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Early renal biopsies:
impact of chronic
lesions
Maarten Naesens
Actualités Néphrologiques
Jean Hamburger
Institut Pasteur / Hôpital Necker 2015
Starzl et al Ann Surg 1974
64 cases transplanted between 1962-
1964 in Colorado and Denver
ct ci ah cv
1970 1980 1990 2000 20100
50
100
150
Calendar Year
Nu
mb
er
of a
rtic
les
pe
r y
ea
r
PubMed articles onFibrosis and Kidney Transplantation
Research on fibrosis in kidney transplantation
has emerged after 1993
Chronic allograft nephropathy was coined at
the 1st Banff conference in 1991 and refined
Solez et al Kidney Int 1993 Racusen et al Kidney Int 1999
The Helsinki group demonstrated that chronic
damage increases importantly in the first years
Yilmaz et al J Am Soc Nephrol 2003
Baseline Month 12 Month 360
2
4
6
8
Mean CADI score
N=111 N=302 N=206
Chronic injury increases early after
transplantation
Nankivell et al New Engl J Med 2003
Chronic injury increases early after
transplantation in TAC-MMF treated patients
Naesens et al J Am Soc Nephrol 2009
Chronic injury
Prevalence
Impact
Causes
Clinical use
The Sydney group demonstrated that chronic
damage determines graft outcome
Nankivell et al Transplantation 2001
ci=0
ci=1
ci=2-3
Early chronic damage associates with
death-censored graft survival
Naesens et al Am J Transplant 2012
interstitial fibrosis/tubular atrophy
P<0.0001
Death-censored graft survival(all patients)
0
20
40
60
80
100
IFTA = 0
IFTA = 1
5 10 15 20
IFTA = 2-3
Max IFTA grade in 1st year
Time postTX (years)
Perc
en
t su
rviv
al
Death-censored graft survival(all patients)
0
20
40
60
80
100
IFTA = 0
IFTA = 1
5 10 15 20
IFTA = 2-3
Max IFTA grade in 1st year
Time postTX (years)
Perc
en
t su
rviv
al
N=1197; indication biopsies within the FIRST YEAR posttransplant (N=963)
70%
30%
Early chronic damage associates with
death-censored graft survival
From Loupy et al New Eng J Med 2013
eGFR at 1 year 30-60 vs. >60 mL/min
eGFR at 1 year <30 vs. >60 mL/min
IFTA grade 2/3 vs 0/1
Presence of cg/ptc/g
Presence of C1q-binding DSA
10 1001.0
Hazard ratio (95% CI)for kidney graft loss
HR 2.45 (1.09-5.53)
HR 12.5 (5.56-28.1)
HR 2.22 (1.41-3.49)
HR 2.26 (1.31-3.89)
HR 4.78 (2.69-8.49)
Chronic damage associates with
death-censored graft survival
From Naesens et al J Am Soc Nephrol 2015 (In press)
Proteinuria 0.3-1.0 vs. <0.3 g/24h
Proteinuria 1.0-3.0 vs. <0.3 g/24h
Proteinuria >3.0 vs. <0.3 g/24h
eGFR 30-45 vs. >45 mL/min/m2
eGFR 15-30 vs. >45 mL/min/m2
eGFR <15 vs. >45 mL/min/m2
Microcirculation inflammation g+ptc >2 vs. <2
IF/TA grade Banff grade 1 vs. 0
IF/TA grade Banff grade 2-3 vs. 0
Transplant glomerulopathy Banff grade 1 vs. 0
Transplant glomerulopathy Banff grade 2-3 vs. 0
De novo/recurrent glomerular disease Present vs. absent
Polyomavirus associated nephropathy Present vs. absent
10 1001
Hazard ratio (95% CI)for kidney graft loss
HR 1.14 (0.81-1.60)
HR 2.17 (1.49-3.18)
HR 3.01 (1.75-5.18)
HR 1.76 (0.59-5.30)
HR 5.53 (1.99-15.4)
HR 11.7 (4.17-33.0)
HR 1.36 (0.97-1.91)
HR 1.82 (1.25-2.64)
HR 3.45 (2.34-5.07)
HR 1.00 (0.55-1.82)
HR 1.83 (1.11-3.04)
HR 1.35 (0.84-2.19)
HR 5.51 (3.06-9.92)
Chronic damage associates with
death-censored graft survival
Naesens M et al Transplantation 2014
Unsupervised clustering analysis illustrates
