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Jacquelin O'Leary Lecture Novartis Sofitel
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Donor-Specific Antibodies
in Liver Transplantation
Jacqueline G. O'Leary, MD MPH
Medical Director, Hepatology Research
Baylor University Medical Center
DSA is not Dichotomous
Level N No DSA Class I Class II Class I & II p-valueNegative 1117 96% 61% 83% 14% <.0001
T-cell+ 22 1% 12% 0 12%
B-cell+ 32 2% 4% 10% 2%
T-cell+ B-cell+ 67 1% 23% 6% 71%
DSA testing ≠ Pregnancy Testing
DSA testing has improved
DSA testing is still imperfect Denatured antigens
MFI is at best semi-quantitative
Effects of DSA are spectral
Liver’s Relative Resistance Ab
Liver is relatively resistant to AMR: Soluble class I HLA antigens
Kupffer cells clearance Immune complexes
Activated complement
Size – 100x microvasculature vs. kidney
Regeneration
Decreased clotting Low Platelets
Coagulopathy
Dual blood supply
Hypocomplementemia
O’Leary JG, et al. AJT 2014
Many Faces of DSA in LT
Acute AMR
Acute rejection
Chronic rejection
Plasma cell hepatitis
Biliary strictures
“Idiopathic” fibrosis
Fibrosis progression – HCV+
Renal AMR in SLKT
Prevalence
1-2%
10% Year 1
8% At risk
O’Leary JG, et al. AJT, 2014
In the Beginning… Early reports of LT did not show preformed DSA
increased graft loss/rejection. Graft failure rates were high
Technology and medications were limited
Gordon RD, et al. Surgery 1986
The Liver Is Different.
Early Graft Loss
Takaya S, et al. Transplant Proceedings 1991;
Ogura K., et al. Transplant Proceedings 1992;
Ogura K, et al. Clin Transplantation 1994;
Retrospective evaluations since the early 90s have
shown graft failure in pts w/ + crossmatch.
1-Month Graft Loss Year 1991 1992
Takaya/Starzl
(n=600)
Ogura/Terasaki
(n=290)
Technology Crossmatch Crossmatch
Positive 29% 47%
Negative 16% 12%
Stratification by strength of crossmatch
“Rejection”
Takaya S, et al. Transplant Proceedings 1991
“Rejection was the most common cause of primary liver allograft failure” w/ + crossmatch.
+12.4%
- 4.2%
Graft loss from rejection
0 1 9
Months
Hyperacute Rejection?
3 cases of SLKT. Hyperacute rejection of the kidney
Precipitous liver allograft loss
Kindey = “canary” heralding liver AMR
Histology = diffuse coagulative necrosis with IgM and C1q + staining = hyperacute rejection
“Rejection”
Manez R, et al. Hepatology 1995
Manez R, et al. Transplant Proceedings 1993
Rejection leading to early graft loss:
High-titer anti-donor IgG antibodies
Crossmatch remained +
Falling complement
Increased CIC
Refractory thrombocytopenia
Pathology = “Rejection”
Graft Loss from DSA197 transplants over 3 years 10% crossmatch +.
15/19 had repeat - crossmatch 2 weeks post-LT.
3 pts “AMR” (DSA, allograft dysfunction, C4d)
3-7 distinct HLA DSA
MFI 4,982-14,174
Outcome:
2 died (40 and 116 days)
One re-transplanted--13 months
Kozlowski T, et al. LT 2011:17; 357
Many preformed DSA “resolve”
Those that do not may lead to devastating AMR
1-Year Graft Loss & Rejection?
Castillo-Rama M, et al. Liver Transplantation 2008
896 LT for preformed HLA Ab:
rejection in patients with Class II +/- I DSA.
Class 1 -Year Graft Loss
I 25%
II 29%
I & II 32%
None 17%
Problem: No multivariate analysisA, B, DR
Acute & Chronic Rejection Evaluated 43 LT –indication liver biopsy—C4d & DSA.
