Transcript Effective Treatment of Antibody

Experience with
Antibody-Mediated Rejection
Millie Samaniego, M.D.
Associate Professor of Medicine
University of Wisconsin
and
Robert A. Montgomery, M.D., D.Phil.
Chief, Division of Transplantation
Director, The Johns Hopkins Comprehensive Transplant Center
The Johns Hopkins Hospital
Diagnostic Criteria for Acute AMR
•Characteristic histologic features including:
Grade 1
Grade 3
1) glomerulitis/capillaritis
2) margination of neutrophils in the PTC
3) fibrin thrombi
4) interstitial hemorrhage
5) severe or necrotizing vasculitis
•Diffuse, linear C4d staining in the PTC
•Identification of DSA
Patterns of Rejection in
ABO Incompatible Transplants
AMR
Cellular
Accommodation
Therapeutic Options For The
Treatment Of AMR
Antibody Reduction
Immunomodulation
•Plasmapheresis/IA
•IVIg
•IVIg
•ATG
B-cell Modulation
•IL-2R blockers
•Splenectomy
•Fk 506, Rapamycin
•Anti-CD20
•MMF/DSG
•Cytoxan
•CAMPATH?
Antibody Reduction Therapy
•High dose IVIG (1-2 gms/kg)
•Mechanism:
•Anti-idiotypic networks probably important
•Many putative immunomodulatory pathways identified
•Advantages:
•In vitro test for predicting efficacy
•Ease of administration?
•Disadvantages:
•Non-responders
•Different techniques required to follow DSA titers
•Less rapid Ab removal, unproven for high-titer DSA
•Toxicity & batch-to-batch variability
•Unproven for ABOi Tx
Antibody Reduction Therapy
•Plasmapheresis/Low Dose IVIg (100 mg/kg)
•Mechanism:
•Rapid reduction in anti-HLA or isoagglutinin Ab
•Induces donor specific unresponsiveness (HLA) or
accommodation (ABOI)
•Advantages:
•Predictable kinetics of plasmapheresis
•No evidence of “nonresponders”
•Able to easily follow DSA levels during/after therapy
•Disadvantages:
•DSA may rebound between treatments or if discontinued
•Treatment may be prolonged and immunosuppressive
•Expensive and resource intensive
B-Cell Modulation
•Anti-CD20
•Mechanism:
•Rapid ablation of the peripheral B-cell compartment
•Advantages:
•Probably reduces precursor cells responsible for clonal
expansion during AMR
•May produce more effective antibody reduction when
combined with plasmapheresis or IVIG
•Well-tolerated, little apparent toxicity
•Effect on the immune system is temporary (6-months)
•Disadvantages:
•Plasma cells persist in the spleen
•May not, on its own, reduce DSA titers during AMR
•Immunosuppressive
Case Study: AMR in (+) Cytotoxic XM with
High Titer Anti-HLA DSA
512
DSA titer
Cr 6.5
128
120
100
100100
Cr 4.4
100
98
90
Cr 2.1
Cr 1.5
85
100
Cr 1.680
70
80
60
58
64
50
60
Anti-CD20
CD20=23.7
40
32
CD20=0
CD19=0
40
30
32
Tx
20
16
20
16
8
4
8 8
4 4 2 4
4
8 8
16 16 16
8
10
2 2 1
1
0
-19
-17
-15
-12
-8 -7 -6 -5 -4 -3 -2 -1
0
+2 +3 +4 +5 +6 +7 +8 +9
Days from Transplant
+11 +12 +13
+16
1
0
+18 +19
0
PRA
DSA titer
PP/ CMVIg
PRA
B-cell Modulation
•Splenectomy
•Mechanism:
•Reduces plasma cells, precursor cells, B-cell immune
surveillance capabilities
•Advantages:
•Can be performed using minimally invasive techniques
•May produce more effective antibody reduction when
combined with plasmapheresis or IVIG
•Disadvantages:
•Life-long risk of sepsis from encapsulated bacteria
•Does not appear on its own to reduce DSA titers
•Effect on immune system is permanent
The Effect of Splenectomy on Anti-Blood Group Ab
PP/IVIg
512
256
4
3
128