collation of chronic injury in the same biopsies
Naesens M et al Am J Transplant 2012
Inflammation + C4d deposition
Inflammation – C4d deposition
Normal
Chronic - inflammation
Chronic + inflammation
Transplant glomerulopathy
gs
cv
mm
ah
ct ci
cg
ti i t
ptc
g
v
C4
d g
lom
C4
d p
tc 0 max
Individual lesion score
All early chronic damage associates with
death-censored graft survival
Naesens et al Am J Transplant 2012
interstitial fibrosis
0
20
40
60
80
100
ci=0
ci=1
ci=2-3
1 5 10 15 20
p=0.0005
308
10974
ci=0
ci=1ci=2-3
N at risk
271
8456
203
5842
83
2417
Time after transplantation (years)
Perc
en
t su
rviv
al
tubular atrophy
0
20
40
60
80
100
ct=0
ct=1
ct=2-3
1 5 10 15 20
p<0.0001
247
21232
ct=0
ct=1ct=2-3
N at risk
221
17021
169
12212
84
383
Time after transplantation (years)
Perc
en
t su
rviv
al
arteriolar hyalinosis
0
20
40
60
80
100
ah=0
ah=1
1 5 10 15 20
p<0.0001ah=2-3
275
13679
ah=0
ah=1ah=2-3
N at risk
241
11257
183
8337
91
249
Time after transplantation (years)
Perc
en
t su
rviv
al
mesangial matrix increase
0
20
40
60
80
100
mm=0
mm=1
1 5 10 15 20
p=0.0001mm=2-3
383
4464
mm=0
mm=1mm=2-3
N at risk
333
3642
247
2333
100
1015
Time after transplantation (years)
Perc
en
t su
rviv
al
glomerulosclerosis
0
20
40
60
80
100
gs=0
gs=1
gs=2
1 5 10 15 20
p=0.0009
334
12235
gs=0
gs=1gs=2-3
N at risk
283
10028
217
6917
101
195
Time after transplantation (years)
Perc
en
t su
rviv
al
vascular intimal thickening
0
20
40
60
80
100
cv=0
cv=1
1 5 10 15 20
p=0.008cv=2-3
39358
37
cv=0cv=1
cv=2-3
N at risk
33647
28
25135
16
1146
5
Time after transplantation (years)
Perc
en
t su
rviv
al
interstitial fibrosis
0
20
40
60
80
100
ci=0
ci=1
ci=2-3
1 5 10 15 20
p=0.0005
308
10974
ci=0
ci=1ci=2-3
N at risk
271
8456
203
5842
83
2417
Time after transplantation (years)
Perc
en
t su
rviv
al
tubular atrophy
0
20
40
60
80
100
ct=0
ct=1
ct=2-3
1 5 10 15 20
p<0.0001
247
21232
ct=0
ct=1ct=2-3
N at risk
221
17021
169
12212
84
383
Time after transplantation (years)
Perc
en
t su
rviv
al
arteriolar hyalinosis
0
20
40
60
80
100
ah=0
ah=1
1 5 10 15 20
p<0.0001ah=2-3
275
13679
ah=0
ah=1ah=2-3
N at risk
241
11257
183
8337
91
249
Time after transplantation (years)
Perc
en
t su
rviv
al
mesangial matrix increase
0
20
40
60
80
100
mm=0
mm=1
1 5 10 15 20
p=0.0001mm=2-3
383
4464
mm=0
mm=1mm=2-3
N at risk
333
3642
247
2333
100
1015
Time after transplantation (years)
Perc
en
t su
rviv
al
glomerulosclerosis
0
20
40
60
80
100
gs=0
gs=1
gs=2
1 5 10 15 20
p=0.0009
334
12235
gs=0
gs=1gs=2-3
N at risk
283
10028
217
6917
101
195
Time after transplantation (years)
Perc
en
t su
rviv
al
vascular intimal thickening
0
20
40
60
80
100
cv=0
cv=1
1 5 10 15 20
p=0.008cv=2-3
39358
37
cv=0cv=1
cv=2-3
N at risk
33647
28
25135
16
1146
5
Time after transplantation (years)
Perc
en
t su
rviv
al
interstitial fibrosis
0
20
40
60
80
100
ci=0
ci=1
ci=2-3
1 5 10 15 20
p=0.0005
308
10974
ci=0
ci=1ci=2-3
N at risk
271
8456
203
5842
83
2417
Time after transplantation (years)
Perc
en
t su
rviv
al
tubular atrophy
0
20
40
60
80
100
ct=0
ct=1
ct=2-3
1 5 10 15 20
p<0.0001
247
21232
ct=0
ct=1ct=2-3
N at risk
221
17021
169
12212
84
383
Time after transplantation (years)
Perc
en
t su
rviv
al
arteriolar hyalinosis
0
20
40
60
80
100
ah=0
ah=1
1 5 10 15 20
p<0.0001ah=2-3
275
13679
ah=0
ah=1ah=2-3
N at risk
241
