April 2015 - Maarten Naesens - Early renal biopsies- impact of chronic lesions - Hôpital Necker Paris - Actualités Néphrologiques Jean Hamburger

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 2010
0
50
100
150
Calendar Year
Numberofarticlesperyear
PubMed articles on
Fibrosis 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 36
0
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
Prevale
nce
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)
Percentsurvival
(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)
Percentsurvival
N=1197; indication biopsies within the FIRST YEAR posttransplant (N=963)
70%
30%

Early chronic damage associates with
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
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
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
C4dglom
C4dptc
0 max
Individual lesion score

All early chronic damage associates with
interstitial fibrosis
0
20
40
60
80
100
ci=0
ci=1
ci=2-3
1 5 10 15 20
p=0.0005
308
109
74
ci=0
ci=1
ci=2-3
N at risk
271
84
56
203
58
42
83
24
17
Time after transplantation (years)
Percentsurvival
tubular atrophy
0
20
40
60
80
100
ct=0
ct=1
ct=2-3
1 5 10 15 20
p<0.0001
247
212
32
ct=0
ct=1
ct=2-3
N at risk
221
170
21
169
122
12
84
38
3
Percentsurvival
arteriolar hyalino
0
20
40
60
80
100
ah=0
ah=1
1 5 10 15
ah=2-3
275
136
79
ah=0
ah=1
ah=2-3
N at risk
241
112
57
183
83
37
9
2
9
Time after transplantatio
Percentsurvival
mesangial matrix increase
0
20
40
60
80
100
mm=0
mm=1
1 5 10 15 20
p=0.0001mm=2-3
383mm=0
N at risk
333 247 100
Percentsurvival
glomerulosclerosis
0
20
40
60
80
100
gs=0
gs=1
gs=2
1 5 10 15 20
p=0.0009
334gs=0
N at risk
283 217 101
Percentsurvival
vascular intimal thic
0
20
40
60
80
100
cv=0
cv=1
1 5 10 15
cv=2-3
393cv=0
N at risk
336 251 11
Time after transplantatio
Percentsurvival
20
0.0005
ars)
tubular atrophy
0
20
40
60
80
100
ct=0
ct=1
ct=2-3
1 5 10 15 20
p<0.0001
247
212
32
ct=0
ct=1
ct=2-3
N at risk
221
170
21
169
122
12
84
38
3
Percentsurvival
arteriolar hyalinosis
0
20
40
60
80
100
ah=0
ah=1
1 5 10 15 20
p<0.0001ah=2-3
275
136
79
ah=0
ah=1
ah=2-3
N at risk
241
112
57
183
83
37
91
24
9
Percentsurvival
20
0.0005
ears)
tubular atrophy
0
20
40
60
80
100
ct=0
ct=1
ct=2-3
1 5 10 15 20
p<0.0001
247
212
32
ct=0
ct=1
ct=2-3
N at risk
221
170
21
169
122
12
84
38
3
Percentsurvival
arteriolar hyalinosis
0
20
40
60
80
100
ah=0
ah=1
1 5 10 15 20
p<0.0001ah=2-3
275
136
79
ah=0
ah=1
ah=2-3
N at risk
241
112
57
183
83
37
91
24
9
Percentsurvivalase
20
0.0001
ears)
glomerulosclerosis
0
20
40
60
80
100
gs=0
gs=1
gs=2
1 5 10 15 20
p=0.0009
334
122
35
gs=0
gs=1
gs=2-3
N at risk
283
100
28
217
69
17
101
19
5
Percentsurvival
vascular intimal thickening
0
20
40
60
80
100
cv=0
cv=1
1 5 10 15 20
p=0.008cv=2-3
393
58
37
cv=0
cv=1
cv=2-3
N at risk
336
47
28
251
35
16
114
6
5
Percentsurvival