Tx
2
64
1
32
16
0
-28 -23 -21 -18 -16-15 -14 -12 -10 -6 -4
-3 -2
-1
0 3
5
7
8 10 12 14 17 21 25 27 31 32 34 40 42 45
Day With Respect to Transplant
Serum Creatinine
(mg/dL)
Anti-A Titers (1:X)
Splenectomy
Targets of Strategies for Antibody Removal
Plasma cells
Plasmapheresis/IVIG
Splenectomy
Clonal Expansion
B-cells &
Pre B-cells
Anti-CD20
Acute De Novo AMR
•Occurs in 4-6% of transplants (80-100% fail)
•By definition the current XM is negative
•Risk factors include: + historic XM,
history of sensitizing event(s), high risk
donor/recipient combination
•Historically suspected only after there is a poor
response to anti-lymphocytic agents
•Diagnosis should be made by histology and
demonstration of the appearance of DSA
PP/CMVIg Treatment Protocol
for Acute De Novo AMR
Plasmapheresis – single plasma volume exchange
Steroid bolus
-ORa-thymocyte globulin
IVIG – 100mg/kg following each PP treatment
(CMV hyperimmune globulin)
PP/Ig
PP/Ig
PP/Ig
PP/Ig
PP/Ig
Dx of
AMR
2
4
6
8
Time Relative to Initiation of Therapy
(Days)
High Grade:
Heparin
D/C FK 506
De Novo AMR: Renal Allograft Function
* p<0.001
15
10
Serum Creatinine
(mg/dL)
*
*
*
5
1994-2003: 22 recipients
of deceased or live donor
kidney transplants
with AMR by Bx or DSA
treated with PP/IVIg
0
Nadir
1 Week
Current
Rejection
1 Month
Mean f/u: 5 1/2 years
Median
Nadir Cr
(IQR)
Median
Cr at AMR
(IQR)
Median
1 week Cr
(IQR)
Median
1 month Cr
(IQR)
Median
Current Cr
(IQR)
3.3
(2.2 – 7.1)
6.4
(3.2 – 9.3)
4
(2.3 – 7.9)
1.9
(1.5 – 3.0)
1.5
(1.2 – 2.1)
PP/CMVIg Treatment for De Novo AMR
100
90
Allograft Survival
80
70
Live
p = NS
60
p = NS
50
40
30
Deceased
1-Year: 87.5%
85.8%
3-Year: 87.5%
77.1%
20
10
0
365
Time (days)
Live
Live donor
donor
730
Deceased
Deceased donor
donor
1095
5-Year: Overall 81.1%
Kaplan-Meier Estimate of Graft Survival for recipients who
developed de novo AMR and were treated with PP/CMVIg therapy
Bx and DSA Proven De Novo AMR
n
LD
DD
5
13
Median Days to AMR
11
(Range) (8-253)
Median Months F/U 13.6
(Range) (4-76)
9
(7-50)
11.2
(3-89)
p
0.25
0.77
0
Serum Creatinine (mg/dL)
3
6
9
12
15
De Novo Renal Function
LD
Creatinine at Biopsy
Creatinine 1 mo
DD
Creatinine 1 week
Current Cr
P=NS for comparison between groups at each timepoint
De Novo AMR Allograft Survival
100.00
90.00
80.00
70.00
60.00
Survival
(%)
50.00
40.00
30.00
20.00
10.00
0.00
0
6
12
18
Time (Months)
Live
24
Deceased
30
36
Rejection and Clinical Outcomes Following
(+) XM and ABOi
POSITIVE CROSSMATCH
# OF PATIENTS
86
1
2
3
31
12
5
Previous Txs
AMR
27/86 (31%)
CELLULAR REJECTION 26/86 (30%)
7/86 (8%)*
SUBCLINICAL AMR
SUBCLINICAL CELLULAR 16/86 (19%)
1-YEAR GRAFT SURVIVAL
3-YEAR GRAFT SURVIVAL
*Bx @ 1, 3, 6, 12 mos
89.8%
80.9%
ABO INCOMPATIBLE
28
# OF PATIENTS
Previous Txs
1
2
3
AMR
CELLULAR REJECTION
4
1
0
3/28 (11%)
4/28 (14%)
0/28 (0%)
SUBCLINICAL AMR
SUBCLINICAL CELLULAR 7/28 (25%)
1-YEAR GRAFT SURVIVAL
3-YEAR GRAFT SURVIVAL
**1 death WNE
1 Noncompliance
92.9%**
92.9%
(+) XM vs. De Novo AMR
n
Median Days to AMR
(Range)
Median Months F/U
(Range)
De Novo
Desensitized
18
31
10
(7-253)
12.4
(3-89)
20
(2-634)
14.1
(0.6-65)
p
0.16
0.76
(+) XM vs. De Novo AMR Outcomes
15
P=0.04
P=0.01
0
Serum Creatinine (mg/dL)
3
6
9
12
P=0.002
PP/CMVIg Desensitized
Creatinine at Biopsy
Creatinine 1 mo
De Novo Rejection
Creatinine 1 week
Current Cr