11257
183
8337
91
249
Time after transplantation (years)
Perc
en
t su
rviv
al
mesangial matrix increase
0
20
40
60
80
100
mm=0
mm=1
1 5 10 15 20
p=0.0001mm=2-3
383
4464
mm=0
mm=1mm=2-3
N at risk
333
3642
247
2333
100
1015
Time after transplantation (years)
Perc
en
t su
rviv
al
glomerulosclerosis
0
20
40
60
80
100
gs=0
gs=1
gs=2
1 5 10 15 20
p=0.0009
334
12235
gs=0
gs=1gs=2-3
N at risk
283
10028
217
6917
101
195
Time after transplantation (years)
Perc
en
t su
rviv
al
vascular intimal thickening
0
20
40
60
80
100
cv=0
cv=1
1 5 10 15 20
p=0.008cv=2-3
39358
37
cv=0cv=1
cv=2-3
N at risk
33647
28
25135
16
1146
5
Time after transplantation (years)
Perc
en
t su
rviv
al
Clustering analysis illustrates
collation of chronic injury in the same biopsies
Sis et al Am J Transplant 2010
Unsupervised clustering analysis illustrates
collation of chronic injury in the same biopsies
Naesens M et al Am J Transplant 2012
i t
ti v
g
ptc
C4
d p
tc
C4d
glo
m
ci
ct
ah
m
m
cv
g
s
cg
r -1
1
-0.5 0.0 0.5 1.0-0.2
0.0
0.2
0.4
0.6
0.8
t iv
C4d ptc
C4d glom
g
cict
cg
ah
cv
mm
ptc
ti
gs
PC1 (23.9% of variance)
PC
2 (1
8.9
% o
f v
ari
an
ce
)
Chronic histological damage
Inflammation andC4d deposition
Transplantglomerulopathy
Unsupervised clustering analysis illustrates
collation of chronic injury in the same biopsies
Naesens M et al Am J Transplant 2012
i t
ti v
g
ptc
C4
d p
tc
C4d
glo
m
ci
ct
ah
m
m
cv
g
s
cg
r -1
1
Graft survival
0
20
40
60
80
100
No chronic damage
Chronic damage
1 2 5 10 15 20
P<0.0001
Time after transplantation(years)
Death
-cen
so
red
gra
ft
su
rviv
al
Co-clustering of different histological lesions is
the consequence of their pathophysiology
From Nankivell and Chapman Transplantation 2006
Interstitial
fibrosis Tubular atrophy
Glomerulo-
sclerosis
cv / ah
Transplant glomerulopathy doesn’t correlate
well with to the other chronic lesions
Naesens M et al Am J Transplant 2012
i t
ti v
g
ptc
C4
d p
tc
C4d
glo
m
ci
ct
ah
m
m
cv
g
s
cg
r -1
1
Early transplant glomerulopathy
leads to rapid graft failure
Naesens et al Am J Transplant 2012
Transplant glomerulopathy
independently associates with proteinuria
Naesens et al J Am Soc Nephrol 2015 (In press)
Pro
tein
uri
a (
g/2
4h
)
Transplant glomerulopathy and proteinuria
interact with each other
From Naesens et al J Am Soc Nephrol 2015 (In press)
1 5 100
20
40
60
80
100
Time after biopsy (years)
De
ath
-ce
ns
ore
d g
raft
su
rviv
al (%
)
No cg - proteinuria <1.0g/24 h
No cg - proteinuria >1.0g/24h
log-rankP<0.0001
Cg - proteinuria <1.0g/24 h
Cg - proteinuria >1.0g/24h
Chronic injury
Prevalence
Impact
Causes
Clinical use
CNIs are a major contributor to decreased
renal function after nonrenal TX
cyclosporine
tacrolimus
Acute CNI nephrotoxicity
Chronic CNI nephrotoxicity
Calcineurin inhibitor nephrotoxicity was
suggested as primary cause of chronic injury
Nankivell et al New Engl J Med 2003
CNI avoidance trials were
not very successful
Sharif et al J Am Soc Nephrol 2011
Calcineurin inhibitor nephrotoxicity was
suggested as primary cause of chronic injury
Snanoudj et al Am J Transplant 2011
0
1
2
3
4
mean ah grade
3 months 12 months 10 years
p=0.8
p=0.01
p<0.0001No CNI
Cyclosporine
0
1
2
3
mean IFTA grade
3 months 12 months 10 years
p=0.01 p=0.02
p<0.0005 No CNI
Cyclosporine
Donor age associates with chronic injury
