Welche Donor-spezifischen HLA Antikörper sind schädlich?
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1 Welche Donor-spezifischen HLA Antikörper sind schädlich? Prof. Dr. med. Caner Süsal Transplantationsimmunologie Institut für Immunologie Universität Heidelberg
2 Sensitization Alloantibody Production
3 Alloantibodies Before Transplantation Hyperacute rejection Accelerated humoral rejection Delayed graft function After Transplantation (de novo) Chronic rejection
4 Alloantibodies HLA (A, B, C, DRB1/3/4/5, DQA1, DQB1, DPA1, DPB1) Non-HLA Angiotensin II Typ 1 R MIC-A Endothelial antigens
5 Antibody Specification CDC-PRA ELISA-PRA Luminex (PRA, Single Antigen)
6 Sensitization against HLA-B27 MM from the previous Tx CDC-PRA: 1 Specificity ELISA-PRA: 6 Specificities Luminex-SA: 33 Specificities Süsal et al, Transfus Med Hemother 2013
7 Pre-Tx Anti-HLA Antibody Status (ELISA) CDC-PRA <5% Süsal, Opelz Transplantation 2002
8 Pre-Tx Luminex SA Testing (DSA or Non-DSA) CDC- and ELISA-Negative Kidney Tx Recipients cut-off 1,000 MFI 55% Class I 34% 69% Class II 50% 66% 45% 50% 31% 66% 45% 50% 31% Graft Loss Non-Rejector Graft Loss Non-Rejector Class I Graft Loss Non-Rejector Positive Graft Loss Patients Class II Graft Loss Non-Rejector Positive Non-Rejectors Süsal et al. Transplantation 2011
9 Disadvantages of Presensitization 1. Prolonged waiting time 2. Inferior graft survival
10 Heidelberg Algorithm for Transplantation of High-Risk Sensitized Patients 1. Pre-Tx identification of high-risk patients 2. Good HLA-match 3. ET Acceptable Mismatch Program 4. Pretreatment with PPh/IA + Rituximab + ATG 5. Infection prophylaxis 6. Apheresis after Tx 7. Post-Tx antibody monitoring 8. Protocol biopsies on post-tx days 7 and Desensitization in positive-dsa/xm living-tx Morath et al., Transplantation 2010
11 Four High Risk Groups
12 DSA- and XM-Positive Patients
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15 Pre-Tx HLA Antibody Status (ELISA) Deceased Donor Kidney Transplants CTS Serum Study Hum Immunol 70: , 2009
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18 Heidelberg Algorithm for Transplantation of High-Risk Sensitized Patients 1. Pre-Tx identification of high-risk patients 2. Good HLA-match 3. ET Acceptable Mismatch Program 4. Pretreatment with PPh/IA + Rituximab + ATG 5. Infection prophylaxis 6. Apheresis after Tx 7. Post-Tx antibody monitoring 8. Protocol biopsies on post-tx days 7 and Desensitization in positive-dsa/xm living-tx Morath Süsal, Transplantation 2010
19 Heidelberg Algorithm Since April 2006 Total Kidney Tx, Heidelberg Tx Center verstorbenen Spende 150 Lebendspender
20 CTS Serum Study (
21 Donor-Specific HLA Alloantibodies (DSA) 1. Pre-existing DSA 2. Loss of pre-existing DSA 3. Persistence of pre-existing DSA 4. Reappearance of pre-existing DSA 5. de novo development of DSA 6. C1q-/C3d-DSA
22 Donor-Specific HLA Alloantibodies (DSA) Zecher et al, NDT, 2017
