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Interplay of subclinical fibrosisand
inflammation
D. SerónNephrology Department Hospital Vall d’HebronBarcelona
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Inflammation with and without fibrosis
Inflammation and CHR
Innate immunity and inflammation
Surveillance biopsies
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Inflammation with and without fibrosis
Inflammation and CHR
Innate immunity and inflammation
Surveillance biopsies
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Inflammation
Inflammation and fibrosis in
surveillance Bx
Dimény E, Clin Transplantation 1995; 58(11): 1195Serón D, Kidney Int 1997; 51: 310Nankivell BJ et al, Transplantation 2004; 78:242Choi BS et al, Am J Transplant 2005; 5: 1354
Fibrosis
Graft survival
Graft survival
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SCR and CAN in paired biopsiesn=598 Bx, (no SCR 462, SCRB 102, SCRA 34)
Nankivell BJ et al, Transplantation 2004; 78:242Ibernon et al et al, Kidney Int 2006; 76: 557
* p<0.05***p<0.001
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Proper classification of inflammation and fibrosis
Normal (no inflammation no fibrosis)
Inflammation and fibrosis
Inflammation (no fibrosis)
Fibrosis (no inflammation)
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SCR & IF/TA
Shishido et al, JASN 2003; 14: 1046Cosio FG et al, Am J Transplant 2005; 5: 2464, Moreso F et al Am J Transplant 2006; 6:747
IF/TA without SCR
IF/TA with SCR
Normal1 year protocol BxSCR + IF/TA
SCR + IF/TA
SCR + IF/TA
1 year protocol Bx
.25
.5
.75
1
0 50 100 150 200 months
Normal=186
SCR=74
IF/TA=110
IF/TA+SCR=65
< 6 month protocol Bx
IF/TA without SCR
IF/TA with SCR
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Hig
h in
flam
matio
n
Low
infla
mm
atio
n
CD45 CD3 CD20 CD68 CD15
High (upper tertile) and low (two lower tertiles) inflammation
Inflammation with or whitout IF/TA
Moreso F et al. AJT 2007; 7: 2739
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0
500
1000
1500
2000
2500
NORMAL SCRa IF/TA SCR+IF/TAa,c0
300
600
900
1200
1500
NORMAL SCRa IF/TA SCR+IF/TAa,c
0
200
400
600
800
NORMAL SCR IF/TAa SCR+IF/TAa,b,c 0
500
1000
1500
2000
2500
3000
3500
NORMAL SCRa IF/TA SCR+IF/TAa,c
CD
45 p
osit
ive c
ells /
mm
2 in
ters
titi
um
CD
20 p
osit
ive c
ells /
mm
2 in
ters
titi
um
CD
68 p
osit
ive c
ells /
mm
2 in
ters
titi
um
CD
3 p
osit
ive c
ells /
mm
2 in
ters
titi
um
Interstitial infiltrating cells
Moreso F et al. AJT 2007; 7: 2739
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Renal allograft survival(univariate)
0
,2
,4
,6
,8
1
Survival (%)
0 20 40 60 80 100 120 140
months
T1T2
T3
Moreso F et al Am J Transplant 2006; 6: 747
P=0.001
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Renal allograft survival(multivariate)
Variable Univariate MultivariateRR (95% CI) p RR (95% CI) p
Retransplant (yes) 2.5 (0.9-6.9) 0.06 1.2 (0.3-5.3) ns
PRA > 50% 4.6 (1.7-12.6) <0.01 4.5 (1.0-20.4) 0.05
CD20 (upper tertile) 3.3 (1.4-8.3) <0.01 3.0 (1.2-7.3) 0.01
Moreso F et al Am J Transplant 2006; 6: 747
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B cells, acute rejection and outcome inindication biopsies
Sarwal et al. et al. NEJM 2003; 349: 125.Hippen BE et al. Am J Transplant 2005; 5: 2248Alausa M et al. Clin Transplant 2005; 10: 137Eileen WT et al. Transplantation 2006; 82: 1769Lehnhardt et al. Am J transplant 2006; 6: 847Zarkhin V et al. Kidney Int 2008; 74: 664Mourah MR et al. Pediatr Transplant 2009; 13
B cells associated with poor outcome in AR
B cells not associated with poor outcome in ARScheepstra C et al. Transplantation 2008; 86:772Bagnasco SM et al. Am J Transplant 2007; 7: 1968-1973
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Immunophenotype in protocol biopsies from TAC vs CsA treated patients
n= 44TAC vs 22 CsA
P<0.01
P<0.01 P<0.05ns
Serón D et al, Transplantation 2007; 83:649
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B cell survival in CHR after rituximabn=38 explanted grafts with CHR 2 after treatment with rituximab
Intragraft B cells
BAFF positivity
Thaunat et al. Transplantation 2008; 85:1648
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SCR vs SCR+IF/TA and FoxP3
Bestard et al. JASN 2008; 19: 2010
SCR SCR +No IF/TA IF/TA p
N 19 18___________________________________________________%FoxP3 + cells 14.2 +/-16.3 8.2+/-8.1 0.035___________________________________________________
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T regs in pts ACR and BL (indication (12 ACR, 12 BL) and surveillance (8ACR, 8 BL)
Taflin et al. Transplantation 2010; 89: 194
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Surveillance Bx cytokine transcripts
Hueso M et al. Am J Pathol 2010; 176: 1696
P< 0.01
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IL10
Inflammation+IFTA
B cellsTregs
Th2 responseAg presentation
Persistent inflammation?CHR?