already at time of transplantation (baseline bx)
De Vusser K et al J Am Soc Nephrol 2013
N=548 baseline biopsies
Donor age (and renal senescence)
are a primary cause of chronic injury
Naesens M et al J Am Soc Nephrol 2009
Donor age > 60 yrs
Donor age 40-60 yrs
Donor age < 40 yrs
Development of chronic CNI nephrotoxicity
is dependent on donor age
Legendre et al Clin Transplant 2007
TCMR increases chronic injury
in subsequent biopsies
Nankivell et al Transplantation 2004
Development of chronic injury determines
outcome of TCMR
No AR AR + 1-y IFTA=0 AR + 1-y IFTA=1
AR + 1-y IFTA=2-3
AR + 1-y IFTA>0 + i
AR + 1-y cg>0
El Ters et al Am J Transplant 2013
mRNA in histologically
normal biopsies at 6
months
Affymetrix HG U133
microarray signature
Prediction of CADI
by 24 months
Naesens, Butte, Sarwal et al. Kidney Int 2011
T cell proliferationat 6 months
Low CADI High CADI0.50
0.75
1.00
1.25
1.50
p = 0.009p = 0.009
Histology at 24 months
Sco
re
B cell proliferationat 6 months
Low CADI High CADI0.50
0.75
1.00
1.25
1.50p = 0.002
Histology at 24 months
Sco
re
NK cell activationat 6 months
Low CADI High CADI0.50
0.75
1.00
1.25
1.50
p = 0.007
Histology at 24 months
Sco
re
0 20 40 60 80 1000
20
40
60
80
100
AUC = 0.82p = 0.008
T cell proliferation
100% - Specificity%
Sen
sit
ivit
y (
%)
0 20 40 60 80 1000
20
40
60
80
100
B cell proliferation
AUC = 0.88p = 0.002
100% - Specificity%S
en
sit
ivit
y (
%)
0 20 40 60 80 1000
20
40
60
80
100
AUC = 0.83p = 0.006
NK cell activation
100% - Specificity%
Sen
sit
ivit
y (
%)
0 20 40 60 80 1000
20
40
60
80
100
AUC = 0.92p = 0.0005
Dendritic cell migration
100% - Specificity%
Sen
sit
ivit
y (
%)
Dendritic cell migrationat 6 months
Low CADI High CADI0.50
0.75
1.00
1.25
1.50p = 0.006
Histology at 24 months
Sco
re
A
B
Data-driven analysis of
unexplained progression of chronic injury
Naesens et al Kidney Int 2011
Fehr et al Kidney Int 2011
Drachenberg et al Kidney Int 2012
O’Connell et al (GOCAR study) - submitted
IHC for immune
cells?? •
Molecular microscope for
diagnosis of “subtle inflammation”
Naesens et al Kidney Int 2011
Fehr et al Kidney Int 2011
Drachenberg et al Kidney Int 2012
O’Connell et al (GOCAR study) – undergoing review
“Subtle inflammation”
IHC for immune
cells?? •
Molecular microscope for
diagnosis of “subtle inflammation”
Chronic ABMR is preceded by
microcirculation inflammation
From Lerut et al Transplantation 2007
Transplant glomerulopathy is preceded by
subclinical ABMR
Loupy et al J Am Soc Nephrol 2015
Chronic injury
Prevalence
Impact
Causes
Clinical use
Chronic injury
Prevalence
Impact
Causes
Clinical use
- Surrogate endpoint
for intervention studies
- Target for treatment
- Treatment decisions
The optimal surrogate endpoint requires a
simple causal relation
Disease Surrogate endpoint Clinical endpoint
Intervention
The optimal surrogate endpoint requires a
simple causal relation
Transplantation Graft loss
Better AR prevention
The optimal surrogate endpoint requires a
simple causal relation
Transplantation TCMR Graft loss
Better AR prevention
The optimal surrogate endpoint requires a
simple causal relation
Transplantation eGFR Graft loss
Better AR prevention
Budde et al Lancet 2011; Budde et al Am J Transplant 2014
eGFR as surrogate endpoint in renal
transplantation?
