experience with antibody-mediated rejection millie samaniego, m.d. associate professor of medicine...
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Experience withAntibody-Mediated Rejection
Millie Samaniego, M.D.Associate Professor of Medicine
University of Wisconsinand
Robert A. Montgomery, M.D., D.Phil.Chief, Division of Transplantation
Director, The Johns Hopkins Comprehensive Transplant CenterThe Johns Hopkins Hospital
•Characteristic histologic features including:1) glomerulitis/capillaritis2) margination of neutrophils in the PTC3) fibrin thrombi4) interstitial hemorrhage5) severe or necrotizing vasculitis
•Diffuse, linear C4d staining in the PTC
•Identification of DSA
Diagnostic Criteria for Acute AMR
Grade 1
Grade 3
AMR Cellular Accommodation
Patterns of Rejection in ABO Incompatible Transplants
Therapeutic Options For The Treatment Of AMR
Antibody Reduction
•Plasmapheresis/IA
•IVIg
B-cell Modulation
•Splenectomy
•Anti-CD20
•Cytoxan
Immunomodulation
•IVIg
•ATG
•IL-2R blockers
•Fk 506, Rapamycin
•MMF/DSG
•CAMPATH?
Antibody Reduction TherapyAntibody 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
•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
Antibody Reduction TherapyAntibody Reduction Therapy
B-Cell ModulationB-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
Days from Transplant
-19 -17 -15 -12 -8 -7 -6 -5 -4 -3 -2 -1 0 +2 +3 +4 +5 +6 +7 +8 +9 +11 +12 +13 +16 +18 +19
64
32 32
16
84
8 84 4 2 4 4
8 8
16
8
16 16 16
2 2 1 1 1
98
85
100
0
20
40
60
80
100
120
0
10
20
30
40
50
60
70
80
90
100
512
128
100100
58
0
Tx
Anti-CD20
DSA titer
PRAPP/ CMVIg
PR
A
DS
A t
iter
Case Study: AMR in (+) Cytotoxic XM withHigh Titer Anti-HLA DSA
Cr 6.5
Cr 1.5
Cr 4.4
Cr 2.1Cr 1.6
CD20=23.7 CD20=0CD19=0
B-cell ModulationB-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
0
16
32
64
128
256
-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
An
ti-A
Tit
ers
(1:
X)
Seru
m C
reatinin
e(m
g/d
L)
4
3
1
2
The Effect of Splenectomy on Anti-Blood Group Ab
512
Tx
Splenectomy
PP/IVIg
Targets of Strategies for Antibody Removal
Plasma cells
B-cells &Pre B-cells
Clonal Expansion
Plasmapheresis/IVIG
Anti-CD20
Splenectomy
Acute De Novo AMR•Occurs in 4-6% of transplants (80-100% fail)
•Risk factors include: + historic XM,history of sensitizing event(s), high risk donor/recipient combination
•Diagnosis should be made by histology anddemonstration of the appearance of DSA
•Historically suspected only after there is a poor response to anti-lymphocytic agents
•By definition the current XM is negative
PP/CMVIg Treatment Protocolfor Acute De Novo AMR
8642Dx ofAMR
PP/Ig
Steroid bolus-OR-
-thymocyte globulin
PP/Ig PP/Ig PP/Ig PP/Ig
Time Relative to Initiation of Therapy (Days)
Plasmapheresis – single plasma volume exchange
IVIG – 100mg/kg following each PP treatment(CMV hyperimmune globulin)
HeparinD/C FK 506
High Grade:
De Novo AMR: Renal Allograft Function
0
5
10
15
Serum Creatinine (mg/dL)
Nadir Rejection1 Week 1 MonthCurrent
* * *
MedianNadir Cr
(IQR)
MedianCr at AMR
(IQR)
Median1 week Cr
(IQR)
Median1 month Cr
(IQR)
MedianCurrent 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)
* p<0.001
1994-2003: 22 recipients of deceased or live donor kidney transplants with AMR by Bx or DSAtreated with PP/IVIg
Mean f/u: 5 1/2 years
PP/CMVIg Treatment for De Novo AMR
Kaplan-Meier Estimate of Graft Survival for recipients who developed de novo AMR and were treated with PP/CMVIg therapy
Allograft Survival
10
20
30
40
50
60
70
80
90
100
0 365 730 1095Time (days)
Live donor Deceased donor
p = NS
10
20
30
40
50
60
70
80
90
100
0 365 730 1095Time (days)
Live donor Deceased donor
10
20
30
40
50
60
70
80
90
100
0 365 730 1095Time (days)
Live donor Deceased donor
p = NS
1-Year: 87.5% 85.8%
Live Deceased
