Current problems in kidney
transplantation: Clinical point of view
Stefan Schaub
Transplantation Immunology and Nephrology
University Hospital Basel, Switzerland
schaubs@uhbs.ch
Allograft loss
Recipient death
with functioning
allograft
Allograft
failure
50%
50%
Age!!
Cardiovascular
Infection
Malignancy
Why do renal allograft fail?
Unknown
10%
Acute rejection
12%
Medical, surgical
16%
„Chronic“ rejection
24%
(Recurrent) GN
22%
CNI-toxicity
1%
IF-TA: other,
specified causes
8%
PyVAN
7%
Adapted from El-Zoghby. AJT, 2008
How to prevent acute / chronic rejection?
1) Avoid transplantation in high risk constellations
(e.g. preformed donor-specific memory)
2) Screening for early / subclinical rejection
How to prevent acute / chronic rejection?
1) Avoid transplantation in high risk constellations
(e.g. preformed donor-specific memory)
2) Screening for early / subclinical rejection
HLA-antibodies as a surrogate for memory
Pregnancy
Naive T-cell
Activated T-cell
Memory T-cell
Tn
Transfusion
Transplant
Bn
Naive B-cell
IgM positiv
Ta
Tm
PC
Plasma cell
IgG positiv
IgG HLA-Ab
Luminex Multiplex technology
Color-coded beads
A1
A11
bea
d
A2
A3
A24
A25
Flow cytometer
Data
B7
B8
B27
B51
B52
B62
Clinical relevance of HLA-DSA
detected by Luminex
Author
Year
N
DSA+
AMR
Graft
survival
Patel
2007
60
20
↑
=
Gupta
2008
121
16
↓
Berg Loonen
2008
34
13
=
Aubert
2009
114
11
=
=
Amico
2009
334
67
↑
↓
Wahrmann
2009
338
39
↑
↓
Vlad
2009
325
27
↑
=
Lefaucheur
2010
402
76
↑
↓
Willicombe
2011
480
45
↑
↓
Caro-Oleas
2012
892
50
↑
↓
Otten
2012
837
290
↓
Complex biology…
T-cell
1. Magnitude and durability
of the humoral memory
response
B-cell
Plasma cell
Complement
anti-HLA-antibodies
4. Density of
HLA-molecule
expression
2. Binding strength of HLA-DSA to the target epitope
3. Capacity of HLA-DSA to activate complement
Donor
HLA
5. Protective factors and ‚absorptive capacity‘
of endothelial cells
Amico P. Curr Opin Organ Transplant 2009
Organ allocation
HLA-antibodies
No HLA-antibodies
Try to transplant around DSA
Proceed with transplant
- Acceptable mismatch program
- Living donor exchange program
Transplantation around DSA
not achievable
- Adapt immunosuppression!!
How to prevent acute / chronic rejection?
1) Avoid transplantation in high risk constellations
(e.g. preformed donor-specific memory)
2) Screening for early / subclinical rejection
Subclinical allograft pathologies
„Clinical“ pathologies
Serum creatinine threshold
„Subclinical“
pathologies
- Rejection (AMR, TCMR)
Nickerson P. JASN 1998
Rush D. AJT, 2007
Loupy A. AJT, 2009
- CNI-toxicity
Nankivell B. NEJM, 2003
- Polyomavirus nephropathy
Schaub S. AJT, 2010
Clinical relevance of subclinical “TCMR”
Interstitial fibrosis with inflammation at one year
predicts decline of allograft function
Park WD. JASN, 2010
Natural history of de novo DSA and AMR
Hourmant. JASN 2005
Moreso. Transplant 2012
Wiebe. AJT 2012
Liefeldt. AJT 2012
Wiebe C. AJT 2012;12: 1157–1167
Screening for subclinical TCMR/AMR
Surveillance biopsies
In which patients?
When?
How often?
Non-invasive rejection biomarkers
to tailor surveillance allograft biopsy
frequency to the individual needs of
every patient.