5-year graft loss:
2.1% in CsA group
2.6% in EVR group
P = 1.00
Z ZEUS trial
Rostaing, Vincenti et al Am J Transplant 2013
eGFR as surrogate endpoint in renal
transplantation?
5-year graft loss:
5% in CsA group
5-6% in BELA group
P = NS
Belatacept LI
Belatacept MI
Cyclosporine
BENEFIT trial
BELA MI BELA LI CsA0%
5%
10%
15%
20%
Acute rejection incidence
14%
9%
6%
BELA MI BELA LI CsA0
50
100
eGFR (mL/min/1.73m2)
BELA MI BELA LI CsA0%
50%
100%
Graft loss at 3 years
95% 96% 95%
BELA MI BELA LI CsA0
50
100
IFTA grade > 0 at 1 year
19% 20%
44%
From Vincenti et al New Engl J Med 2005;Vincenti et al Am J Transplant 2010; Rostaing et al Am J Transplant 2013
The BENEFIT trial shows uncoupling of
acute rejection from eGFR and from failure
***
*
*** *
BELA MI BELA LI CsA0%
5%
10%
15%
20%
Acute rejection incidence
14%
9%
6%
BELA MI BELA LI CsA0
50
100
eGFR (mL/min/1.73m2)
BELA MI BELA LI CsA0%
50%
100%
Graft loss at 3 years
95% 96% 95%
BELA MI BELA LI CsA0
50
100
IFTA grade > 0 at 1 year
19% 20%
44%
From Vincenti et al New Engl J Med 2005;Vincenti et al Am J Transplant 2010; Rostaing et al Am J Transplant 2013
The BENEFIT trial shows uncoupling of
acute rejection from eGFR and from failure
***
*
*** *
*** *
The optimal surrogate endpoint requires a
simple causal relation
Transplantation Graft loss
Innovative prevention/
treatment
IFTA
?
The optimal surrogate endpoint requires a
simple causal relation
TCMR Graft loss
Innovative prevention/
treatment
IFTA
Donor
age/senescenc
e
CNI
nephrotoxicity
Ischemia/reperf
usion
Reflux
nephropathy …
Transplant glomerulopathy as surrogate
endpoint for treatment of ABMR
ABMR Graft loss
Innovative
prevention/treatment
Transplant
glomerulopathy
Transplant glomerulopathy as surrogate
endpoint for treatment of ABMR: EMA view
“CHMP agrees with the Company that the further development of xxxx for
treatment of AMR could be suitable for Conditional Marketing Authorization.
From a pathophysiological point of view, it is likely that adequate treatment
of AMR will lower the risk of transplant glomerulopathy, and that hereby
the risk for graft loss will decrease.
However, worsening or new transplant glomerulopathy 6 months post
treatment has not yet been established in previous studies as a surrogate for
impending graft loss.
The use of TG as the sole primary end point is therefore
questionable. We therefore propose to support this primary
endpoint by a positive trend in mGFR at 6 months.“
CHMP advise February 2015
Prevention of fibrosis is a specific target for
treatment in kidney transplantation
Tampe and Zeisberg, Nat Rev Nephrol 2014
Extensive IFTA could be used
to withhold treatment
Naesens et al Unpublished data
Death-censored graft survival
1 5 100
20
40
60
80
100
Time after indication biopsy (years)
Pe
rce
nt s
urv
iva
l
TCMR, IFTA 0/1, untreated
TCMR, IFTA 0/1, treated
Death-censored graft survival
1 5 100
20
40
60
80
100
Time after indication biopsy (years)
Pe
rce
nt s
urv
iva
l
TCMR, IFTA 0/1, untreated
TCMR, IFTA 0/1, treated
TCMR, IFTA 2/3, untreated
TCMR, IFTA 2/3, treated
Extensive IFTA could be used
to withhold treatment
Naesens et al Unpublished data
Chronic injury
Prevalence
Impact
Causes
Clinical use
- Surrogate endpoint
for intervention studies
- Target for treatment
- Treatment decisions
Conclusion
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