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)

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

Antibody specificityAnti-HLA

Lefaucheur AJT 2008

Antibody specificityAnti-Angiotensin II receptors

Dragun, NEJM 2005

Antibody specificityAnti-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 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

Impact of a single agent difficult to juge..

Kapotzas, Clin Tx 2008

Impact of a single agent difficult to judge..

Slatinska, Ther Aph Dial 2009

N=13

N=11

P=0,044

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

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….

Dragun, NEJM 2005

ARBs

Adapted treatment may vary according to the Ab

specificity….

Sumitran-Holgersson, Transpl. 2002

Anti-thrombotic

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

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

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

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

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

• Glomerular and capillary PMNs (first bx)

Histologic factors associated with bad outcome in AMR pts

Lefaucheur AJT 2007

Histologic factors associated with bad outcome in AMR pts

• Glomerular and capillary MNCs (bx > 3 mo)

CD68

CD68Lefaucheur AJT 2007

• Vascular lesions (v1-v3) (p=0.01)

Histologic factors associated with bad outcome in AMR pts

C4d staining: no correlation

CD68

Lefaucheur AJT 2007

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

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

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)

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

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

DSA Monitoring is keyThe absence of decrease of DSA post-treatment is associated with poor prognosis

Everly, A.J.T. 2009

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%

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

Many Thanks to:

-C. Lefaucheur, C. Antoine

Nephrology and Transplantation

-C. Superbielle, J. Andrade

Histocompatibility

-D. Nochy, G. Hill

Pathology