Welche Donor-spezifischen HLA Antikörper sind schädlich?

Prof. Dr. med. Caner Süsal Transplantationsimmunologie

Institut für Immunologie Universität Heidelberg

Sensitization – Alloantibody Production

Before Transplantation Hyperacute rejection Accelerated humoral rejection Delayed graft function

After Transplantation (de novo)

“Chronic rejection”

Alloantibodies

Alloantibodies

HLA (A, B, C, DRB1/3/4/5, DQA1, DQB1, DPA1, DPB1) Non-HLA

Angiotensin II Typ 1 R MIC-A Endothelial antigens

Antibody Specification

CDC-PRA ELISA-PRA Luminex (PRA, Single Antigen)

Süsal et al, Transfus Med Hemother 2013

Sensitization against HLA-B27 MM from the previous Tx

CDC-PRA: 1 Specificity

ELISA-PRA: 6 Specificities

Luminex-SA: 33 Specificities

Süsal, Opelz Transplantation 2002

Pre-Tx Anti-HLA Antibody Status (ELISA) CDC-PRA <5%

Pre-Tx Luminex SA Testing (DSA or Non-DSA) CDC- and ELISA-Negative Kidney Tx Recipients

cut-off 1,000 MFI

45%

66%

Graft Loss Non-Rejector

Class I

31%50%

Graft Loss Non-Rejector

Class II

45%

55%

66%

34%

31%

69%

50%

50%

Graft Loss Non-Rejector Graft Loss Non-Rejector

Class I Class II

Positive Graft Loss Patients Positive Non-Rejectors

Süsal et al. Transplantation 2011

Disadvantages of Presensitization 1. Prolonged waiting time

2. Inferior graft survival

Morath et al., Transplantation 2010

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 90

9. Desensitization in positive-DSA/XM living-Tx

Heidelberg Algorithm for Transplantation of High-Risk Sensitized Patients

Four High Risk Groups

DSA- and XM-Positive Patients

Pre-Tx HLA Antibody Status (ELISA) Deceased Donor Kidney Transplants 2003-2008

CTS Serum Study

Hum Immunol 70:569-573, 2009

Morath… Süsal, Transplantation 2010

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 90

9. Desensitization in positive-DSA/XM living-Tx

Heidelberg Algorithm for Transplantation of High-Risk Sensitized Patients

Total Kidney Tx, Heidelberg Tx Center 2001-2013

18 19 20 2538 30 37 43

57 5365 57 54

6341

69 54

8077

10574

86 9587

88 8981

60

8979

118107

117

142 143148 152

145

0

50

100

150

200

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 31.12.2013

verstorbenen Spende

Lebendspender143

Heidelberg Algorithm Since April 2006

CTS Serum Study (www.ctstransplant.org)

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

Donor-Specific HLA Alloantibodies (DSA)

Donor-Specific HLA Alloantibodies (DSA)

Zecher et al, NDT, 2017

Morath… Süsal, Transplantation 2010

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 90

9. Desensitization in positive-DSA/XM living-Tx

Heidelberg Algorithm for Transplantation of High-Risk Sensitized Patients

1. International CTS Serum Project

2. Heidelberg Pediatric Cohort

3. Heidelberg High-Risk Population

Clinical Relevance of Post-Tx DSA Monitoring

Association of de novo DSA and Non-DSA with Graft Loss

Association of de novo DSA and Non-DSA with Graft Loss cut-off 500 MFI

P<0.001

P<0.22

Süsal et al, Transplantation 2015

N=83 N=83

P<0.001

P<0.22

C1q Positivity C1q DSA C1q non-DSA

48%

24%

38%

0% 0% 0%

With graft loss Without graft loss

C1q-Positivity in DSA-Positive Patients cut-off 300 MFI

n=51

Süsal et al, Transplantation 2015

Association of C1q-DSA at the Time of Kidney Transplant Biopsy with Late Graft Failure in

Pediatric Renal Transplant Recipients

DSA─

DSA+

p=0.002

DSA─ DSA+, C1q─

DSA+, C1q+ p<0.001

Fichtner et al, Pediatr Nephrol 2016

n=35

n=17

n=9

C1q-DSA: positive predictive value: 89% negative predictive value: 87%

Heidelberg Adult High-Risk Collective Tx: 2006-2011; Follow up: 09.2013

Apheresis + Rituximab

Schäfer et al, HLA 2016

N=74; 16 AMR; 6 AMR-GL; All 6 were post-Tx C1q-DSA-pos.

Pre- and post-transplant DSA status and sCD30

Pre-Tx DSA neg

Pre-Tx DSA pos C1q-DSA neg Pre-Tx C1q-DSA pos Pre-Tx DSA neg

Post-Tx DSA neg.

Post-Tx C1q-DSA neg

Post-Tx C1q-DSA neg

Post-Tx C1q-DSA pos De novo C1q-DSA pos

Number (N) 18 38 11 2 6

Pre-Tx sCD30 3 (17%) 9 (24%) P=0.73 3 (27%) P=0.65 2 (100%) P=0.05 4 (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

Heidelberg High-Risk Collective Tx: 2006-2011; Follow up: 09.2013

Schäfer et al. 2015

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

Pre-Tx DSA (Luminex-SA) CDC-/ELISA-Positive Presensitized Recipients

Süsal et al, EBioMedicine 2016

HR=2.95 P<0.001

62%

Süsal et al, EBioMedicine 2016

Pre-Tx DSA and sCD30 CDC-/ELISA-Positive Presensitized Recipients

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)

JASN 2017, in press

www.efi2017.org

a) 3.000 MFI für Hoch-Risiko (Re-Tx oder Klasse I und II AK im Screening) b) 5.000 MFI für mittelgradiges Risiko (Erst-Tx Empfänger mit nur Klasse I oder II

AK) c) Bereich zwischen 500/1.000 und 3.000 bzw. 5.000 bleibt Spielraum des

Zentrums d) Spielraum: Desensibilisierung, Induktion oder Eingabe als NAHA e) Abweichungen sind möglich, müssen allerdings begründet werden

Süsal et al EBioMedicine 2016