Professional Documents
Culture Documents
Antibodies
What fraction of cadaver donor transplants fails as a result of immunologic and non-immunologic causes?
Deduction of the Fraction of Failure (Clinical Transplant 2003 Chapter 36 by Dr. Terasaki) (Clinical Transplant 2003 Chapter 36)
100
HLA-ID Sib
Living Unrelated
50
Deduction of the Fraction of Failure
HLA-ID Sib LD 1st Cadaver (n=3,287) (n=21,194) (n=86,928)
Cadaver
10
It is increasing recognized that immune responses to both HLA and non-HLA targets act together in the pathogenesis of graft rejection.
Vimentin
TissueSpecific
AT1R
Allo
immune
AT1R antibodies act like HLA antibodies. HLA abs AT1R abs
Signaling
Signaling
ERK
AP-1 NK-kB
DAMAGE
(AT1R activating antibodies in renal allograft rejection. N Engl J Med 2005; 352:558-69)
2
AT1R antibody acts like a ligand.
AT1R: the main mediator of Angiotensin II
(ligand)
Liver Kidney
Adrenal cortex
Angiotensin II receptors
Angiotensinogen
Angiotensin I
Angiotensin II
Aldosterone secretion
Renin
Vasoconstriction
Water-salt balance
Rat
Y= +Anti-AT1R
Water-salt balance
Vasoconstriction
Post- Kidney TX
AT1R activating antibodies in renal allograft rejection. N Engl J Med 2005; 352:558-69
16/20
TX Acute Rejection
Antibody-MR
6/7 0/9
Cellular-MR
What is the impact of post-Tx AT1R antibodies on Graft Failure? (graft outcome)
Study Protocol
Study Protocol
The study enrolled a total of 140 patients who received kidney transplants between 1999 and 2008 at EUC, Pitt county Memorial Hospital, Greenville, NC.
All the patients had rejection episodes (at least one) with or without graft failure as the result.
The serum samples at the time of or during rejection were screened for the presence of AT1R antibodies with ELISA using a plate coated with the extracts from Chinese hamster ovary cells over-expressing the human AT1R.
All the patients were previously screened for the presence of HLA-DSA.
Rejection
Pre-TX
99
Post- antiTX
08
(EFU)
Results
anti
+
LOW
83% (n=116)
HIGH
17% (n=24)
1.2
.15
1.1
.05
1
.95
10
20
30
40
50
60
70
80
Anti-AT1R (U/ml)
anti
LOW anti-AT1R
(n=111)
(Total n 133)
HIGH anti-AT1R
(n=22)
47.8 (+/-12.1)
65% 67% 48% 39% 30%
Age
52% 28%
anti
1
1 1 1
88%
Mann-Whitney P=0.0001
1.2 1
.15
1.1
.05 1
LOW
0 10 20
HIGH
30 40 50 60 70 80
.95
Anti-AT1R (U/ml)
1
1
1 1
Functioning (n=74)
13%
Graft Survival ?
Graft Survival
by HLA
vs.
non-HLA
(AT1R)
HLA-based
(Log-rank P < 0.001)
100
Non-HLA-based
(Log-rank P < 0.001)
% Graft Survival
DSA neg
50
(n=85)
Percent graft survival
anti-AT1R neg
(n=116)
DSA pos
0
(n=55)
anti-AT1R pos
(n=24)
1 2 3 4 5 6 7 8 9 10 11
1 2
9 10 11
Years post-rejection
Survival
in the presence of (or absence of)
100
(P<0.0001)
% graft survival
Anti-AT1R 0
alone
(n=11, GF=9)
(n=13, GF=12)
100
% graft survival
50
Independent
Synergistic
Anti-AT1R
alone
(n=11, GF=9)
(n=13, GF=12)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Years post-rejection
Synergistic
Both increasing anti-AT1R & DSA followed by graft failure.
