Section 2
ARE WE CONFUSING CNI
NEPHROTOXICITY WITH
INFLAMMATION?
Daniel Serón
Hospital Vall d’Hebron
Barcelona
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Temporal evolution of histologic lesions
Biopsy
specimens (%)
Mean Banff score
Mean Banff score
961 biopsies from 119 kidney-pancreas and 1 kidney transplant patients with Type 1 diabetes mellitus
1.5
1.0
0.5
0.0
Banff interstitial infiltrate
Banff tubulitis
0
1
2
3
4
5 6-7
Years after transplantation
Subclinical
rejection
8-10
2.0
Chronic interstitial fibrosis
Tubular atrophy
Arteriolar hyalinosis
Fibrointimal thickening
Chronic glomerulopathy
1.5
1.0
0.5
0.0 0
2
4
6
8
10
Years after transplantation
50
Totally sclerosed
glomeruli
40
30
Periglomerular
fibrosis
20
10
00
Interstitial
fibrosis/tubular
atrophy
2
4
6
8
10
Years after transplantation
Glomerulosclerosis
Partial
glomerulosclerosis
1. Nankivell BJ et al. N Engl J Med 2003; 349:2326–2633;
2. Nankivell BJ et al. Transplantation 2004;78:557–565
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Interstitial fibrosis and arteriolar hyalinosis
at Year 5
Nankivell1
Stegall2
_________________________
++/+++ IF (%)
66
17
AH (%)
90*
19†
*Ungraded; †Moderate/severe lesions
1. Nankivell BJ et al. N Engl J Med 2003;349:2326–2333; 2. Stegall MD et al.
Am J Transplant 2011;11:698–707
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
CNI nephrotoxicity
888 sequential biopsies from 99 patients
Percentage affected
100
75
50
Arteriolar hyalinosis
Striped fibrosis
25
Tubular calcification
0
0
2
4
6
8
Years after transplantation
10
Nankivell BJ et al. Transplantation 2004;78:557–565
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Mayo Clinic 1996–2006; causes of deathcensored graft failure (n=153)
Unclassifiable
7 (5%)
Acute rejection
18 (12%)
Glomerular
disease
56 (37%)
Medical/surgical
25 (16%)
IF/TA
47 (31%)
Follow up 50 ± 33 months
El-Zoghby ZM et al. Am J Transplant 2009;9:527–535
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Mayo Clinic 1996–2006; causes of IF/TA (n=47)
Idiopathic
9 (19.1%)
CNI toxicity
1 (2.1%)
Polyoma
nephropathy
11 (23.4%)
Ureteral stenosis
2 (4.2%)
Poor allograft quality
4 (8.5%)
Recurrent
pyelonephritis
7 (14.8%)
Immunologic
(recurrent rejections)
13 (27.6%)
Follow up 50 ± 33 months
Adapted from El-Zoghby ZM et al. Am J Transplant 2009;9:527–535
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Prevalence of CNI nephrotoxicity after
transplantation
Nankivell BJ et al = 96.8%
(Incidence of CNI nephrotoxicity)
El-Zoghby ZM et al = 0.6%
(Graft loss due to CNI nephrotoxicity)
1. Nankivell BJ et al. N Engl J Med 2003;349:2326–2333; 2. El-Zoghby ZM et al.
Am J Transplant 2009;9:527–535
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Definition of nephrotoxicity post-transplantation
