Current problems in kidney transplantation: Clinical point of view Stefan Schaub Transplantation Immunology and Nephrology University Hospital Basel, Switzerland [email protected]
Feb 10, 2016
Current problems in kidney transplantation: Clinical point of view
Stefan SchaubTransplantation Immunology and Nephrology
University Hospital Basel, [email protected]
Allograft loss
Recipient deathwith functioning
allograft
Allograftfailure
50% 50%
Age!!Cardiovascular
InfectionMalignancy
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%
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 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
Luminex Multiplex technology
bead
A1 A2 A3
A25A24A11
B7 B8 B27
B62B52B51
Color-coded beads Flow cytometer
Data
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 ↓
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…
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
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
- 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
Clinical relevance of subclinical “TCMR”
Park WD. JASN, 2010
Interstitial fibrosis with inflammation at one yearpredicts decline of allograft function
Natural history of de novo DSA and AMR
Wiebe C. AJT 2012;12: 1157–1167
Hourmant. JASN 2005Moreso. Transplant 2012Wiebe. AJT 2012Liefeldt. AJT 2012
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
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
Urinary CXCL10 chemokine as a biomarkerfor subclinical TCMR
CXCL10CXCL10
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
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
Urinary CXCL10 – subclinical pathologies
02468
10121416182022
≥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=0.07p<0.0001p<0.0001p=0.004
p=0.30
p=0.01
Urinary CXCL10 correlates with the extent ofsubclinical 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
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…
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