1. MAARTEN NAESENS, MD, PHD
MAARTEN NAESENS
DEPARTMENT OF NEPHROLOGY AND RENAL TRANSPLANTATION
DEPARTMENT EU
UNIVERSITY HOSPITALS LEUVEN, BELGIUM, OF NEPHROLOGY AND RENAL TRANSPLANTATION
UNIVERSITY HOSPITALS LEUVEN, BELGIUM, EU
DEPARTMENT OF PEDIATRICS
LABORATORY OF NEPHROLOGY
DEPARTMENT OF MICROBIOLOGY AND ISTANFORD UNIVERSITY, CALIFORNIA, USA
MMUNOLOGY
KU LEUVEN, BELGIUM, EU
LEUVEN, SEPTEMBER 27, 2013
TTS – 2ND TRANSPLANTOMICS AND BIOMARKERS MEETING
BARCELONA, MARCH 2011
3. Why do kidney transplants fail?
All renal allograft recipients transplanted between 01/01/1991 – 31/01/2001 (N=1197)
All renal allograft biopsies performed between 01/01/1991 and 14/04/2011 (N=1365)
Naesens et al. submitted
5. The tissue is the issue
Creatinine
Proteinuria
Diagnostic
threshold
Acute dysfunction
Subclinical acute rejection
Chronic
dysfunction
Time
I-BX
I-BX
I-BX
BX for cause
Nankivell et al. NEJM 2003
Lerut et al. Transplantation 2007
Naesens et al. JASN 2009
Ters et al. AJT 2013
6. The tissue is the issue
Creatinine
Proteinuria
Treatment
Diagnostic
threshold
Acute dysfunction
Subclinical acute rejection
Chronic
Chronic
dysfunction
dysfunction
Acute pathology
I-BX
I-BX
I-BX
BX for cause
Time
Nankivell et al. NEJM 2003
Lerut et al. Transplantation 2007
Naesens et al. JASN 2009
Ters et al. AJT 2013
7. The tissue is the issue
Creatinine
Treatment
Proteinuria
Diagnostic
threshold
Acute dysfunction
Subclinical acute rejection
Acute pathology
I-BX
I-BX
BX for cause
I-BX
Chronic pathology
Chronic pathology
Time
Protocol BX
P-BX
P-BX
P-BX
P-BX
Nankivell et al. NEJM 2003
Lerut et al. Transplantation 2007
Naesens et al. JASN 2009
Ters et al. AJT 2013
9. Peripheral blood “5-gene test”
In independent validation set:
ROC AUC=0.74 (0.61-0.86; P<0.001)
mRNA in blood
Micro-array signature
5 gene signature
DUSP1, PBEF1, PSEN1,
MAPK9
and NKTR
Figure 3: Multi-Center Validation of the QPCR Prediction Probability for AR by the 5-Gene Set.
Li, Naesens, Sarwal et al. AJT 2012
10. One step closer to “Rejectostix”
In independent validation set:
ROC AUC=0.74 (0.61-0.86; P<0.001)
mRNA in urine
3 gene signature
CD3ε, IP-10 and 18s
Suthanthiran et al. NEJM 2013
Ingelfinger and Alexander NEJM 2013
11. 0.50
0.50
Low CADI
High CADI
Low CADI
High CADI
Biopsy prediction of later IF/TA
Histology at 24 months
B
Histology at 24 months
T cell proliferation
B cell proliferation
100
80
80
60
40
AUC = 0.82
p = 0.008
20
Sensitivity (%)
Sensitivity (%)
100
0
60
40
AUC = 0.88
p = 0.002
20
0
0
20
40
60
80
100
0
20
100% - Specificity%
60
80
100
100% - Specificity%
NK cell activation
mRNA in histologically
normal biopsies at 6
months
Dendritic cell migration
80
Microarray signature
“subtle inflammation”
100
80
60
40
AUC = 0.83
p = 0.006
20
0
Sensitivity (%)
100
Sensitivity (%)
40
60
40
AUC = 0.92
p = 0.0005
20
0
0
20
40
60
80
100% - Specificity%
Naesens, Butte, Sarwal et al. Kidney Int 2011
100
0
20
40
60
100% - Specificity%
80
100
Prediction of IF/TA by 24
months
12. Biopsy reclassification: TCMR score
77/300 (26%)
biopsies
reclassified
Halloran et al. Am J Transplant 2013: the INTERCOM study
mRNA in biopsy
Microarray signature
“TCMR score”
13. Cross-organ comparison of rejection?
CRM: the Common Rejection Module (11 genes)
Khatri, Naesens, Sarwal et al. J Exp Med. In press
14. Validation of biomarker candidates
“Rejectostix”3
79% sensitivity
78% specificity
Allomap4
NPV 99.6%
PPV 2.3%
Peripheral blood
5-gene test2
91% sensitivity
94% specificity
TCMR score1
Sensitivity?
Specificity?
1Halloran
et al. AJT 2013
Naesens, Sarwal AJT 2012
3Suthanthiran et al NEJM 2013
4Pham et al NEJM 2010
2Li,
All of these specific diseases are diagnosed by histology of the kidney allograft.
So, where are we currently in kidney transplantation biomarker discovery? Not very far. The TCMR score by the Edmonton group is currently still in the exploratory phase, and it is very unclear how this study will be taken forward toward clinical application, as the biomarker aims to replace the gold standard. The 5-gene test is currently being commercialized by Organ-I, and has excellent predictive performance. However, longitudinal and prospective studies still need to be performed. The Rejectostix by Suthan was validated in a large prospective study, but is likely hampered by insufficient predictive performance. The latter is also the case for the commercially available XDX platform by Allomap for heart transplantation. Using the Allomap signature is no better than doing nothing (Jarcho NEJM 2010, editorial), but way more expensive, and therefore not used. So, all these biomarker studies, except perhaps the organ-i approach, fail in a way.
-----------But the next challenge, and perhaps most important in translational research, is to connect the omics or molecular networks to clinical data and disease networks. There is a growing gap between the extent of high throughput molecular data and the translation of these omics features into clinically meaningful concepts. This integration of omics and clinics can only happen if clinical research is combined with molecular work through integrated bioinformatics. Systems biology is an emerging approach applied to biomedical and biological scientific research. Systems biology is a biology-based inter-disciplinary field of study that focuses on complex interactions within biological systems, using a more holistic perspective (holism instead of the more traditional reductionism) approach to biological and biomedical research.