Antibody characteristics:
MFI >500 = +
22 pts class II, 1 class I, 4 both
Musat AI, et al. AJT 2011:11; 500
DSA can play a role in
Acute and Chronic Rejection
DSA/ C4d Other P-value
Number 17 26
Acute
Rejection 88% 50% 0.02
SRR 41% 19% 0.03
N DSA/ C4d
ACR +
Ductopenia 6 100%
Pathology Pathology described in Crossmatch +
Preservation Injury
Vanishing Bile Duct Syndrome
Chronic Rejection
Chronic Rejection
Risk chronic rejection in Crossmatch +
26.3% vs. 4.9%
39 LT patients w/ CR vs. matched comparators.
Chronic Rejection
(N=39)
Comparator
(N=39)
P-value
Any DSA ever 92% 61% P = 0.003
Preformed 60% 41% NS
De novo 62% 38% P = 0.047
DSA post-OLT 79% 56% P = 0.047
Any DSA ever Class I 10% 5% P = 0.008
Class II 38% 33%
Class I & II 44% 23%
none 8% 39%
Demetris AJ, et al. Transplant Proceedings 1987
Takaya S, et al. Transplant Proceedings 1999
O’Leary JG, et al. AJT 2011:11;1868
Post-OLT Total MFI
Post-OLT high MFI Class II DSA.
Cla
ss I
I
Cla
ss I
O’Leary JG, et al. AJT 2011:11;1868
IgG subclass DSA? Does IgG subclass matter?
Multiple IgG subclasses more common in pts w/ graft dysfunction.
IgG3 is present in pts w/ most rapid graft failure.
Multivariable analysis:
IgG3 HR graft loss = 3.35Kaneku H, O’Leary JG, et al. LT 2012
0
10
20
30
40
50
60
70
80
90
100
Pe
rcen
t G
raft S
urv
iva
l
0 1 2 3 4 5 6 7 8 9 10
Years from detection of IgG subclass DSA
Single IgG
Multiple IgGw/o IgG3
Multiple IgG w/IgG3 p=0.009
79%
50%
71%
B
1) Surrogate “robust”
immune attack
2) Intrinsic about IgG3
3) IgG3 test more
specific
Biliary Strictures?
risk of bile duct complications:
37% vs. 10%
Risk factors for anastomotic strictures:
162 LT
ABO-incompatible: 13% vs. 2%
Class II DSA: 23% vs. 8%
Takaya S, et al. Transplant Proceedings 1999
Iacob S, et al. Liver International 2012
BUMC Experience
Large Project:
1/00 to 5/09 Analyze all 1270 pts
(4.2% missing data)
Pre-LT and 1-year
post-LT sample.
Blinded--Terasaki
Foundation
Laboratory
Age 52
Model for End-Stage Liver Disease 16
Cold ischemia time 7.7
Male Sex 65%
Race African-American 8%
Caucasian 73%
Liver Disease HCV 47%
PSC/PBC/AIH 15%
Alcohol 14%
NASH/CC 12%
Hepatocellular Carcinoma 24%
Donor age 42
Rejection 46%
Induction 42%
CNI* 3 months Tacrolimus 65%
Cyclosporine 30%
Steroids* 54%
Mycophenolate* 51%
Antibody Characteristics
1270 patients:
Class I DSA MFI ≥5000Preformed 134 (10.5%)De Novo 3 (0.2%)
Class II DSA MFI ≥5000Preformed 100 (7.9%)De Novo 82 (7.5%)
Pre Post
20,000
15,000
10,000
5,000
MF
I
MFI % persistent P-valuePreformed
Class I1,000-4,999 0% 0.02
5,000-9,999 5%
>10,000 5%
Class I Persistence
O’Leary JG, et al. Liver Transplantation, 2013
Early Graft Loss 60 cases of “Idiopathic” Graft loss <90 days
Pre-transplant sample tested DSA
Path was re-reviewed by Dr. Demetris
Post-perfusion
Indication
Explant / Autopsy
Acute AMR Dx:
1) DSA in serum
2) Diffuse C4d
3) Exclusion of other causes of a similar type of injury
4) Microvascular injury
O’Leary JG, et al. Liver Transplantation, In Press
Case 1Class IgG MFI
(1:3)
IgG
