1. No category

Trends in der Nierentransplantation
Wolfgang Arns
[email protected]
Agenda
Focus on B cell activity in renal transplantation
Stratification and treatment strategies:
• Patient stratification by DSAs before and after transplantation
• New algorithm of organ allocation by virtual crossmatching
• Practical aspects of different immunogenicity of HLAs
• Efficacy of anti B cell therapy
Antibodies of clinical relevance
Amico P, SMW 2008; 138(33–34): 472–476
Testing for alloantibodies in renal transplantation
Mehra N, Ann NY Acad Sci 2013, 1-3
The concept of HLA-DSAs and virtual crossmatching
Amico P, SMW 2008; 138(33–34): 472–476
DSA can be preformed
or arise de novo at anytime after Tx
Development of anti-HLA DSA
due to:1,2
• Pregnancy
• Blood product transfusion
• Previous transplantation
Increased risk of acute or
chronic AMR1
Time
de novo DSA
Transplantation
Preformed DSA
Development of DSA hypothesized to be
related to inadequate immunosuppression and
may appear any time after transplantation at
varying levels1
Chronic low-level DSAs may have no detrimental
effect, may have even protective effect3, some have
been implicated in AMR1
Acute AMR
Chronic AMR
Often associated with
antibodies against
HLA class I and/or II4
Often associated with
antibodies against
HLA class II4
AMR, antibody-mediated rejection; DSA, donor-specific antibody; HLA, human leukocyte antigen.
1. Loupy A, et al. Nat Rev Nephrol. 2012;8:348–357; 2. Nankivell BJ, et al. N Engl J Med. 2010;363:145114–62;
3. Turgeon NA, et al. Transplant Rev. 2009;23:25–33; 4. Colvin RB. J Am Soc Nephrol. 2007;18:1046–1056.
6
The influence of de novo HLA antibodies
on graft survival
100
no antibodies (550)
p<0.0001
89%
Percent graft survival
90
NDSA (152)
p<0.0001
80
DSA (66)
70
70%
60
Patients were tested once, post-transplantation
in 2002, and followed for 4 years
50
0
1
2
51%
3
4
Years after testing
DSA, donor specific antibodies; HLA, human leukocyte antigen;
NDSA, non-donor specific antibodies
Lachmann N et al. Clin Transpl. 2006:171–99
Time to new onset of DSAs
IgM antibodies appear first as sign of de novo DSAs
Late onset of ABMR
Sellares J et al. Am J Transplant 2012;12:388–399
The natural history of antibody-mediated allograft
deterioration
ABMR, antibody-mediated rejection; DSAs, donor-specific anti-HLA
antibodies; ENDATs, endothelial-associated transcripts; g, glomerulitis;
IFTA, interstitial fibrosis and tubular atrophy
Loupy A et al. Nat Rev Nephrol. 2012;17;8(6):348–57
C4d-positive vs C4d-negative ABMR
C4d-positive ABMR
C4d-negative ABMR
● Complement activation
● Ifn-γ effects
Cytokines
● Ifn-γ effects
● Endothelial activation
● Endothelial activation
Complement activation
C4d deposition
● Leukocyte recruitment
● Leukocyte recruitment
No detectable C4d deposition
by immunofluorescence
● Fc receptors
C1q
Cytokines
● Fc receptors
● Platelets
Platelets
Endothel ial activation
● Platelets
Platelets
Glomerulitis
Capillaritis
Increased ge ne expression
Microcirculation is the main target of ABMR
ABMR, antibody-mediated rejection
Sis B, Halloran PF. Curr Opin Organ Transplant. 2010;15:42–8
De novo DSAs: Evolution and clinical correlation
Modifyers: Weaning of Immunosuppression – organ quality - immunogenicity
Wiebe C, AJT 2012, 12, 1157-67
Donor-specific anti-HLA Antibodies after transplantation
may be complement dependent or independent
Loupy A et al. N Engl J Med
2013;369:1215-1226
DSAs isotype may switch from IgG1/IgG3 to IgG2/IgG4
Arnold ML, TPI 2014, 27, 253-261
How big is the problem?
It depends on MFI threshold.
The cumulative incidence of de novo DSAs
Hoshino J, Transplantation 2012; 93:1173-78
The cumulative incidence of DSAs after RTP
MFI threshold 500
Everly MJ, TP 2013; 95(3): 410-17
HLA-DSA antibodies and rejection
AMR
TCMR
Caro-Oleas JL, Transplantation 2012, 94, 338-344
The importance of de novo DQ DSAs
hazard ratio for graft loss: 3.7 (p=0.03)
AR 22% p=0.005
AR 36% p=0.005
hazard ratio for graft loss: 11.4 (p=0.001)
Freitas MCS, TP 2013; 95: 1113-19
Higher immunogenicity of DQ3
60
Incidence of DSAs [% of MM at a specific locus]
50
40
Normal CNI
Low CNI
Very low CNI
30
20
10
0
DQ2
Normal: Tac >4; CsA >75
DQ4
Low: Tac 3-4; CsA 50-75
DQ5/6
DQ7/8/9
very low: Tac <4; CsA <50 [ng/ml]
Hidalgo LG et al, Human Immunology 2012; 73: 35 [Alberta, Edmonton, Canada]
Scheme of drug weaning and de novo DSAs
Hoshino J, Transplantation 2012; 93:1173-78
DSAs and nonadherence
Sellares J et al. Am J Transplant 2012;12:388–399
Renal function slope and DSAs
1.0
0.9
DQ7:1046
B27:580
DQ7:100
0.8
1/Kreatinin
0.7
0.6
0.5
kein HLA AK
0.4
0.3
0.2
A2:380
B27:520
DQ7:1200
DQ7:700
CsA/MPA/P
0.1
0.0
0.00
TAC/MPA/P
0.25
0.50
0.75
1.00
1.25
1.50
Jahre post Op
1.75
2.00
2.25
2.50
ABMR: therapeutic options and their
rationale
Fehr T, TPI 2012; 25: 623–632
Σ 211
CDC
FCXM
Multiplex
CDC
74
95
42
matched controls
Patient survival [%]
Desensitization in HLA-incompatibility by plasmapheresis
HLA-incompatibilty is defined as a positive crossmatch by any of
the three techniques: CDC, FCXM or Multiplex Beads
HLA, human leukocyte antigen
Montgomery RA et al. N Engl J Med. 2011;365:318–26
graft survival [%]
Best matches and resultswith acceptable mismatches
Months
Claas FHJ et al. Transplantation. 2009;88(4):447–52
HLA Class II epitope matching: improves outcome
Wiebe C, AJT 2013; 13: 3114-3122
Heidt S, ET Meeting 2014
Cyclosporine vs. Everolimus:
The natural course of longterm effect
Single center experience from the ZEUS and HERAKLES study
Σ 126 patients
[median 1059 d]
65 CSA
[median 991 d]
7 DSAs (10.8%)
61 RAD
[median 551 d]
14 DSAs (23,0%)
Liefeldt L et al. Am J Transplant. 2012;12:1192–8
Cyclosporine vs. Everolimus:
The natural course of longterm effect
Single center experience from the ZEUS and HERAKLES study
Σ 126 patients
[median 1059 d]
65 CSA
[median 991 d]
61 EVR
[median 551 d]
7 DSAs (10.8%)
14 DSAs (23,0%)
2 AMR
8 AMR
0 graft loss
4 graft loss
Liefeldt L et al. Am J Transplant. 2012;12:1192–8
Translating in to clinical praxis
Renal function slope and DSAs
A2:2500
B13:3900
DR7:100
A2:1400
B13:100
DR7:100
1.0
75 Patienten
mTORi
CNI
de novo DSAs+
12%
23%
1/Kreatinin
0.8
0.6
0.4
A2:100
B13:100
DR7:100
DQ8:100
A2:1200
B13:100
DR7:100
DQ8:400
A2:4000
B13:900
DR7:100
0.2
CsA/MPS/P
Cert/MPS/P
0.0
0.00
0.25
0.50
0.75
1.00 1.25 1.50
Jahre post Op
1.75
2.00
2.25
2.50
Comparison of the effects of mTOR inhibitors and
IMDH inhibitors 14
Everolimus
MPA


