Problemas diagnosticos actuales del injerto renal. ¿qué le exige el clinico al patólogo en la biopsia del trasplante? Jose Maria Morales Hospital 12 de Octubre Madrid CURSO DE PRIMAVERA SOCIEDAD ESPAÑOLA DE ANATOMIA PATOLOGICA Y DIVISION ESPAÑOLA DE LA ACDEMIA INTERNACIONAL DE PATOLOGIA Madrid 17-18 de Mayo de 2012
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Problemas diagnosticos actuales del injerto renal.
¿qué le exige el clinico al patólogo en la biopsia del
trasplante?
Jose Maria Morales
Hospital 12 de Octubre
Madrid
CURSO DE PRIMAVERA
SOCIEDAD ESPAÑOLA DE ANATOMIA PATOLOGICA Y
DIVISION ESPAÑOLA DE LA ACDEMIA INTERNACIONAL
DE PATOLOGIA
Madrid 17-18 de Mayo de 2012
Vida media proyectada: Tx renal
standard vs Tx con donantes
“expandidos”vs lista de espera
0
5
10
15
20
25
30
35
20-39 40-59 60-74
Tx standard
ECD
WL
Pro
ject
ed y
ears
of
life
Age group UNOS 2002
Improvements in acute rejection and
graft survival are associated with more
efficient immunosuppression
Acu
te r
eje
cti
on
/Gra
ft s
urv
iva
l ra
tes (
%)
100
80
60
40
20
0
1960 1965 1970 1975 1980 1985 1990 1995 2000 2005
Year of transplantation 1yr graft
survival Acute rejection
Azathioprine
Antilymphocyte Antibodies
Prednisone
Radiation
Cyclosporine
Tacrolimus
Mycophenolate mofetil
Rapamycine
Thymoglobuline
Daclizumab
Basiliximab
95%
10%
Graft Survival
Acute Rejection
Cortesia Dr H Ekberg
12.5
21.8
Long-term Graft Survival Improvements Half-life (years): Europe
• 1-3 meses 3-6 meses ……..Rechazo agudo celular o humoral o ambos
• 3-6 meses … BK virus
• Mas de 6 meses:
– IFTA
– Recidiva de la enfermedad original
– GN de novo
– Rechazo cronico humoral
Mayo Clinic 1996–2006; causes of IF/TA
(n=47)
Adapted from El-Zoghby ZM et al. Am J Transplant 2009;9:527–535
Follow up 50 ± 33 months
Polyoma
nephropathy
11 (23.4%)
Immunologic
(recurrent rejections)
13 (27.6%) Recurrent
pyelonephritis
7 (14.8%)
Poor allograft quality
4 (8.5%)
Ureteral stenosis
2 (4.2%)
CNI toxicity
1 (2.1%)
Idiopathic
9 (19.1%)
Temporal evolution of histologic lesions
1. Nankivell BJ et al. N Engl J Med 2003; 349:2326–2633;
2. Nankivell BJ et al. Transplantation 2004;78:557–565
Glomerulosclerosis
Subclinical
rejection
Interstitial
fibrosis/tubular
atrophy
0 1
Years after transplantation
2 3 4 5 6-7 8-10
1.5
1.0
0.5
0.0 Mean
Ban
ff s
co
re
Banff interstitial infiltrate
Banff tubulitis
0
2.0
1.5
1.0
0.5
0.0 Mean
Ban
ff s
co
re
2 4 6 8 10
Years after transplantation
Chronic interstitial fibrosis
Tubular atrophy
Arteriolar hyalinosis
Fibrointimal thickening
Chronic glomerulopathy
50
40
30
20
10
0
Bio
psy
sp
ecim
en
s (
%)
0 2 4 6 8 10
Years after transplantation
Totally sclerosed
glomeruli
Periglomerular
fibrosis
Partial
glomerulosclerosis
961 biopsies from 119 kidney-pancreas and 1 kidney transplant patients with Type 1 diabetes mellitus
Prevalence of CNI nephrotoxicity after
transplantation
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
Nankivell BJ et al = 96.8%
El-Zoghby ZM et al = 0.6%
(Incidence of CNI nephrotoxicity)
(Graft loss due to CNI nephrotoxicity)
Dos visiones
Tiziano Van der Weyden
Cross-sectional cohort (n=173) G
raft s
urv
ival
0 3 6 9 12 15 18 21 24
Months from biopsy
CNI+: 53 51 47 46 39 19 17 13 13
CNI–: 108 97 83 72 64 51 42 28 22
100
80
60
40
20
0
p=0.0424
DeKAF study: Biopsy diagnosis of
CNI nephrotoxicity did not predict graft loss
Gaston RS et al. Transplantation 2010;90:68.
“CNI nephrotoxicity”
No “CNI nephrotoxicity”
What are the clinical implications of
over-diagnosing CNI nephrotoxicity?
Over-diagnosis of CNI
nephrotoxicity
Inappropriate reduction in
immunosuppressive therapy
Deteriorating graft function
Graft biopsy misinterpretatio
n of CNI nephrotoxicity
1. Matas AJ. Am J Transp 2011;11:687–692; 2. Einecke G et al. Am J Transplant 2009;9:2520– 2531; 3. Gaston RS et
al. Transplantation 2010;90:68–74; 4. Sellares J et al. Am J Transplant 2012;12:388–399
Opelz G et al. Transplantation 2008;86:371–376
What are the consequences of dose
reduction/withdrawal of tacrolimus?