P=NS between groups at current timepoint
Allograft Survival After AMR (+) XM
vs. De Novo
100.00
90.00
80.00
70.00
p=NS
60.00
Survival
(%)
50.00
40.00
30.00
20.00
10.00
0.00
0
6
12
18
Time (Months)
(+) XM
24
30
DeNovo
36
Kaplan-Meier Estimate of Graft Survival
(+) CDC XM @ Time of Tx vs (-) CDC XM
1 Year
Graft Survival
100
90
80
70
p=NS
60
% Allograft 50
Survival
40
30
20
+XM @ Tx - XM @ Tx
N= 14
N= 32
92.3%
10
0
30
60
90
120 150 180 210 240 270 300 330 360
Time (Days)
+ XM @ Tx
- XM @ Tx
87.2%
Anti-CD20 Rescue Protocol
Inclusion Characteristics
•Failure to Respond to Plasmapheresis/CMVIg Therapy
•Poor or Incomplete Clinical Response
•Persistence of High-Titer DSA
•Persistence of Histologic Evidence of AMR
•Initial Histologic Features That Portend Poor Outcome
and/or Graft Loss (Grade 2-3 AMR)
•Study Group
•Recipients of Deceased or Live Donor Kidneys
•De novo AMR
•AMR After Desensitization
Renal Function Following Anti-CD20 Rescue
p=0.0003
10
p=0.01
p=0.07
9
p=0.25
8
7
17 recipients
undergoing a-CD20
rescue therapy
for AMR
6
5
4
3
2
1
0
Best
AMR
2 weeks 1 Month Current
Best Cr
2 week Cr
Current Cr
AMR Cr
1 month Cr
Best
AMR
2 weeks
1 month
Current
1.8
(1.4 – 2.1)
4.3
(2.5 – 6.5)
3.4
(1.9 – 5.4)
2.1
(1.6 – 3.3)
1.7
(1.1 – 2.6)
Kaplan-Meier Estimate of Graft
Survival for Anti-CD20 Rescue
100
75
%
Survival
50
25
0
1
2
3
4
5
6
7
8
9
Months Following Anti-CD20 Treatment
10
11
12
Splenectomy Rescue
N
4
Median Days to AMR
(Range)
4
(2-15)
Median Days to Splenectomy Following AMR Dx
(Range)
1
(1-4)
Median SCr at Biopsy Dx
(Range)
3.4
(1.5 – 6.0)
Median SCr 1 week
(Range)
2.1
(0.8 – 5.8)
Median SCr 1 month
(Range)
1.5
(0.7 – 2.3)
Median Current SCr
(Range)
1.3
(1.2 – 2.6)
Allograft Survival
Median Months Followup
(Range)
100%
6.9
(2.2 – 11.7)
Paired Donation May Reduce the Incidence of AMR
Conventional KPD
Unconventional KPD
A
B ABOi
A
O ABOi
B
A ABOi
O
A (+) XM
# of KPD: 6 (12 patients)
# of KPD: 5 (13 patients)
Mean PRA: 14
Mean PRA: 58
6 mos Cr: 1.2 mg/dl
6 mos Cr: 1.1 mg/dl
AMR: 0% Cellular 8%
AMR: 0%
Patient Survival: 100%
Patient Survival: 100%
Graft Survival: 91.7%
Graft Survival: 100%
Cellular 23%
Summary
•The diagnosis of AMR can now be made with a high level of certainty
•There are therapeutic interventions for AMR with clinically proven efficacy
•De novo AMR has a good long-term prognosis when treated with PP or IVIg
•Results of PP or IVIg treatment for De novo AMR and AMR in the setting
of desensitization are comparable
•A (+) cytotoxic XM at the time of Tx does not predict a worse outcome
•AMR recalcitrant to PP/IVIg is associated with a lower graft survival rate
•Results of emergent splenectomy at the time of severe AMR look promising
•KPD may decrease AMR by lowering immunologic risk
Algorithm For Approach To AMR
De Novo AMR
AMR after (+) XM
AMR after ABOi
PP/IVIg
Severe AMR
Anti-CD20
Splenectomy
Response
Observe
Incomplete Response
Anti-CD20
Acknowledgements
Johns Hopkins InKTP
Matt Cooper
Lorraine Racusen
Mark Haas
Karen King
Andrea Zachary
Susie Lefell
Donna Lucas
Julie Graziani
Renato Vega
Chris Sonnenday
Dan Warren
Chris Simpkins
Johns Hopkins InKTP
Janet Hiller
Jennie Rickard
Amie Swardson
James Burdick
Edward Kraus
Hamid Rabb
Richard Ugarte
Brigitte Reeb
Mary Jo Holechek
Diane Lepley
Dorry Segev
Tomasz Kazlowski
Columbia
Lloyd Ratner