%) 7 (100%) NS
Serological characteristics
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
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)
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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
Diminution of DSAs levels is significantly greater in patients treatedby PP/IVIg/anti-CD20 as compared to those treated by IVIg
Lefaucheur AJT 2009
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DSA Monitoring is keyThe absence of decrease of DSA post-treatment is associated with poor prognosis
24 patients, DSA at rejection and 3 months post TT
8000
Good evol. (n=18)Bad evol. (n=6)
0
1000
2000
3000
4000
5000
6000
7000
Rejection M3
% Δ: -21%
% Δ: -52%
P: 0,02 P< 0,001
Lefaucheur, A.J.T. 2009
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DSA Monitoring is keyThe absence of decrease of DSA post-treatment is associated with poor prognosis
Everly, A.J.T. 2009
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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.
High levels of DSA post-treatment are associated with a higher risk of graft loss
MFI max > 5000Se 100%Sp 77.8%
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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-AMRto optimize the treatment
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Many Thanks to:
-C. Lefaucheur, C. Antoine
Nephrology and Transplantation
-C. Superbielle, J. Andrade
Histocompatibility
-D. Nochy, G. Hill
Pathology