Nankivell BJ et al = 96.8%
 NTX was arbitrarily defined as striped fibrosis or arteriolar
hyalinosis supported by tubular microcalcification
El-Zoghby ZM et al = 0.6%
 First step, classification in 5 categories, second step, subgroups
of each category, 12 cases with several injuries were classified
according to the best investigators’ judgment
1. Nankivell BJ et al. N Engl J Med 2003;349:2326–2333; 2. El-Zoghby ZM et al.
Am J Transplant 2009;9:527–535
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Direct and indirect effects of CNI use on renal
physiology, histology and function
Naesens M et al. Clin Am Soc Nephrol 2009;4:481–508
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
CNI-free regimens and chronic allograft
nephropathy (IF/TA); belatacept (BENEFIT)
% of patients
IF/TA at Month 12
n=219
n=226
n=221
Vincenti F et al. Am J Transpl 2010; 10: 535–546
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
The CAN (IF/TA) to Month 3 is an independent
predictor of graft survival
CTN: Chronic transplant nephropathy
n=94 patients
100
Normal=53
Graft survival, %
80
IF/TA=41
60
40
p=0.024
20
RR
95%
Cr (µmol/L)
1.026
(1.005-1.047)
IF/TA (yes vs. no)
5.98
(1.15-31.25)
0
0
1
2
3
4
5
6
7
Years
Serón D et al. Kidney Int 1997;51:310–316
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Describing sub-clinical rejection
N=25 patients; 125 biopsies
0 1 2
Banff Criteria
3
6
12 m
Rush DN et al. Transplantation 1995; 59:511–514
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Inflammation in early protocol biopsies
Graft survival rate (%)
Biopsy at Day 14; n=304
100
Normal finding
90
Borderline change
80
70
Acute rejection
60
n=304 patients
50
0
12
24
36
48
60
72
84
96
108
120
Months
Choi BS et al. Am J Transplant 2005;5:1354–1360
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Inflammation and fibrosis in surveillance biopsy
Fibrosis
Graft survival
Inflammation
Graft survival
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Proper classification of inflammation and
fibrosis
Normal (no inflammation, no fibrosis)
Inflammation (no fibrosis)
Fibrosis (no inflammation)
Inflammation and fibrosis
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Inflammation and IF/TA
SCR + IF/TA
SCR + IF/TA
1 year protocol Bx
1 year protocol Bx
Normal n=40
90
Group I n=22
80
P<0.01
70
Group II n=24
60
50
Graft survival
Graft survival (%)
100
1.0
No fibrosis n=87
0.9
Fibrosis only n=131
0.8
0.6
0.5
0.4
40
0
2
4
6
8
10
Years after transplantation
12
Fibrosis and mild
inflammation n=34
0.7
0.3
12
Normal
86
Fibrosis 122
Fib & i=I 32
Fib & i>I 16
75
107
26
12
24
36
Fibrosis and moderate to severe
inflammation n=19
40
55
12
6
18
28
9
3
48
60
Months post-transplant
SCR + IF/TA
<6 month protocol Bx
Fraction surviving
1.00
Normal=186
0.75
SCR=74
IF/TA=110
0.50
IF/TA+SCR=65
0.25
0
50
100
150
Months after transplantation
200
1. Shishido S et al. J Am Soc Nephrol 2003;14:1046–1052; 2. Cosio FG et al. Am J
Transplant 2005;5:2464–2472; 3. Moreso F et al. Am J Transplant 2006;6:747–52
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUe Nov 2012
AR and BK nephropathy as a risk factors for IF
and inflammation
Adapted from Gago M et al. Am J Transplant 2012;doi 10.1111/j.16006143.2011.03911.x (Epub ahead of print)
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Glomerular adaptation, inflammation, IF/TA and
glomerulosclerosis
Glomerular profiles in the 4-month and 1-year protocol biopsies in a renal transplant with
significant glomerular enlargement.
Ibernon M et al. Kidney Int 2006;76:557–561
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Glomerular adaptation post-transplant
n=61
1st
protocol
biopsy
δVg
Glomerular enlargement
2nd protocol
biopsy
4 months
1 year
Increased glomerular volume (yes/no)
Ibernon M et al. Kidney Int 2006;76:557–561
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Glomerular adaptation?
No glomerular adaptation
Glomerular adaptation
δ Vg≥1 (n=32)
*
*
*
4-month biopsy 1-year biopsy
Glomerular enlargement (δVg,x106 m3)
Glomerular enlargement (δVg,x106 m3)
δ Vg<1 (n=29)
*P<0.05
*
*
4-month biopsy 1-year biopsy
Ibernon M et al. Kidney Int 2006;76:557–561
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Glomerular adaptation?
No glomerular adaptation
Glomerular adaptation
δ Vg<1 (n=29)
Glomerulosclerosis (%)
*p<0.05
4-month biopsy
*
Glomerulosclerosis (%)
δ Vg≥1 (n=32)
1-year biopsy
4-month
biopsy
4-month
1-year
biopsy
1-year
Ibernon M et al. Kidney Int 2006;76:557–561
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Glomerular adaptation?
