1. Predictors of outcome in Acute Antibody-Mediated Rejections Experience of the Broussais / H.E.G.P. / Saint-Louis hospitals 1992-2009

2. Possible predictors Histologic type of rejection Renal function at diagnosis Antibody specificity Treatment Histologic lesions Kinetics of DSAs

3. Types of AHR Mauiyyedi, JASN 2002

4. Renal function at diagnosis Good Outcome (N=17) Bad Outcome (N=7) p At time of AMR Scr (µmol/L) ± SD242.6 ± 104.4420 ± 96 <.01 Time Tx-AMR (days)15 Lefaucheur AJT 2007

5. Antibody specificity Anti-HLA Lefaucheur AJT 2008

6. Antibody specificity Anti-Angiotensin II receptors Dragun, NEJM 2005

7. Antibody specificity Anti-MICA Zou, NEJM 2007

8. Antibody specificity Different modes of action Reliable detection assays Allowing diagnosis of AMR Allowing adapted Treatment Reducing delay AMR-TT

9. Adapted Treatment is essential OKT3IVIg PP/IVI g Ritux/ PP PP/IVI g/Ritu x Bort. (Velcade) Pts4321168126 Pt Surv 100%84%100% G Surv 57%70%81%75%94%100% Author Feucht Kidney I 1993 Lefaucheur AJT 2007 Rocha Transpl 2003 Faguer Transpl 2007 Lefaucheur AJT 2009 Everly Transpl 2008

10. Impact of a single agent difficult to juge.. Kapotzas, Clin Tx 2008

11. Impact of a single agent difficult to judge.. Slatinska, Ther Aph Dial 2009 N=13 N=11 P=0,044

12. 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

13. Kaplan Meier plot of graft survival in patients with AMR according to treatment type Lefaucheur AJT 2009

14. Adapted treatment may vary according to the Ab specificity…. Dragun, NEJM 2005 ARBs

15. Adapted treatment may vary according to the Ab specificity…. Sumitran-Holgersson, Transpl. 2002 Anti-thrombotic

16. Anti-endothelial cells Abs S1S2N.H.S.TNF 0 20 40 60 80 100 120 140 160 VCAM ICAM Lucciari Hum Immunol 2000 Anti-adhesion

17. Anti HLA class I antibodies The Good, the Bad and the Ugly… E.F. Reed, JI 2008 Proliferation Cell survival mTor GbL rictor raptor mTor GbL Anti-prolif

18. Renal transplants 1998 – 2004 N=237 AMR + N=10 AMR - N=21 Renal transplants without pretransplant desensitization N=219 Pretransplant Class I or Class II anti-HLA Ab (ELISA) N=60 Pretransplant DSA Class I or Class II N=31 Desensitization (IVIg) N=18 AMR + N=5 AMR - N=13 No Pretransplant DSA AMR + N=6 Study design Determinants of poor graft outcome in patients with AMR Lefaucheur AJT 2007

19. 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

20. Prognostic factors of poor outcome in patients with AMR Bad outcome : GFR < 15 ml/min/1.73m 2 N=8 pts Good outcome : GFR > 15 ml/min/1.73m 2 N=13 pts SCr : 160 µmol/l ± 44 ACR Lefaucheur AJT 2007

21. Histologic factors associated with bad outcome in AMR pts Good OutcomeBad Outcomep First Biopsy 13 pts8 pts Glomerular PMNs 3.2 2.56.8 4.1 0.02 Peritubular Capillary PMNs 1.0 0.73.4 2.5 0.004 Peritubular Capillary Dilatation 1.1 0.92.1 0.9 0.03 Interstitial Edema 0.7 0.81.7 0.8 0.02 Last Biopsy 9 pts5 pts Glomerular Macrophages4.7 ± 3.59.3 ± 3.70.04 g1 – g31.8 ± 0.82.8 ± 0.40.03 Peritubular capillary macrophages5.8 ± 2.717.8 ± 16.50.04 Interstitial inflammation0.5 ± 0.42.0 ± 1.80.03 v1 – v30.2 ± 0.71.7 ± 0.90.01 Lefaucheur AJT 2007

22. Glomerular and capillary PMNs (first bx) Histologic factors associated with bad outcome in AMR pts Lefaucheur AJT 2007

23. Histologic factors associated with bad outcome in AMR pts Glomerular and capillary MNCs (bx > 3 mo) CD68 Lefaucheur AJT 2007

24. Vascular lesions (v1-v3) (p=0.01) Histologic factors associated with bad outcome in AMR pts C4d staining: no correlation CD68 Lefaucheur AJT 2007

25. DSAp* PreTransplant Class I and/or Class IINS 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 II0.035 Persistence of Class I0.020 Persistence of Class II0.10** 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

26. 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

27. Good Outcome (N=17) Bad Outcome (N=7) p At time of AMR Scr (µmol/L) ± SD242.6 ± 104.4420 ± 96 <.01 Histological characteristics * Glomerular PMNs1.5 ± 1.46.5 ± 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 ± SD8360 ± 586913638 ± 2121.045 DSA mean MFI ± SD 3804 26826758 2188.018 Total MFI ± SD 17742 1220426650 8306 NS Comparison of clinical, histologic and serologic data of patients with Good Outcome (GFR > 15 mL/min/1.73m 2 ) and patients with Bad Outcome (GFR 15 mL/min/1.73m 2 )

28. 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 treated by PP/IVIg/anti-CD20 as compared to those treated by IVIg Lefaucheur AJT 2009

29. 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 Good evol. (n=18) Bad evol. (n=6) 0 1000 2000 3000 4000 5000 6000 7000 RejectionM3 % Δ: -21% % Δ: -52% P: 0,02P< 0,001 Lefaucheur, A.J.T. 2009

30. DSA Monitoring is key The absence of decrease of DSA post-treatment is associated with poor prognosis Everly, A.J.T. 2009

31. 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 > 5000 Se 100% Sp 77.8%

32. 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

33. Many Thanks to: -C. Lefaucheur, C. Antoine Nephrology and Transplantation -C. Superbielle, J. Andrade Histocompatibility -D. Nochy, G. Hill Pathology