B cell apoptosis
Induces
Induces
B cell activation


B cell proliferation


B cell differentiation

–
Direct effect
Ig production

 Ig-producing B cells

Indirect effect
T cell dependent
B cell activation


T cell dependent
Ig production


, has direct inhibitory effect; –, no direct effect.
Ig, immunoglobulin; MPA, mycophenolic acid.
1. Heidt S, et al. Clin Exp Immunol. 2010;159:199–207; 2. Haneda M, et al. Transplantation. 2014;97: doi: 10.1097/01.tp.0000441826.70687.f6;
3. Heidt S, et al. Transplantation. 2008;86:1292–1300; 4. Matz M, et al. Transplant Int. 2012:25:1106–1116.
Cellular rejection needs to be controlled to prevent the
formation of de novo DSA1
●
Cellular rejection has been found to coincide with the presence of de novo DSA and
antibody-mediated microvascular injury and may accelerate the time to graft
dysfunction and graft loss1
●
Sufficient inhibition of the cellular/humoral immune response through the use of a
combination of therapies may be required
Antibodies
Antimetabolites (MMF/MPA)
.
1. Srinivas TR, et al. Am J Transplant. 2007;7:586–594;
Figure adapted from Halloran PF, et al. N Engl J Med. 2004;351:2715–2729.
Risk stratification by virtual crossmatch:
higher rejection rate
Amico P, TPI 2011, 24, 560-569
ATG induction in XM-/low DSA+ recipients
Bächler K, AJT 2010; 10: 1254-1262
Therapeutic aspects of the de novo DSA/AMR concept
dnDSA+
biopsy
neg
pos
wait and
see
steroids
ATG
PE/IA
IVIG
rituximab
bortezimib
AMR/TCR
TCR
AMR
Summary
Perspective: B and T cells in Transplantation
Stratification and treatment strategies:
• The approach to immunosuppression is done by stratification of
immunisation, which is defined by HLA antibodies (DSAs).
Allocation by virtual crossmatch is implemented in
Eurotransplant very soon.
• Effect of immunosuppression should avoid de novo DSA, the
influence on preformed DSA is limited.
• Role of induction therapy is not well defined.
• Chronic AMR has a great impact on longterm graft survival with
limited therapeutic effect. A maintenance drug combination is
recommended.
Trends in der Nierentransplantation
Wolfgang Arns
[email protected]