Kidney graft survival; p<0.001 for both comparisons
Cu
mu
lati
ve s
urv
ival
0 1 5 7
0
100
65
80
85
90
3 2 4 6
70
75
95
Years post-transplantation
Withdrawal, n=296
Continuation, n=1736
Dose reduction, n=352
KDIGO clinical practice guidelines for the care of kidney
transplant recipients (AJT 2009)
Kidney allograft biopsy
• 9.5 We suggest kidney allograft biopsy
when there is:
– New onset of proteinuria (2C)
– Unexplained proteinuria g/g creatinine or 3.0
g per 24 hours (2C)
Rx crónico mediado
por células T
Rx crónico
mediado por Ac
+ Ac anti-donante
específicos
C4d
Chronic humoral rejection (CHR)
• Histologic patterns:
– Transplant glomerulopathy
– Peritubular capillaropathy (PTCBMML)
– Transplant arteriopathy
• Early CHR:
– Peritubular capillaritis
– Glomerular subendothelial lucency & early GBM
duplication by electron microscopy
Wavamunno, Am J Transplant. 2007 Dec;7(12):2757-68.
Transplant glomerulopathy: prognostic
implications of C4d in PTC
Months of follow up
483624120
Gra
ft s
urv
ival
1.0
.8
.6
.4
.2
0.0
(Issa N et al Transplantation 86:681, 2008)
No TG
TG C4d –
(70%)
TG C4d +
(30%; Ab
levels) p<0.0001
Pattern of transplant glomerulopathy
Pattern of transplant glomerulopathy
Recurrent MPGN in tx
HCV infection is an independent risk factor for
Transplant glomerulopathy
Acute rejection, HCV+ and Anti-HLA antibodies are risk
factors for TG.
Gloor et al, AJT 2007
High incidence of HCV antibody (Cosio Am J Kid Dis 1996)
•Representan el 2% de las pérdidas de los injertos
• GN recurrentes GN novo
– H SyF* GN Membranosa
– GN IgA GN MP
– GN MP tipo I, II, III
– GN Membranosa
Lesiónes glomerulares en
pacientes con trasplante renal
Berthoux et al. EBPG, NDT 2000
KDIGO 2009
* idiopatica
PERDIDA DEL INJERTO: GN, RECHAZO AGUDO, MUERTE
Y RECHAZO CRONICO: Kaplan-Meier
Briganti et al, NEJM 2002
Analisis de la perdida del injerto
acorde al tipo de GN recurrente
• Briganti et al, NEJM 2002
MPGN
HSF
IgA MGN
Biopsias de protocolo
Controversias • A favor:
– Diagnostico del rechazo agudo subclinico
– Diagnostico de “inflamacion” asociado o no a fibrosis
– Diagnostico precoz del rechazo humoral agudo, GN de novo o de recidiva, BK
– Diagnostico precoz del Rechazo humoral cronico (“glomerulitis, capilaritis”)
• En contra: – Con Tacro+MMF la presencia de RA subclinico es insignificante
– Falta de consenso en los diagnosticos
– Infraestructura potente
– En centros con gran numero de Tx es practicamente imposible en nuestro medio
– No son inocuas. Riesgos
– Posiblemente indicadas en pacientes de alto riesgo inmunologico
Inflammation and IF/TA
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
Group I
Group II
Normal
1 year protocol Bx
SCR + IF/TA SCR + IF/TA 1 year protocol Bx
Fibrosis only
Fibrosis and moderate to severe
inflammation
0 2 4 6 8 10 12
Years after transplantation
100
90
80
70
60
50
40
Gra
ft s
urv
ival (%
)
P<0.01
12
Gra
ft s
urv
ival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3 24 36 48 60
Months post-transplant
86
122
32
16
75
107
26
12
40
55
12
6
18
28
9
3
Normal
Fibrosis
Fib & i=I
Fib & i>I
SCR + IF/TA
0.25
0.50
0.75
1.00
0 50 100 150 200 Months after transplantation
Normal=186
SCR=74
IF/TA=110
IF/TA+SCR=65
<6 month protocol Bx
Fra
cti
on
su
rviv
ing
No fibrosis
Fibrosis and mild
inflammation
AR and BK nephropathy as a risk factors for IF
and inflammation
Gago M et al. Am J Transplant 2012;doi 10.1111/j.1600-6143.2011.03911.x (Epub
ahead of print)
PVAN
ACR
None
Normal=322
IF=222
IF+i=79
1.0
0.8
0.6
0.4
0.2
0.0 Cu
mu
lati
ve i
nc
ide
nce
of
GIF
wit
h IF
in
are
as w
ith
ou
t G
IF
60 48 36 24 12 0
Month
1.0
0.9
0.8
0.7
0.6
0.5
Pro
po
rtio
n o
f fu
ncti
on
ing
gra
fts
120 96 72 48 24 0
Months of follow-up
GIF: graft interstitial fibrosis; PVAN: BK nephropathy
Treatment inflammation and fibrosis
Nankivell BJ et al. Transplantation 2004;78:242–249
3
2
1
0
Pre
vale
nce a
t
3 m
on
ths (
%)
1-y
ear
Ban
ff
sco
res
80
60
40
20
0 CsA-S & AZA CsA-ME & AZA CsA-ME & MMF TAC & MMF
***
*** *
Subclinical rejection – acute
Subclinical rejection – borderline
CsA-S & AZA CsA-ME & AZA CsA-ME & MMF TAC & MMF
Chronic interstitial fibrosis
Tubular atrophy
Immunosuppression
***
*
*p<0.05
***p<0.001
Ojo, A. O. et al. N Engl J Med 2003;349:931-940
Cumulative Incidence of Chronic Renal Failure among 69,321 Persons Who Received Nonrenal Organ Transplants in the United States between January 1, 1990, and December 31, 2000