De novo DSA as a non-invasive biomarker
for subclinical AMR
Not useful <1 year post-transplant (low prevalence)
Annually beyond the 1st year. Restricted to patients at risk?
Detection of de novo DSA should be followed by a biopsy
Treatment options for chronic active AMR are very limited
Prevention of development of de novo DSA is important:
- Screen for and treat subclinical TCMR
- Do not minimize IS in patients with repeated TCMR
- Reinforce drug adherence and improve DR/DQ-matching
Urinary CXCL10 chemokine as a biomarker
for subclinical TCMR
CXCL10
CXCL10
CXCL10
CXCL10
Jackson JA, AJT 2011
Ho J, Transplantation 2011
Schaub S, AJT 2009
Hu H. Transplantation 2009
Matz M, KI 2006
Hauser IA, JASN 2005
Hu H, AJT 2004
CXCL10
Demographic data – surveillance biopsies (n=362)
Acute
score zero
(n=206)
Interstitial
infiltrates
only
(n=37)
Tubulitis t1
+ any
i/v/g/ptc
(n=86)
Tubulitis t2-3
+ any
i/v/g/ptc
(n=21)
Isolated
vascular
compartment
inflammation
(n=12)
0
0
0
0
0
1.2±0.4
0
0
0
0
1.2±0.6
1
0.1±0.3
0.2±0.4
0.2±0.5
2.0±0.7
2.2±0.4
0.2±0.5
0
0
0.3±0.5
0
0.6±0.5
0.3±0.5
0.3±0.5
eGFR
47 (39-58)
51 (45-59)
47 (37-58)
43 (31-57)
48 (36-58)
0.57
Proteinuria
- Prot/creat
- a1m/creat
13 (8-21)
4 (2.5-8.1)
13 (10-24)
6 (3.7-8.5)
14 (9-24)
5 (3.0-7.6)
12 (8-19)
6 (3.2-10.8)
12 (8-15)
5 (1.8-5.4)
0.40
0.21
Acute Scores
-i
-t
-v
-g
- ptc
P-level
<0.0001
Hirt-Minkowski P. AJT 2012
Urinary CXCL10 – subclinical pathologies
p=0.07
p<0.0001
p<0.0001
p=0.004
≥24
22
20
18
16
14
CXCL10/creat 12
[ng/mmol] 10
8
6
4
2
0
p=0.01
p=0.30
Acute Banff
score zero
(n=206)
Interstitial
infiltrates
only
(n=37)
Tubulitis t1
+ any i/v/g/ptc
(n=86)
Tubulitis t2-3
+ any i/v/g/ptc
(n=21)
Isolated
vascular
compartment
inflammation
(n=12)
Urinary CXCL10 correlates with the extent of
subclinical tubulo-interstitial inflammation
Hirt-Minkowski P. AJT 2012
Urinary CXCL10 as a non-invasive biomarker
Urinary CXCL10 correlated with the extent of clinical
and subclinical tubulointersitital inflammation.
Moderate sensitivity (61-63%) and specificity (72-80%)
- Problem 1: tubulitis t1 (=borderline changes)
 clinical relevance of tubulitis t1?
- Problem 2: Urinary CXCL10 does not reflect
vascular compartment inflammation
Summary
Current problems in kidney transplantation
To adapt the immunosuppression to the individual
needs of every patient
- Surveillance biopsies
- Non-invasive biomarker to guide performance of
surveillance biopsies
To accept the facts, that…
- allograft recipients are getting older…
- organ donors are getting older…
- the deceased donor pool will not match the demand
of the ever increasing waiting list…
Acknowledgement
Transplant Immunology
and Nephrology
Transplantation and Nephrology
Winnipeg, Canada
Gideon Hönger
Patrizia Amico
Patricia Hirt-Minkowski
Felix Burkhalter
Michael Dickenmann
Jürg Steiger
Denise Bielmann
Doris Lutz
Claudia Petit
Peter Nickerson
David Rush
Julie Ho
Institute of Pathology
Helmut Hopfer
Michael Mihatsch