0.00
5.00
10.00
15.00
20.00
25.00
30.00
35.00
40.00
.0
20000 15000 10000
0.0
12.0
24.0
36.0
sCr
10
48.0
60
40
20
5000
0
HD
5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0
Anti-HLA (MFI)
0 10
sCr (mg/dL)
Anti-AT1R (IU/ml)
60 40 20 0
II
sCr
10000
5000
5
DSA
HD
36.0
30.0 35.0 40.0
0
48.0
0.0
0.0 5.0 10.0
12.0
15.0 20.0
24.0
25.0
10 5 sCr
12.0 24.0 36.0
60 40 20
III
HD
0
48.0
2.0
0.0
Months post-Tx
Independent
Increasing anti-AT1R alone
in the absence of HLA antibodies
0.0 50 40
12.0
24.0
36.0
48.0
60.0
10
Anti-AT1R
sCr
H D
8 6
30
Anti-AT1R (IU/ml)
20
4 2
10
0
sCr (mg/dL)
0
0.0 12.0 24.0 36.0 48.0 60.0
40
30 20 Anti-AT1R
2
n d
10
0
0.0 0.0 12.0 12.0 24.0 24.0 36.0 36.0
sCr t x p l
48.0 48.0
60.0 60.0
10 8 6 4 2 0
Months post-Tx
(stable BP)
HTNstage 2 (140/100)
HTNstage 2
200
Systolic
(132/100)
150 100 50 0
Diastolic
BP
(mmHg)
0.0
45 40 35 30 25 20 15 10 5 0
12.0
24.0
36.0
48.0
60.0
H D
(42 IU/ml)
10
8 6
Anti-
AT1R
(IU/ml)
sCr
4 mg/dL 2 0
0.0
12.0
24.0
36.0
48.0
60.0
Months Post-Tx
The patient anti-AT1R level was stable during the first 36 post-Tx months, and the BP was controlled at pre-HTN level.
However, within a couple of months, the level was dramatically increased despite the stable sCr level. And the highest anti-AT1R 42U/ml was finally reached at 40 post Tx month. After this time period, (the patient BP had been HTN-stage 1, and finally) in 8 months after the highest anti-AT1R record, there were two records of HTN stage2 before the patient returned to hemodialysis.
0.0
12.0
24.0
HTNstage 1
36.0
2nd txpl
(127/90)
100 50 0
BP
(mmHg)
35 30 25 20 15 10 5 0
0.0 12.0
10
8
Anti-AT1R (IU/ml)
(33 IU/ml)
sCr
4 mg/dL
2
24.0 Months Post-Tx 36.0 48.0
This patient maintained relatively lower anti-AT1R levels during the first 3 post-Tx years.
The hypertension admitted at the time of Tx was controlled to the normal level at least during two years.
For the last three months before GF (in 3 years of post-Tx), antiAT1R level suddenly jumped up from undetectable level to very high level (33U/ml) . After about 5 months, the BP returned from normal level to HTN stage 1 and the patient was referred back to the 2nd txpl.
Variable Recipient Male Non-black Deceased Donor Age Total HLA mismatch Biopsy-proven Acute Rejection Biopsy-proven Chronic Rejection High anti-AT1R alone DSA alone Both anti-AT1R and DSA Pre-Tx antibodies
Hazard Ratio 0.70 1.53 1.47 0.99 1.05 0.62 1.05 2.31 1.88 2.95 1.13
P 0.16 0.13 0.12 0.41 0.43 0.05 0.87 0.02 0.01 0.00 0.69
95% CI 0.43 0.88 0.91 0.97 0.93 1.15 2.66 2.40 1.01 1.19
Univariable
0.38 - 1.01 0.62 - 1.78 1.14 1.15 1.56 0.62 4.67 3.10 5.57 2.08
5.81
0.00
2.7 - 12.5
Multivariable
4.95
4.00 0.54
0.00
0.00 0.02
2.2 - 11.1
2.2 - 7.4 0.3 - 0.9
Multivariable Analysis
and the patients with AT1R antibodies alone were 5 to 5.8 times more likely to lose their graft than those who dont.
by anti-AT1R P=0.02
by DSA P=0.79
85%
(17/20)
53%
(23/43)
66%
(25/38)
60%
(15/25)
Anti-AT1R positive
Anti-AT1R negative
DSA Positive
DSA negative
Summary
Stratification
of the patients with high AT1R antibodies failed.
32%
Anti-AT1R HIGH
39%
DSA alone
Both neg
29%
Total Failures
Survival
The presence of both DSA & anti-AT1R and anti-AT1R alone showed significantly lower graft survival.
The higher risk of graft failure was observed in the presence of both DSA & anti-AT1R Anti-AT1R alone
Risk
5.8 x
Higher chance of failure
(higher risk than DSA alone which has 4 times higher risk of failure)
Conclusions
AT1R
Non-HLA
AT1R antibodies
can ALSO lower graft survival.
AT1R
Monitoring non-HLA
AT1R antibodies
(as well as HLA antibodies)
AT1R
&
Blockage of AT1 receptors