subclass
C1q
(1:3)
I 6,365 Neg 0
I 23,091 1+2+3 16,307
I 4,373 Neg 0
I 23,127 1+2+3 17,309
II 9,531 3 0
II 24,883 1+3 16,389
II 23,158 1+3 9,512
II 17,068 1+3 10,6920
5000
10000
15000
20000
25000
neat 1:3 1:9 1:27 1:81
MF
I
mean class I
mean class II
0
5
10
15
20
25
30
0
500
1000
1500
2000
2500
1 2 3 4 5 6 10 14 18
Biliru
binA
ST
POD
Plts 55 45 51 12 23 20 11
Tx plts 3 1 2
Read as
“biliary obstruction”
↓
Indication Bx
Variable inflammation
+ C4d
Early Graft Loss
AMR - caused or contributed to:
20% idiopathic graft loss if DSA +
Preformed DSA with bead
saturation at 1:27
80% DSA caused or contributed to
graft loss
AMR No AMR
Highest Class I 20,000 3,000
Highest Class II 12,000 2,000
MFISUM 96,000 3,500
Early Graft Loss
AMR - caused or contributed to:
20% idiopathic graft loss if DSA +
Preformed DSA with bead
saturation at 1:27
80% DSA caused or contributed
to graft loss
AMR No AMR
Highest Class I 20,000 3,000
Highest Class II 12,000 2,000
MFISUM 96,000 3,500
Antibody Soup
Pre Post
25,000
20,000
15,000
10,000
5,000
MFI
%
persistent P-valuePreformed
Class II1,000-4,999 1.5% <0.001
5,000-10,000 23%
>10,000 33%
Class II Persistence
O’Leary JG, et al. Liver Transplantation, 2013
MF
I
Preformed Class II - Risk of
Acute RejectionAll other patients
Class II DSA >5000
% R
eje
ction
P = 0.046
Months
HR p-value
Preformed Class II MFI ≥5000 1.58 0.004Non-compliance 1.31 0.12
Autoimmune Etiology 0.99 0.9
Recipient age >50 0.72 <0.001
Recipient African-American 1.37 0.04
Steroids week 4 1.54 <0.001
Mycophenolate week 4 1.23 0.04
Induction Therapy%
Reje
cti
on
Months
P < 0.001
Class II, Ø
Ø, Ø
Ø, Induction
Class II, Induction
1) Induction rejection
2) No ∆ in survival
SurvivalP
atient
Surv
ival
Preformed Class I Preformed Class II
P < 0.001No Antibody
Class I DSA >5000 P = 0.018No Antibody
Class II DSA >5000
Years Years HR p-value
Preformed Class I or II MFI ≥5000 vs. no MFI ≥1000 1.51 0.015Recipient African-American 2.48 <0.001
Hepatitis C viremia* 2.13 <0.001
Donor age > 50 1.51 0.012
Cytomegalovirus infection 1.54 0.015
Recipient age > 60 1.58 0.028
Alcohol, NASH or cryptogenic cirrhosis 1.6 0.045*Censored at aviremia
Multivariable Modeling
De Novo DSA Patient Survival
HR P-value
De Novo Class II DSA (>5000) 1.99 0.005
HCV viremia 1.68 0.002
Recient Age >60 1.76 0.008
Donor age >50 1.52 0.01
African-American Race 1.77 0.02
Kaneku H, et al. AJT 2013
Incidence de novo DSA
8% in first year
Multivariable Modeling
De Novo DSA Formation
Independent predictors of de novo Class II >5000
DSA
HR P-value
Cyclosporine 2.5 0.004
Low CNI levels 2.66 0.02
MELD >15 0.47 0.02
Recipient age >60 0.26 0.03
Kaneku H, et al. AJT 2013
Fibrosis?
Miyagawa-Hayashino A, et al Liver Transplantation 2012
79 pediatric LT—fibrosis progression:
Stage 3/4: 88% vs. 17%
HCV & Fibrosis Progression
1/00 to 5/09
507 HCV viremic patients.
>80% compliance w/ protocol liver bx at year 1, 2, 5.
HCV fibrosis progression is immune mediated.
Hypothesized: Preformed DSA Accelerated fibrosis
in HCV viremic pts.