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Inflammation with and without fibrosis
Inflammation, IF/TA and CHR
Innate immunity and inflammation
Surveillance biopsies
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Tx Inflammation CAN±
Inflammation
Survival
SCR and CHR
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Tx Inflammation IF/TA±
Inflammation
Survival
SCR and CHR
CHR
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SCR and Chronic humoral rejection1988-2006
Protocol Bx n = 517
CHR 44IF/TA nos 42Recurrence 11De novo GN 7Acute rejection 4Polyoma 1
Bx for cause: n = 109
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Clinical characteristics at the time of biopsy
Variable CHR (44) IF/TA (42) p
Protocol biopsyTime (m) 4.5 ± 2.4 4.6 ± 3.3 nsSCr (mol/L) 149 ± 37 144 ± 44 nsProteinuria (g/d) 0.3 ± 0.2 0.3 ± 0.2 ns
Biopsy for causeTime (y) 6.4 ± 3.4 8.2 ± 4.4 0.037SCr (mol/L) 240 ± 141 204 ± 80 nsProteinuria (g/d) 2.3 ± 2.4 1.4 ± 1.7 0.061
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Clinical characteristics of patientsVariable CHR IF/TA p-value
(n=44) (n=42)__________________________________________________Donor age (years) 40 ± 16 34 ± 15 nsDonor gender (% male) 65.9 78.6 nsPatient age (years) 43 ± 12 40 ± 12 nsPatient gender (male) 59.1 69.0 nsPRA (%) 7 ± 18 3 ± 10 nsVirus hepatitis C 18.2 9.5 nsRe-transplants (%) 15.9 2.3 0.058HLA DR mm 0.7 ± 0.5 0.7 ± 0.6 ns
Cold ischemia time (hours)23 ± 6 21 ± 6 nsImmunosuppression
CNI without MMF 24 27CNI with MMF 18 12CNI with mTOR-i 1 2CNI free 1 1 ns
Delayed graft function (%) 25 19 nsAcute rejection (%) 22.7 26.2 ns_________________________________________________________
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(p=0.003)
Acute score
Acute Banff score in surveillance Biopsies
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SCR, CHR and IF/TA
CHR IF/TA p__________________________________SCR (%) 52.3 28.6 0.025__________________________________
RR 95% CI p__________________________________SCR 2.52 1.1-6.3 0.047ReTx 6.7 0.8-58.8 ns__________________________________
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n=34 n=17 n=17 n=18
% of cases with CHR and IF/TA in the biopsy for cause
Dg categoryin surveillance Bx
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Is inflammation in SCR different from SCR + IFTA?
Are early Bx findings different in patients developing IFTA in comparison with patients developing CHR
Innate immune alterations and inflammation
Surveillance biopsies
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Risk factors associated with early inflammation in surveillance biopsies
Immunosuppressive treatment
Acute rejection before surveillance Bx
Innate immunity & inflammation in the general population
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TLR-2 expression in 6 m surveillance Bx is associated wit lower SCR257 surveillance Bx 6w, 3m, 6m and 108 indication Bx
De Groot K et al. Am J Nephrol 2008; 28: 583
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MBL 96KDa protein made of 3 identical 32 KDa structures
Carbohydrate recognition domain
Collagen like domain
N-terminal cross linking region
N-acetylglucosamine D-mannoseN-acetyl mannosamineL-fructose
Bouwman LH et al. 2006; 67:247
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Defense collagens
Bohlson SS et al. Mol Immunol 2007; 44:33
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MBL in Renal TransplantsMar 2005 –Oct 2006, 125 RT, 111 with a functioning graft at 3 m
0
,5
1
1,5
2
2,5
3
3,5
4
Cel
l Mea
n
MBL-T1 MBL-T2 MBL-T3Cell
Interaction Bar Plot for CualquierMBLEffect: MBL-terciles
T 1
Low MBLN=42
T 2,3
High MBLN=83Log MBL
(ng/ml)
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sTNFR2 before Txsoluble TNFR
p=0.05
Ibernon M et al. Transplantation 2009: 88: 272
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MBL and infection (bacterial or fungal)March 2005-Oct 2006, 125 pts,
111 with a functioning graft at 3 m
Ibernon M et al. Transplantation 2009: 88: 272
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MBL and NODAT March 2005-Oct 2006, 125 pts,
111 with a functioning graft at 3 m
Ibernon M et al. Transplantation 2009: 88: 272
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P=0,0054
Low MBL and SCR(n=60)
Ibernon M et al. Kidney Int (in press)
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(N=6)
(N=32)
Low MBL, subclinical rejection and Tx CAD
Arnt RF et al. Eur Heart J 2005; 26: 1660
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C1q and MBL and rejection
Bohlson SS et al. Mol Immunol 2007; 44:33
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C1q deficiency and acute rejectionHeart transplant in C1q deficient mice
Csencsits K et al. AJT 2008; 8: 1622
WT
C1q-/-
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C1q deficiency and acute rejectionHeart transplant in C1q deficient mice
Csencsits K et al. AJT 2008; 8: 1622
T cell response is not enhanced in C1q-/- mice
More intense anti-donor Ab response
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Tissue injury and repair
TxInjuryApotosisNecrosis
RepairNormalIFTA
Progression of injurySCR + IFTACHR
-
+
Inflammation(SCR)
Innnate Immunity