Clustering analysis illustrates
Sis et al Am J Transplant 2010

i
t
ti
v
g
ptc
C4dptc
C4dglom
ci
ct
ah
mm
cv
gs
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
ci
ct
cg
ah
cv
mm
ptc
ti
gs
PC1 (23.9% of variance)
PC2(18.9%ofvariance)
Chronic histological damage
Inflammation and
C4d deposition
Transplant
glomerulopathy

i
t
ti
v
g
ptc
C4dptc
C4dglom
ci
ct
ah
mm
cv
gs
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-censoredgraft
survival

Co-clustering of different histological lesions is
the consequence of their pathophysiology
From Nankivell and Chapman Transplantation 2006
Interstitial
fibrosisTubular atrophy
Glomerulo-
sclerosis
cv / ah

Transplant glomerulopathy doesn’t correlate
well with to the other chronic lesions
i
t
ti
v
g
ptc
C4dptc
C4dglom
ci
ct
ah
mm
cv
gs
cg
r
-1
1

Early transplant glomerulopathy
leads to rapid graft failure

Transplant glomerulopathy
independently associates with proteinuria
Naesens et al J Am Soc Nephrol 2015 (In press)
Proteinuria(g/24h)

Transplant glomerulopathy and proteinuria
interact with each other
From Naesens et al J Am Soc Nephrol 2015 (In press)
1 5 10
0
20
40
60
80
100
Time after biopsy (years)
Death-censoredgraftsurvival(%)
No cg - proteinuria <1.0g/24 h
No cg - proteinuria >1.0g/24h
log-rank
P<0.0001
Cg - proteinuria <1.0g/24 h
Cg - proteinuria >1.0g/24h

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<0.0001
No 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
Low CADI High CADI
0.50
0.75
Histology at 24 months
0 20 40 60 80 100
0
20
40
60
80
100
AUC = 0.82
p = 0.008
T cell proliferation
100% - Specificity%
Sensitivity(%)
0 20 40 60 80 100
0
20
40
60
80
100
B cell proliferation
AUC = 0.88
p = 0.002
100% - Specificity%Sensitivity(%)
0 20 40 60 80 100
0
20
40
60
80
100
AUC = 0.83
p = 0.006
NK cell activation
100% - Specificity%
Sensitivity(%)
0 20 40 60 80 100
0
20
40
60
80
100
AUC = 0.92
p = 0.0005
Dendritic cell migration
100% - Specificity%
Sensitivity(%)
Low CADI High CADI
0.50
0.75
Histology at 24 months
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) – 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
Prevale
nce
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

Transplantation Graft loss
Better AR prevention

Transplantation TCMR Graft loss

Transplantation eGFR Graft loss

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 CsA
0%
5%
10%
15%
20%
Acute rejection incidence
14%
9%
6%
BELA MI BELA LI CsA
0
50
100
eGFR (mL/min/1.73m2)
BELA MI BELA LI CsA
0%
50%
100%
Graft loss at 3 years
95% 96% 95%
BELA MI BELA LI CsA
0
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
***
*
*** *
*** *

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

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
1 5 10
0
20
40
60
80
100
Time after indication biopsy (years)
Percentsurvival
TCMR, IFTA 0/1, untreated
TCMR, IFTA 0/1, treated

1 5 10
0
20
40
60
80
100
Time after indication biopsy (years)
Percentsurvival
Extensive IFTA could be used
to withhold treatment
Naesens et al Unpublished data

Chronic
injury
Prevale
nce
Impact
Causes
Clinical
use
- Surrogate endpoint
for intervention studies
- Target for treatment
- Treatment decisions
Conclusion

Thank you
maarten.naesens@uzleuven.be

April 2015 - Maarten Naesens - Early renal biopsies- impact of chronic lesions - Hôpital Necker Paris - Actualités Néphrologiques Jean Hamburger

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April 2015 - Maarten Naesens - Early renal biopsies- impact of chronic lesions - Hôpital Necker Paris - Actualités Néphrologiques Jean Hamburger