O’Leary JG, et al Liver Transplantation ePub
Preformed DSA – Fibrosis Progression
Years Years
Sta
ge 2
-4 F
ibro
sis
Fibrosis Progression HR P-value
Preformed Class I MFI 5000 1.44 0.04
Recipient African-American 1.89 0.002
Induction 1.74 <0.001
Donor African-American 0.60 0.003
Cytomegalovirus infection 1.49 0.007
Rejection 1.26 0.05
Donor > 50 years old 1.14 0.30
MELD >15 at transplant 1.27 0.06
Recipient > 50 years old 0.74 0.58
P = 0.02No Antibody
Class I DSA >5000
Fibrosis ≥ Stage 2 HR P-value
Preformed Class II MFI 5000 1.86 <0.001
Recipient African-American 1.87 0.002
Induction 1.73 <0.001
Donor African-American 0.53 <0.001
Cytomegalovirus infection 1.51 0.006
Rejection 1.22 0.10
Donor > 50 years old 1.19 0.19
MELD >15 at transplant 1.35 0.02
Recipient > 50 years old 0.73 0.01
P = 0.006No Antibody
Class II DSA >5000
Preformed DSA - Patient SurvivalP
atie
nt S
urv
iva
l
Years
HR P-value
Preformed Class I MFI 5000 1.63 0.03
Sustained Virologic Response 0.21 <0.001
Recipient African-American 2.85 <0.001
Cytomegalovirus 1.60 0.02
At Risk381 370 350 336 324 300
59 49 44 42 39 37
0
1
0 1 2 3 4 5
Years
0.0
0.2
0.4
0.6
0.8
1.0
Patie
nt S
urv
ival
1
0
Logrank p= 0.014
0 1 2 3 4 5
Years
0.0
0.2
0.4
0.6
0.8
1.0
Patie
nt S
urv
ival
1
0
Logrank p= 0.014P = 0.02
No Antibody
Class I DSA >5000
HR P-value
Preformed Class II MFI 5000 1.72 0.03
Sustained Virologic Response 0.22 <0.001
Recipient African-American 2.62 <0.001
Cytomegalovirus 1.74 0.003
Induction 1.44 0.04
At Risk381 370 350 336 324 300
46 38 34 33 32 31
0
1
0 1 2 3 4 5
Years
0.0
0.2
0.4
0.6
0.8
1.0
Patie
nt S
urv
ival
1
0
Logrank p= 0.043
0 1 2 3 4 5
Years
0.0
0.2
0.4
0.6
0.8
1.0
Patie
nt S
urv
ival
1
0
Logrank p= 0.043P = 0.043
No Antibody
Class II DSA >5000
Dogma: “Liver protects kidney”
Saidman SL, Transplant Immunology 1994
17%
Liver “protects” kidney
from hyperacute rejection from class I
86 patients: Preformed De Novo
In those with DSA:
DSA MFI >2000 MFI >2000 Class I 10 (11.6%) 0Class II 10 (11.6%) 8 (9%)Class I & II 10 (11.6%) 1 (1%)None 56 (65%) 56 (65%)No sample 0 21 (25%)
Median MFI IQR Median MFI IQRClass I 18,550 5,000-23,000 10,000 NA
Class II 19,400 9,100-25,100 10,000 9,000-23,000
Preformed De Novo
SLKT
Saidman SL, et al. Transplant Immunology 1994
Olausson M, et al. AJT 2007
Dar W, et al. AJT 2011
Reichman TW, et al. AJT 2009
O’Leary JG, et al, AJT 2011
Preformed Class I DSA MFI>2000
Months Months
Kidney Liver
% R
eje
cti
on P = NS
None
Class I DSAP = NSNone
Class I DSA
No effect of Preformed Class I DSA on: Patient survival
Liver allograft survival
Renal allograft survival
Renal function
Preformed Class II DSA MFI>2000
Months Months
ACR AMR
% R
eje
cti
on
P = NS None
Class II DSAP = 0.006None
Class II DSA
Renal
Preformed Class II DSA Survival
Years
Patient
% S
urv
ival
P = 0.02
None
Class II DSA
HR p-value
Class II DSA 2.2 0.043
Steroids 1 month 0.03 0.004
Recipient Age >50 6.4 <0.001
Conclusions 3 main reasons why DSA has been under-
appreciated in LT:
DSA is not dichotomous.
Liver is relatively resistant to AMR.
Many faces of DSA in LT.
Acute AMR occurs in LT but is rare.
Highest risk = Class I DSA MFI >15,000 at 1:27
dilution.
Preformed and de novo DSA can impair graft
outcomes.
Acknowledgements
Baylor University Medical Center
Göran Klintmalm, MD PhD
Linda Jennings, PhD
Terasaki Foundation Laboratory
Hugo Kaneku, MD
Paul Terasaki, PhD
University of Pittsburgh Medical Center
Anthony J. Demetris, MD
Emory University
Howie Gebel, PhD
Allan Kirk, MD