23 Heidelberg Algorithm for Transplantation of High-Risk Sensitized Patients 1. Pre-Tx identification of high-risk patients 2. Good HLA-match 3. ET Acceptable Mismatch Program 4. Pretreatment with PPh/IA + Rituximab + ATG 5. Infection prophylaxis 6. Apheresis after Tx 7. Post-Tx antibody monitoring 8. Protocol biopsies on post-tx days 7 and Desensitization in positive-dsa/xm living-tx Morath Süsal, Transplantation 2010
24 Clinical Relevance of Post-Tx DSA Monitoring 1. International CTS Serum Project 2. Heidelberg Pediatric Cohort 3. Heidelberg High-Risk Population
25
26 Association of de novo DSA and Non-DSA with Graft Loss
27 Association of de novo DSA and Non-DSA with Graft Loss cut-off 500 MFI P<0.001 P<0.22 N=83 N=83 Süsal et al, Transplantation 2015
28 C1q-Positivity in DSA-Positive Patients cut-off 300 MFI n=51 48% P< % 24% P<0.22 0% 0% 0% C1q Positivity C1q DSA C1q non-dsa With graft loss Without graft loss Süsal et al, Transplantation 2015
29 Association of C1q-DSA at the Time of Kidney Transplant Biopsy with Late Graft Failure in Pediatric Renal Transplant Recipients Fichtner et al, Pediatr Nephrol 2016 DSA DSA n=35 DSA+, C1q n=17 DSA+ p=0.002 p<0.001 DSA+, C1q+ n=9 C1q-DSA: positive predictive value: 89% negative predictive value: 87%
30 Heidelberg Adult High-Risk Collective Tx: ; Follow up: Apheresis + Rituximab N=74; 16 AMR; 6 AMR-GL; All 6 were post-tx C1q-DSA-pos. Schäfer et al, HLA 2016
31 Heidelberg High-Risk Collective Tx: ; Follow up: Pre- and post-transplant DSA status and scd30 Pre-Tx DSA neg Post-Tx DSA neg. Pre-Tx DSA pos C1q-DSA neg Post-Tx C1q-DSA neg Post-Tx C1q-DSA neg Pre-Tx C1q-DSA pos Post-Tx C1q-DSA pos Pre-Tx DSA neg De novo C1q-DSA pos Number (N) Pre-Tx scd30 3 (17%) 9 (24%) P= (27%) P= (100%) P= (66%) P=0.04 Post-Tx scd30 2/16 (13%) 9/38 (24%) P=0.47 3/10 (30%) P=0.34 1/2 (50%) P=0.31 4/4 (100%) P=0.003 Schäfer et al. 2015
32 Donor-specific antibodies require preactivated immune system to harm renal transplant Caner Süsal1, Bernd Döhler1, Andrea Ruhenstroth1, Christian Morath2, Antonij Slavcev3, Thomas Fehr4, Eric Wagner5, Bernd Krüger6, Margaret Rees7, Sanja Balen8, Stela Živčić-Ćosić8, Douglas J. Norman9, Dirk Kuypers10, Marie-Paule Emonds11, Przemyslaw Pisarski12, Claudia Bösmüller13, Rolf Weimer14, Joannis Mytilineos15 Sabine Scherer1, Thuong H. Tran1, Petra Gombos1, Peter Schemmer16, Martin Zeier2, and Gerhard Opelz1 A Collaborative Transplant Study Report EBioMedicine 2016
33 Pre-Tx DSA (Luminex-SA) CDC-/ELISA-Positive Presensitized Recipients Süsal et al, EBioMedicine 2016
34 Pre-Tx DSA and scd30 CDC-/ELISA-Positive Presensitized Recipients 62% HR=2.95 P<0.001 Süsal et al, EBioMedicine 2016
35 JASN 2017, in press 205 patients with AMR in indication biopsy Graft Survival 8 years after AMR: Pre-existing DSA: 63% vs. De novo DSA: 34% (P<0.001)
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37 a) MFI für Hoch-Risiko (Re-Tx oder Klasse I und II AK im Screening) b) MFI für mittelgradiges Risiko (Erst-Tx Empfänger mit nur Klasse I oder II AK) c) Bereich zwischen 500/1.000 und bzw bleibt Spielraum des Zentrums d) Spielraum: Desensibilisierung, Induktion oder Eingabe als NAHA e) Abweichungen sind möglich, müssen allerdings begründet werden
38
39 Süsal et al EBioMedicine 2016
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