current problems in kidney transplantation: clinical point of view stefan schaub transplantation...
TRANSCRIPT
![Page 1: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/1.jpg)
Current problems in kidney transplantation: Clinical point of view
Stefan SchaubTransplantation Immunology and Nephrology
University Hospital Basel, [email protected]
![Page 2: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/2.jpg)
Allograft loss
Recipient deathwith functioning
allograft
Allograftfailure
50% 50%
Age!!Cardiovascular
InfectionMalignancy
![Page 3: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/3.jpg)
Why do renal allograft fail?
Adapted from El-Zoghby. AJT, 2008
Acute rejection12%
„Chronic“ rejection24%
IF-TA: other, specified causes
8%PyVAN
7%
CNI-toxicity1%
(Recurrent) GN22%
Medical, surgical16%
Unknown10%
![Page 4: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/4.jpg)
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
![Page 5: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/5.jpg)
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
![Page 6: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/6.jpg)
HLA-antibodies as a surrogate for memory
Pregnancy Transfusion Transplant
Naive B-cellIgM positiv
Plasma cellIgG positiv
Naive T-cell
Memory T-cell
Tn
Tm
Bn
PC
TaActivated T-cell
IgG HLA-Ab
![Page 7: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/7.jpg)
Luminex Multiplex technology
bead
A1 A2 A3
A25A24A11
B7 B8 B27
B62B52B51
Color-coded beads Flow cytometer
Data
![Page 8: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/8.jpg)
Clinical relevance of HLA-DSAdetected 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 ↓
![Page 9: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/9.jpg)
DonorHLA
anti-HLA-antibodies
Complement
Plasma cell
B-cell
T-cell
2. Binding strength of HLA-DSA to the target epitope3. Capacity of HLA-DSA to activate complement
5. Protective factors and ‚absorptive capacity‘ of endothelial cells
1. Magnitude and durability of the humoral memory response
4. Density of HLA-molecule expression
Amico P. Curr Opin Organ Transplant 2009
Complex biology…
![Page 10: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/10.jpg)
Organ allocation
HLA-antibodies No HLA-antibodies
Try to transplant around DSA - Acceptable mismatch program - Living donor exchange program
Transplantation around DSAnot achievable - Adapt immunosuppression!!
Proceed with transplant
![Page 11: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/11.jpg)
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
![Page 12: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/12.jpg)
Subclinical allograft pathologies
- Rejection (AMR, TCMR)
- CNI-toxicity
- Polyomavirus nephropathy
„Clinical“ pathologies
„Subclinical“pathologies
Serum creatinine thresholdNickerson P. JASN 1998Rush D. AJT, 2007Loupy A. AJT, 2009
Nankivell B. NEJM, 2003
Schaub S. AJT, 2010
![Page 13: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/13.jpg)
Clinical relevance of subclinical “TCMR”
Park WD. JASN, 2010
Interstitial fibrosis with inflammation at one yearpredicts decline of allograft function
![Page 14: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/14.jpg)
Natural history of de novo DSA and AMR
Wiebe C. AJT 2012;12: 1157–1167
Hourmant. JASN 2005Moreso. Transplant 2012Wiebe. AJT 2012Liefeldt. AJT 2012
![Page 15: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/15.jpg)
Screening for subclinical TCMR/AMR
Non-invasive rejection biomarkersto tailor surveillance allograft biopsy frequency to the individual needs of
every patient.
In which patients?When?How often?
Surveillance biopsies
![Page 16: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/16.jpg)
De novo DSA as a non-invasive biomarkerfor subclinical AMR
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
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
![Page 17: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/17.jpg)
Urinary CXCL10 chemokine as a biomarkerfor subclinical TCMR
CXCL10
CXCL10
CXCL10
CXCL10
CXCL10
Jackson JA, AJT 2011Ho J, Transplantation 2011Schaub S, AJT 2009Hu H. Transplantation 2009Matz M, KI 2006Hauser IA, JASN 2005Hu H, AJT 2004
![Page 18: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/18.jpg)
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)
P-level
Acute Scores - i - t - v - g - ptc
00000
1.2±0.40000
1.2±0.61
0.1±0.30.2±0.40.2±0.5
2.0±0.72.2±0.40.2±0.5
00
0.3±0.50
0.6±0.50.3±0.50.3±0.5
<0.0001
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)
0.400.21
Hirt-Minkowski P. AJT 2012
![Page 19: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/19.jpg)
Urinary CXCL10 – subclinical pathologies
02
4
68
10
1214
16
1820
22
≥24
CXCL10/creat[ng/mmol]
Interstitialinfiltrates
only(n=37)
Tubulitis t1+ any i/v/g/ptc
(n=86)
Tubulitis t2-3+ any i/v/g/ptc
(n=21)
Acute Banffscore zero
(n=206)
Isolated vascular
compartmentinflammation
(n=12)
p=0.07
p<0.0001
p<0.0001
p=0.004
p=0.30
p=0.01
Urinary CXCL10 correlates with the extent ofsubclinical tubulo-interstitial inflammation
Hirt-Minkowski P. AJT 2012
![Page 20: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/20.jpg)
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
![Page 21: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/21.jpg)
SummaryCurrent 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…
![Page 22: Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland](https://reader036.vdocument.in/reader036/viewer/2022062516/56649dcd5503460f94ac15ec/html5/thumbnails/22.jpg)
Acknowledgement
Gideon HöngerPatrizia AmicoPatricia Hirt-MinkowskiFelix BurkhalterMichael DickenmannJürg SteigerDenise BielmannDoris LutzClaudia Petit
Transplant Immunologyand Nephrology
Institute of Pathology
Transplantation and NephrologyWinnipeg, Canada
Peter NickersonDavid RushJulie Ho
Helmut HopferMichael Mihatsch