3-Year: 87.5% 77.1%
5-Year: Overall 81.1%
Bx and DSA Proven De Novo AMR
LD DD p
n 5 13
Median Days to AMR
(Range)
11
(8-253)
9
(7-50)
0.25
Median Months F/U
(Range)
13.6
(4-76)
11.2
(3-89)
0.77
De Novo Renal Function
03
69
12
15
Se
rum
Cre
atin
ine
(m
g/d
L)
LD DD
Creatinine at Biopsy Creatinine 1 week
Creatinine 1 mo Current Cr
P=NS for comparison between groups at each timepoint
De Novo AMR Allograft Survival
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
100.00
Survival (%)
0 6 12 18 24 30 36Time (Months)
Live Deceased
POSITIVE CROSSMATCH ABO INCOMPATIBLE
# OF PATIENTS
1-YEAR GRAFT SURVIVAL3-YEAR GRAFT SURVIVAL
86 28
Rejection and Clinical Outcomes Following(+) XM and ABOi
Previous Txs123
31125
# OF PATIENTS
Previous Txs
AMRCELLULAR REJECTION
3/28 (11%)4/28 (14%)
1-YEAR GRAFT SURVIVAL3-YEAR GRAFT SURVIVAL
89.8%80.9%
AMRCELLULAR REJECTION
SUBCLINICAL AMRSUBCLINICAL CELLULAR
SUBCLINICAL AMRSUBCLINICAL CELLULAR
0/28 (0%)7/28 (25%)
92.9%**92.9%
**1 death WNE 1 Noncompliance
7/86 (8%)*16/86 (19%)
27/86 (31%)26/86 (30%)
123
410
*Bx @ 1, 3, 6, 12 mos
(+) XM vs. De Novo AMR
De Novo Desensitized p
n 18 31
Median Days to AMR
(Range)
10
(7-253)
20
(2-634)
0.16
Median Months F/U
(Range)
12.4
(3-89)
14.1
(0.6-65)
0.76
(+) XM vs. De Novo AMR Outcomes
03
69
12
15
Se
rum
Cre
atin
ine
(m
g/d
L)
PP/CMVIg Desensitized De Novo Rejection
Creatinine at Biopsy Creatinine 1 week
Creatinine 1 mo Current Cr
P=0.002
P=0.01
P=0.04
P=NS between groups at current timepoint
Allograft Survival After AMR (+) XM vs. De Novo
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
100.00
Survival (%)
0 6 12 18 24 30 36Time (Months)
(+) XM DeNovo
p=NS
Kaplan-Meier Estimate of Graft Survival (+) CDC XM @ Time of
Tx vs (-) CDC XM
10 20 30 40 50 60 70 80 90
100
% Allograft Survival
0 30 60 90 120 150 180 210 240 270 300 330 360 Time (Days)
+ XM @ Tx - XM @ Tx
+XM @ Tx - XM @ Txp=NS
1 Year Graft Survival
92.3% 87.2%
N= 14 N= 32
Anti-CD20 Rescue ProtocolInclusion Characteristics
•Failure to Respond to Plasmapheresis/CMVIg Therapy
•Study Group•Recipients of Deceased or Live Donor Kidneys
•De novo AMR
•AMR After Desensitization
•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)
Renal Function Following Anti-CD20 Rescue
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)
0
1
2
3
4
5
6
7
8
9
10
Best Cr AMR Cr
2 week Cr 1 month Cr
Current Cr
Best AMR 2 weeks1 MonthCurrent
p=0.0003
p=0.25
p=0.07
p=0.01
17 recipients undergoing -CD20 rescue therapy for AMR
Kaplan-Meier Estimate of Graft Survival for Anti-CD20
Rescue
25
50
75
100
0 1 2 3 4 5 6 7 8 9 10 11 12
Months Following Anti-CD20 Treatment
%Survival
Splenectomy RescueN 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 100%
Median Months Followup
(Range)
6.9
(2.2 – 11.7)
Conventional KPD
A B
B A
# of KPD: 6 (12 patients)
Mean PRA: 14
Unconventional KPD
A O
O A
ABOi
(+) XM
ABOi
ABOi
6 mos Cr: 1.2 mg/dl
AMR: 0%
Patient Survival: 100%
Graft Survival: 91.7%
# of KPD: 5 (13 patients)
Mean PRA: 58
6 mos Cr: 1.1 mg/dl
AMR: 0%
Patient Survival: 100%
Graft Survival: 100%
Cellular 23%Cellular 8%
Paired Donation May Reduce the Incidence of AMR
Summary 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
De Novo AMR AMR after (+) XM AMR after ABOi
PP/IVIg
Response Incomplete Response
Observe
Severe AMR
Anti-CD20 Splenectomy Anti-CD20
Algorithm For Approach To AMR
Acknowledgements Acknowledgements
Matt Cooper
Lorraine Racusen
Mark Haas
Karen King
Andrea Zachary
Susie Lefell
Donna Lucas
Julie Graziani
Renato Vega
Chris Sonnenday
Dan Warren
Chris Simpkins
Janet HillerJennie RickardAmie SwardsonJames BurdickEdward KrausHamid RabbRichard UgarteBrigitte ReebMary Jo HolechekDiane LepleyDorry SegevTomasz Kazlowski
Johns Hopkins InKTP
ColumbiaLloyd Ratner
Johns Hopkins InKTP