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

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) ± SD242.6 ± ± 96 <.01 Time Tx-AMR (days)15 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 OKT3IVIg PP/IVI g Ritux/ PP PP/IVI g/Ritu x Bort. (Velcade) Pts 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

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) regimen 01/ /2003 N=12 pts Group B: Plasmapheresis (PP) / IVIg / anti-CD20 (PP/IVIg/anti-CD20) regimen 01/ /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 Anti-thrombotic

Anti-endothelial cells Abs S1S2N.H.S.TNF 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 Proliferation Cell survival mTor GbL rictor raptor mTor GbL Anti-prolif

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

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/1.73m 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

Histologic factors associated with bad outcome in AMR pts Good OutcomeBad Outcomep First Biopsy 13 pts8 pts Glomerular PMNs Peritubular Capillary PMNs Peritubular Capillary Dilatation Interstitial Edema Last Biopsy 9 pts5 pts Glomerular Macrophages4.7 ± ± g1 – g31.8 ± ± Peritubular capillary macrophages5.8 ± ± Interstitial inflammation0.5 ± ± v1 – v30.2 ± ± 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 Lefaucheur 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

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

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/ /2003 N=12 pts Group B: Plasmapheresis (PP) / IVIg / anti-CD20 (PP/IVIg/anti-CD20) regimen 01/ /2005 N=12 pts Lefaucheur AJT 2009

Good Outcome (N=17) Bad Outcome (N=7) p At time of AMR Scr (µmol/L) ± SD242.6 ± ± 96 <.01 Histological characteristics * Glomerular PMNs1.5 ± ± 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 ± ± DSA mean MFI ± SD Total MFI ± SD 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 )

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

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) RejectionM3 % Δ: -21% % Δ: -52% P: 0,02P< 0,001 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

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%

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