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Treatment of sub-clinical rejection with steroid
boluses
(n=72; 36 pts per group)
Biopsy group
Randomisation
1
2
3
6
12
Control group
Biopsy group
Control group
Chronic score at 6m
0.50±0.13
1.02±0.31
ns
ci + ct score at 6m
0.21±0.09
0.62±0.18
0.05
Rush D et al. J Am Soc Nephrol 1998;9:2129–2134
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Tacrolimus versus ciclosporin: a case
control study
All treated with MMF and prednisone; n=98
Borderline
50
Acute rejection grade I
% of patients
40
Acute rejection grade II
30
20
10
0
Ciclosporin
Tacrolimus
Moreso F et al. Transplantation 2004;78:1064–1068
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Treatment and prevalence of inflammation
n=435
Percentage of patients
50
Normal
Subclinical rejection
IF/TA
IF/TA+subclinical
rejection
40
30
20
10
0
Ciclosporin Tacrolimus
n=363
n=49
CNI-free
n=23
Moreso F et al. Am J Transplant 2006;6:747–752
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Tacrolimus exposure and evolution of histology
in Year 1 post-transplantation
n=61 pairs of biopsies
Mean tacrolimus C0 <9ng/mL
Mean tacrolimus C0 9–12ng/mL
Mean tacrolimus C0 >12ng/mL
5
4
3
2
**
1
*
0
Chronicity score
at 3 months
Chronicity score
Delta chronicity
at 12 months
score 3–12 months
∗p < 0.05; ∗∗p < 0.01 for low- vs. high-tacrolimus exposure groups
Naesens M et al. Am J Transplant 2007;7:2114–2123
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Impact of sub-clinical inflammation in 1-year
protocol biopsies: The CONCEPT trial
Continuation versus conversion to sirolimus at Month 3; n=121
n
SCI (%)
eGFR (ml/min/1.73m2)
80
70
63.0
60
50
61.4
56.7
51.6
SRL
CsA
p
62
59
–
45.2
15.3
<0.01
CsA-SCI (-)
SRL-SCI (-)
CsA-SCI (+)
SRL-SCI (+)
60.4
55.2
55.0
54.7
54.6
49.4
47.9
40
55.1
52.4
45.8
p=0.023
30
12
18
Months
24
30
Thierry A et al. Am J Transplantation 2011;11:2153–2161
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
CNI plus MMF versus CNI plus SRL: prospective
randomised (June 2000–Oct 2004)
Basiliximab and stop steroids at Day 2
CsA+MMF
(n=50)
CsA+SRL
(n=50)
TAC+MMF
(n=50)
TAC+SRL
(n=50)
18
8
14
4
SCR%
(1y)
22
8
16
6
IF/TA%
(5y)
54
20
42
20
BPAR%
(1y)
Kumar A et al. Transpl Immunol 2008;20:32–42
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
SCR and Chronic humoral rejection
1988–2006
Protocol Bx n = 517
Bx for cause: n = 109
At a mean time of 7 years
CHR
IF/TA nos
Recurrence
De novo
GN
Acute rejection
Polyoma
44
42
11
7
4
1
Moreso F et al. Transplantation 2012;93:41
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Acute Banff score in surveillance Biopsies
Acute score
(p=0.003)
Moreso F et al. Transplantation 2012;93:41
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Surveillance Bx at 6 months in patients
developing DSA
N=315 (DSA=47, no DSA=268)
DSA at 4.6 ±3.0 years
0.7
0.6
0.5
0.4
i
ptc
0.3
0.2
0.1
0
DSA
No DSA
Wiebe C et al. Am J Transplant 2012;12:1157
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Graft survival in patient with de novo DSA
Wiebe C et al. Am J Transplant 2012;12:1157
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Nephrotoxicity or inflammation?
i
NTX
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012
Nephrotoxicity or inflammation?
NTX
i
The step programme was funded and developed by Astellas Pharma Europe Ltd
ADV/12/0034/EUf Nov 2012